WO2007066068A2

WO2007066068A2 - Calcium ion channel receptor antagonist

Info

Publication number: WO2007066068A2
Application number: PCT/GB2006/004304
Authority: WO
Inventors: Alyn Morice
Original assignee: University of Hull
Current assignee: University of Hull
Priority date: 2005-12-08
Filing date: 2006-11-17
Publication date: 2007-06-14
Anticipated expiration: 2008-06-08
Also published as: WO2007066068A3; GB0525029D0

Abstract

The invention relates to pharmaceutically useful agents that antagonize the activity of a calcium ion channel receptor and their use in the inhibition of receptor activation in the treatment of conditions that would benefit from said inhibition; and including screening assays to identify antagonists of receptor activation and other subject matter. The agent may be a pheniramine.

Description

Receptor Antagonist

The invention relates to pharmaceutically useful agents that antagonize the activity of a vanilloid receptor and their use in the modulation of receptor activation in the treatment of conditions that would benefit from said modulation; and including screening assays to identify antagonists of receptor activation and other subject matter.

BACKGROUND The calcium ion channel receptor referred to as transient receptor potential vanilloid receptor 1 (TRPV 1) or simply vanilloid receptor 1 (VR 1) is a capsaicin response receptor primarily expressed by unmyelinated peripheral nerve fibres. It is predicted to have six transmembrane domains and a short, pore-forming hydrophobic stretch between the fifth and sixth transmembrane domains. TRPV-1 is part of a superfamily of ion channels known as transient receptor potential (TRP) receptors. The superfamily is broadly split into three categories: TRPV receptors, TRPC (transient receptor potential canonical) and TRPM (transient receptor potential melatasin). A related receptor referred to as VRL 3 shows approximately 46% sequence identity to VR 1 and also encodes a calcium ion channel. Both VR 1 and VRL 3 are associated with a number of pain related conditions. These include by way of example, pain, chronic pain, neuropathic pain, post operative pain, rheumatoid pain, osteoarthritic pain, back pain, visceral pain, cancer pain, neuralgia, migraine, neuropathies, diabetic neuropathy, sciatica, HIV related neuropathty, post herpetic neuralgia, fibromyalgia, nerve fibre injury, ischaemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, inflammatory disorders, inflammatory bowel disease, asthma, cystitis, burns and psoriasis. These are not meant to be limiting but merely illustrative of the disease conditions with which these receptors are associated.

When VR 1 is activated by agonists such as capsaicin, heat or acidosis, calcium enters the cell and pain signals are initiated. When pain receptors (nociceptors) are continually activated through disease or injury the result is chronic pain. When VR1 receptors are continuously activated through exposure to an agonist, for example capsaicin, excessive calcium enters the nerve cell and results in long term but reversible impairment of nociceptor function. This is thought to be the mechanism of pain relief provided by capsaicin.

The anti-histamine dexbrompheniramine is a generic drug that is recommended for the control of chronic cough due to upper air ways diseases such as post nasal drip syndrome. It is also used to treat conditions such as sneezing, itching and other symptoms associated with allergies such as hay fever. Brief Disclosure of the Invention

The present invention relates, amongst other things, to the use of dexbrompheniramine and other agents as a ligand for the TRPV-1 receptor. The present invention relates, at least in part, to clinical applications in the treatment of conditions or diseases that would benefit from the inhibition of TRVP-1 activation. TRPV-1 is representative of the TRP protein superfamily and, as described further below, the disclosure is throughout applicable to all members of this superfamily, i.e. relates inter alia to inhibitors of such proteins.

The present disclosure relates in one aspect to the use of an active agent disclosed herein to treat disorders which are treatable by modulation of a calcium ion channel receptor. In one embodiment, the calcium ion channel receptor is TRPV-1 (transient receptor potential vanilloid receptor-1) or another TRP protein. The present disclosure also relates to novel combinations of active agents disclosed herein and other therapeutic agents, particularly for use in treating disorders in which inhibition of TRPV-1 activity or other TRP protein activity would be beneficial.

In a first aspect of the present invention, there is provided a method for the treatment of a disease or condition that would benefit from inhibition of a calcium ion channel receptor, comprising administering an effective amount of an active agent selected from dexbrompheniramine and structural variants thereof.

In one embodiment, the calcium ion channel receptor is a transient receptor potential vanilloid receptor, for example, TRPV-1. In one embodiment, the TRPV is TRPV-1.

In a further aspect of the present invention, there is provided use of an active agent which is selected from dexbrompheniramine and structural variants thereof for the manufacture of a medicament for the treatment of a disease or condition that would benefit from inhibition of a calcium ion channel receptor. In one embodiment, the active agent is a histamine H₁ receptor antagonist of the alkylamine class. In one embodiment, the active agent is a pheniramine or a prodrug or pharmaceutically acceptable salt thereof.

Reference herein to the term "active agent" also encompasses salts and prodrugs (e.g. esters) of the active agent, and also other pharmaceutically acceptable forms of the agent. For example, reference to one such substituted alkylamine, e.g. dexbrompheniramine, encompasses salts of dexbrompheniramine, e.g. dexbrompheniramine maleate. The present invention also encompasses use of salts and esters of substituted alkylamines e.g. salts of dexbrompheniramine. Also contemplated by the present disclosure are products for the treatment of disorders that would benefit from inhibition of a calcium ion channel receptor, e.g. a TRVP-1 protein. Such products include an active agent, as defined herein. In one embodiment, the product comprises dexbrompheniramine or a structural variation thereof.

The products of the present invention may also include at least one further therapeutic agent. Thus, the active agents of the disclosure may be combined and/or co-administered with other therapeutic agents. The choice of the further therapeutic agent(s) will depend on the nature of the disorder to be treated. Such therapeutic agents may be available in commercial use, in clinical evaluation or in pre-clinical development, which could be selected for use with an active agent of the disclosure for the prevention of disorders as described herein by combination drug therapy.

The present disclosure teaches that the disclosed active agent, for example, dexbrompheniramine, inhibits capasaicin-induced calcium mobilisation and therefore indicates the inhibition of TRP protein activation by active agents of the disclosure.

Detailed Description BRIEF DESCRIPTION OF THE DRAWINGS

An embodiment of the invention will now be described by example only and with reference to the following figures:

Figure 1 is the nucleic acid sequence of human TRPV-1;

Figure 2 is the amino acid sequence of human TRPV-1;

Figure 3 illustrates the antagonistic effect of dexbrompheniramine on TRPV-1 activation in the presence of the TRPV-1 agonist capsaicin; and

Figure 4 is the structure of dexbrompheniramine.

Figure 5A is a graph showing the capsaicin concentration effect curve for hTRPV1-HEK following pre-incubation with and without dexbrompheniramine (1mM and 100μM). Squares indicate no dexbrompheniramine, triangles represent pre-incubation with dexbrompheniramine at concentration of 100μM and diamonds represent pre-incubation with dexbrompheniramine at concentration of 1mM.

Figure 5B is a graph showing resiniferatoxin concentration effect curve for hTRPV1-HEK following pre-incubation with and without dexbrompheniramine (100μM).). Circles indicate no dexbrompheniramine, crosses represent pre-incubation with dexbrompheniramine at concentration of 100μM

Figure 6A is a graph showing the capsaicin concentration effect curve for rTRPV1-HEK following pre-incubation with and without dexbrompheniramine (1mM and 100μM). Squares indicate no dexbrompheniramine, triangles represent pre-incubation with dexbrompheniramine at concentration of 100μM.

Figure 6B is a graph showing the resiniferatoxin concentration effect curve for rTRPV1-HEK following pre-incubation with and without dexbrompheniramine (1mM and 100μM). Circles indicate no dexbrompheniramine, crosses represent pre-incubation with dexbrompheniramine at concentration of 100μM, diamonds represent pre-incubation with dexbrompheniramine at concentration of 1 mM. Figure 6C is a graph showing the capsaicin concentration effect curve for rTRPV1-Pro-5 following pre-incubation with and without dexbrompheniramine (100μM). Stars indicate no dexbrompheniramine, Crosses represent pre-incubation with dexbrompheniramine at concentration of 100μM. Figure 7A is a graph showing the effect of histamine on TRPV1.

Figure 7B is a graph showing the effect of histamine on the capsaicin concentration curve.

Figure 8A is a graph showing the effect of diphenhydramine hydrochloride on hTRPV-1-HEK cells in response to capsaicin.

Figure 8B is a graph showing the effect of fexofenadine on hTRPV-1-HEK cells in response to capsaicin. Figure 8C is a graph showing the effect of chlorpheniramine on hTRPV-1-HEK cells in response to capsaicin.

Figure 9 is a graph showing Inhibition of calcium mobilisation by dexbrompheniramine in rat dorsal root ganglia. Typical tracings (A) and plotted data (B) showing the inhibitory effect of dexbrompheniramine maleate (DXB) or its vehicle (VEH, phosphate buffer solution) on capsaicin (CAPS, 0.1 μM)-induced Ca²⁺ mobilization in cultured rat dorsal root ganglia neurons. Data are expressed as mean ± SEM of at least 60 cells. *, p<0.05; Dunnett's-Test vs. VEH. Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of the words, for example "comprising" and "comprises", means "including but not limited to", and is not intended to (and does not) exclude other moieties, additives, components, integers or steps.

Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.

The present invention provided methods for the treatment of a disease or condition that would benefit from inhibition of a calcium ion channel receptor, comprising administering an effective amount of an active agent as defined herein. The present invention also provides uses of an active agent selected from dexbrompheniramine and structural variants thereof for the manufacture of a medicament for the treatment of a disease or condition that would benefit from inhibition of a calcium ion channel receptor.

The term "inhibition" includes the decreasing, blocking, prevention, delaying of activation, inactivation, desensitizing, or down regulation of the calcium ion channel receptor channel, or the speeding up or enhancement of its deactivation. TRPV-1 is believed to act as a ligand-, proton- and heat-activated molecular integrator of nociceptive stimuli. Activation of TRPV1 leads to central pain and to local "sensory-efferent" effects, which include the release of vasoactive agents

(e.g. calcitonin gene related peptide, CGRP) and subsequent vasorelaxation. The active agents disclosed herein are believed to act as an antagonist to the TRPV-1 receptor and therefore it is expected that administration of such agents will reduce or inhibit activation of the TRPV-1 receptor and so prevent or reduce the downstream effects of TRPV-1 activation.

Where a structural formula herein comprising a chiral centre does not indicate chirality (e.g. where all bonds are shown as lines and there is no "wedge" bond), then, unless the context otherwise requires, the structure refers to all corresponding compounds or moieties irrespective of chirality and includes reference to individual compounds or moieties in which the chiral centre is of (R)- configuration, individual compounds or moieties in which the chiral centre is (S)-configuration and mixtures of (R)- and (S)- isomers as, for example, in the case of racemic mixtures, amongst others. Active Agent

Definitions

Hydrocarbyl

The term "hydrocarbyl" as used herein includes reference to a moiety consisting exclusively of hydrogen and carbon atoms; such a moiety may comprise an aliphatic and/or an aromatic moiety. The moiety may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. Examples of hydrocarbyl groups include C_1-6 alkyl (e.g. C₁, C₂, C₃ or C₄ alkyl, for example methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl); C_1-6 alkyl substituted by aryl (e.g. benzyl) or by cycloalkyl (e.g cyclopropylmethyl); cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl); aryl (e.g. phenyl, naphthyl or fluorenyl) and the like.

Alkyl

The terms "alkyl" and ¹¹C_1-6 alkyl" as used herein include reference to a straight or branched chain alkyl moiety having 1, 2, 3, 4, 5 or 6 carbon atoms. This term includes reference to groups such as methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl or tert-butyl), pentyl, hexyl and the like. In particular, alkyl may have 1, 2, 3 or 4 carbon atoms.

Aryl or aromatic The terms "aryl" or "aromatic" as used herein include reference to an aromatic ring system comprising 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring carbon atoms. Aryl is often phenyl but may be a polycyclic ring system, having two or more rings, at least one of which is aromatic. This term includes reference to groups such as phenyl, naphthyl, fluorenyl, azulenyl, indenyl, anthryl and the like.

Heterocyclyl

The term "heterocyclyl" as used herein includes reference to a saturated (e.g. heterocycloalkyl) or unsaturated (e.g. heteroaryl) heterocyclic ring moiety having from 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15 or 16 ring atoms, at least one of which is selected from nitrogen, oxygen, phosphorus, silicon and sulphur. In particular, heterocyclyl includes a 3- to 10-membered non-aromatic ring or ring system and more particularly a 5- or 6-membered ring, which may be fully or partially saturated. A heterocyclic moiety is, for example, selected from oxiranyl, azirinyl, 1 ,2-oxathiolanyl, imidazolyl, thienyl, furyl, tetrahydrofuryl, pyranyl, thiopyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl, chromenyl, 2H-pyrroIyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl, pyr- azinyl, pyrimidinyl, piperidyl, piperazinyl, pyridazinyl, morpholinyl, thiomorpholinyi, especially thiomorpholino, indolizinyl, isoindolyl, 3H-indolyl, indolyl, benzimidazolyl, cumaryl, indazolyl, triazolyl, tetrazolyl, purinyl, 4/-/-quinolizinyl, isoquinolyl, quinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, octahydroisoquinolyl, benzofuranyl, dibenzofuranyl, benzothiophenyl, dibenzothiophenyl, phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, furazanyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromenyl, isochromanyl, chromanyl and the like.

Heterocycloalkyl The term "heterocycloalkyl" as used herein includes reference to a saturated heterocyclic moiety having 3, 4, 5, 6 or 7 ring carbon atoms and 1, 2, 3, 4 or 5 ring heteroatoms selected from nitrogen, oxygen, phosphorus and sulphur. The group may be a polycyclic ring system but more often is monocyclic. This term includes reference to groups such as azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxiranyl, pyrazolidinyl, imidazolyl, indolizidinyl, piperazinyl, thiazolidinyl, morpholinyl, thiomorpholinyi, quinolizidinyl and the like.

Heteroaryl or heteroaromatic

The terms "heteroaryl" and "heteroaromatic" as used herein include reference to an aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, at least one of which is selected from nitrogen, oxygen and sulphur. The group may be a polycyclic ring system, having two or more rings, at least one of which is aromatic, but is more often monocyclic. This term includes reference to groups such as pyrimidinyl, furanyl, benzo[b]thiophenyl, thiophenyl, pyrrolyl, imidazolyl, pyrrolidinyl, pyridinyl, benzo[b]furanyl, pyrazinyl, purinyl, indolyl, benzimidazolyl, quinolinyl, phenothiazinyl, triazinyl, phthalazinyl, 2H-chromenyl, oxazolyl, isoxazolyl, thiazolyl, isoindolyl, indazolyl, purinyl, isoquinolinyl, quinazolinyl, pteridinyl and the like.

The present invention relates to methods which comprise the use of an active agent selected from dexbrompheniramine and structural variants thereof.

In one embodiment, the active agent is a histamine Hi receptor antagonist of the alkylamine class.

In one embodiment, the active agent is a pheniramine or a prodrug or pharmaceutically acceptable salt thereof. Pheniramines are compounds having the skeleton of formula (I) which may be unsubstituted or substituted by one or more substituents:

In one embodiment, the active agent is pheniramine which is unsubstituted or substituted by one or more substituents selected from the group consisting of trifluoromethyl and species having 1 , 2 or 3 non-hydrogen atoms and optionally one or more hydrogen atoms, or a prodrug or pharmaceutically acceptable salt thereof.

The pheniramine can be, for example, a D-pheniramine. The term D-pheniramine refers to compounds have the skeleton of formula (II) whether substituted or unsubstituted:

The chiral centre shown in formula (II) is considered to be of (S)-configuration and this designation will be used hereinafter.

In one embodiment, the one or more substituents of the pheniramine (e.g. D-pheniramine) are selected from the group consisting of halogen, hydroxy, methyl, trifluoromethyl, formyl (-CHO), methoxy, amino, methylamino, dimethylamino, amidino, hydroxylamino, cyano, thiol and methylthio.

In one embodiment, the one or more substituents are selected from chlorine and bromine. Particularly, the one or more substituents can be bromine.

In one embodiment, the pheniramine is substituted by a single substituent.

The disclosure includes pheniramines (for example D- or D/L- pheniramines) substituted at, in an exemplary embodiment, the 2-position of the phenyl group. The disclosure includes pheniramines (for example D- or D/L- pheniramines) substituted at the 3- position of the phenyl group.

The disclosure in particular includes pheniramines (for example D- or D/L- pheniramines) substituted at the 4-position of its phenyl group.

In one class of compounds, the active agent has the formula (III):

wherein: the symbol * designates a chiral centre of (R)- or (S)- configuration;

D and E are the same or different and are each a substituted or unsubstituted ring moiety, and wherein D and E are optionally joined together as part of a fused ring system;

W is O, S(O)_t where t is 0, 1 or 2, or CH₂, l is O oM, m is 0, 1 ,2, 3 or 4, e.g. 0, 1 or 2,

R¹⁰ is a group of Formula (IV):

wherein

V is a bond, -NR - or, when not linked to SO or SO₂, is -C(O)-; R¹³ is selected from R¹⁸, -OR¹⁸, -C(O)R¹⁸, -C(O)OR¹⁸, -OC(O)R¹⁸, -N(R¹⁸)R¹⁹, -

C(O)N(R¹⁹)R²⁰, -S(O)|R¹⁸ and -C(R¹⁸J₃;

R¹⁴ and R¹⁵ are the same or different and selected from R¹⁸, -OR¹⁸, -C(O)R¹⁸, -C(O)OR¹⁸, -OC(O)R¹⁸, -N(R¹⁸)R¹⁹, -C(O)N(R¹⁹)R²⁰, -S(O)₁R¹⁸ and -C(R¹⁸)₃; or R¹⁴ and R¹⁵ taken together form =NR²⁰, =0 or =S; R¹⁶ and R¹⁷ are the same or different and selected from hydrogen, C_1-6 alkyl, -OR²¹ and -NR¹⁸R¹⁹; or R¹⁶ and R¹⁷ together form a ring which is unsubstituted or substituted; R¹⁸ and R¹⁹ are the same or different and selected from hydrogen, R²¹, hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R²¹; and heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R²¹;

R²⁰ is hydrogen or Ci_-6 alkyl; and each R²¹ is independently selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, oxo, amidino, -B(OH)₂, =NR¹², -OR¹², -C(O)R¹², -C(O)OR¹², -OC(O)R¹², -N(R¹²)R¹³, - C(O)N(R¹²)R¹³, -S(O)|R¹², -C(R¹²)₃ and R¹⁴. In embodiments, (I = m) is 0. In other embodiments, (I = m) is 1. W is in particular CH₂.

In one embodiment of Formula (IV), -W-(CH₂)_m-V- is alkylene ,e.g. having 1 , 2, 3 or 4 carbon atoms. Included is a class of compounds in -W-(CH₂)_m-V- is alkylene having 2 carbon atoms. Included is a further class of compounds in -W-(CH₂)_m-V- is alkylene having 3 carbon atoms.

In one embodiment of Formula (IV), -W-(CH₂)_m-V- is oxyalkylene ,e.g. having, 2 or 3 carbon atoms.

In a class of compounds, R¹⁶ and R¹⁷ together form a ring which is unsubstituted or substituted by one or more R²¹ groups. Where R¹⁶ and R¹⁷ together form a ring, the ring is in some instances mono- or bicyclic; the ring or rings forming the mono- or bicyclic may each have 5 or 6 ring members in some compounds. In embodiments, there are 0, 1, 2 or 3 R²¹ substituents.

In a further embodiment, R¹⁴ and R¹⁵ taken together form =NR²⁰, wherein R²⁰ is usually hydrogen or hydroxy.

The chiral centre indicated by the symbol * is in particular of (S)-configuration.

D and E are each the same or different and in embodiments are mono- or bicyclic rings.

Monocyclic rings and each ring of a bicyclic ring may have 5, 6 or 7 ring members, for example.

Rings may be aromatic or heteroaromatic; in some embodiments rings are alicyclic. In some embodiments, one or both (e.g. exactly one) of D and E is a heterocyclic structure; the heteroatom may be O, S or N, for example, particularly N. Heterocyclic rings may have a heteroatom, e.g. N, at the 2-position. Some heterocycles have one heteroatom, e.g. N; other heterocycles have two heteroatoms, e.g. of which one or both are N; further heterocycles fall outside these categories. Included are compounds in which D and E are each an aromatic or heteroaromatic 6-membered ring; one may be aromatic and the other heteroaromatic, for example, one may be phenyl and the other pyridyl, e.g. 2-pyridyl. D and E each independently unsubstituted or substituted unsubstituted or substituted by one or more substituents. Substituents may be the same or different and selected from R²¹ groups. In embodiments, there are 0, 1, 2 or 3 substituents, e.g. a single substituent. Included are rings, particularly but not exclusively aromatic rings, having a 4- substituent; sometimes the 4-substituent is the sole substituent but sometimes it is not the sole substituent. Exemplary substituents are halogen, e.g. Br or Cl.

In some compounds, one of D and E is phenyl which is unsubstituted or substituted as aforesaid (e.g. having a 4-substituent, for example halo and particularly Br or Cl)₁ whilst the other of D and E is pyridyl, particularly 2-pyridyl, which often has 0 or 1 substituents and may for example be unsubstituted.

In some embodiments, D and E are coupled together as part of a fused ring system, e.g. have a further fused ring (e.g. having 5, 6 or 7 ring-members) fused between them. In other embodiments, D and E are not coupled together as part of a fused ring system.

Exemplary compounds are of Formula (V):

The meanings of the symbols in formula (V) are the same as for formula (IV).

In formula (V), m is often 1 or 2.

In particular compounds, -W-(CH₂)_m- contains 2 or 3 in-chain atoms, e.g. 2. Included are compounds in which W is CH₂.

In one embodiment, the active agent has the formula (Vl):

wherein X is O or CH₂,

A and B are each the same or different and an aromatic or heteroaromatic 6-membered ring, A and B each independently unsubstituted or substituted unsubstituted or substituted by one or more substituents selected from the group consisting of trifluoromethyl and species having 1 , 2 or 3 non-hydrogen atoms and optionally one or more hydrogen atoms, and

* indicates a chiral centre of (R) or (S) configuration.

The one or more substituents are selected from the group consisting of halogen, hydroxy, methyl, trifluoromethyl, formyl (-CHO), methoxy, amino, methylamino, dimethylamino, amidino, hydroxylamino, cyano, thiol and methylthio. In an exemplary embodiment, the one or more substituents are selected from chlorine and bromine. Particularly, the one or more substituents can be bromine. In one embodiment, exactly one of A and B is substituted by a single substituent. For example, in one embodiment, at least one of A and B is phenyl. Particularly, at least one of A and B may be substituted phenyl.

In embodiments, exactly one or both of A and B is a heteroaromatic ring. More particularly, a single one of A and B is a heteroaromatic ring. The or each heteroaromatic ring may for example contain one or two heteroatoms. The heteroatom(s) may for example be N, O or S; often, heteroaromatic rings include a nitrogen. In embodiments, the or each heteroaromatic ring contains as heteroatom a single nitrogen. Included are compounds in which the or each heteroaromatic ring has a heteroatom at the 2-position.

In an embodiment, at least one of A and B is substituted at its 4-position. In a particular embodiment, one of A and B is substituted or unsubstituted phenyl and the other of A and B is substituted or unsubstituted pyridinyl. Particularly, the pyridinyl group can be pyridin-2-yl. In one embodiment, the pyridinyl group is unsubstituted.

In one embodiment, the phenyl group is substituted solely at the 4-position. In an exemplary embodiment, the substituent can be bromine. Alternatively, the substituent can be chlorine.

In one embodiment, the chiral centre is of (S)-configuration. In an embodiment, neither of A and B is substituted.

The disclosure includes compounds of formula (Vl) in which X is CH₂.

Novel compounds of formula (III) are an aspect of the invention, e.g. those which are not pheniramines or not of formula (Vl). In one embodiment, the active agent is selected from pheniramine, chlorpheniramine, dexchlorpheniramine, brompheniramine, dexbrompheniramine and triprolidine and prodrugs and pharmaceutically acceptable salts thereof. In one embodiment, the active agent is not fexofenadine or diphenhydramine.

Particularly, in one embodiment, the active agent is dexbrompheniramine or a prodrug or pharmaceutically acceptable salt thereof. In one embodiment, the active agent is not fexofenadine or diphenhydramine.

Compounds containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound contains an alkenyl or alkenylene group, geometric cis/trans (or ZJE) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism. Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula I, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counter ion is optically active, for example, d-lactate or /-lysine, or racemic, for example, (//-tartrate or c//-arginine.

Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person. Chiral compounds (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.

When any racemate crystallises, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.

While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel and S. H. Wilen (Wiley, 1994).

The present disclosure includes all pharmaceutically acceptable isotopically-labelled compounds) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.

Examples of isotopes suitable for inclusion in the compounds of the disclosure include isotopes of hydrogen, such as ²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶CI, fluorine, such as ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as ³⁵S.

It will be understood that the disclosure specifically includes variants of individual or exemplary compounds or compound classes in which one or more moieties have been replaced by alternatives described in this application.

The compounds of the disclosure may be administered in the form of pharmaceutically acceptable salts. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., US, 1985, p. 1418, the disclosure of which is hereby incorporated by reference; see also Stahl et al, Eds, "Handbook of Pharmaceutical Salts Properties Selection and Use", Verlag Helvetica Chimica Acta and Wiley-VCH, 2002. The disclosure thus includes pharmaceutically-acceptable salts of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof, for example the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases. Examples of such acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.

The invention includes prodrugs for the active pharmaceutical species of the invention, for example in which one or more functional groups are protected or derivatised but can be converted in vivo to the functional group, as in the case of esters of carboxylic acids convertible in vivo to the free acid, or in the case of protected amines, to the free amino group. The term "prodrug," as used herein, represents in particular compounds which are rapidly transformed in vivo to the parent compound, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; H Bundgaard, ed, Design of Prodrugs, Elsevier, 1985; and Judkins, et al. Synthetic Communications, 26(23), 4351-4367 (1996), each of which is incorporated herein by reference.

Prodrugs therefore include drugs having a functional group which has been transformed into a reversible derivative thereof. Typically, such prodrugs are transformed to the active drug by hydrolysis. As examples may be mentioned the following:

Functional Group Reversible derivative

Carboxylic acid Esters, including e.g. acyloxyalkyl esters, amides

Alcohol Esters, including e.g. sulfates and phosphates as well as

carboxylic acid esters Amidine Amidoximes, carbamateamidino

Amine Amides, carbamates, imines, enamines,

Boron ic acid Diol ester

Carbonyl (aldehyde, Imines, oximes, acetals/ketals, enol esters, oxazolidines ketone) and thiazoxolidines

Prodrugs also include compounds convertible to the active drug by an oxidative or reductive reaction. As examples may be mentioned: Oxidative activation

• N- and O- dealkylation

• Oxidative deamination

• N-oxidation

• Epoxidation

Reductive activation

• Azo reduction

• Sulfoxide reduction

• Disulfide reduction

• Bioreductive alkylation

• Nitro reduction.

Also to be mentioned as metabolic activations of prodrugs are nucleotide activation, phosphorylation activation and decarboxylation activation. For additional information, see "The Organic Chemistry of Drug Design and Drug Action", R B Silverman (particularly Chapter 8, pages 497 to 546), incorporated herein by reference.

The use of protecting groups is fully described in ^'Protective Groups in Organic Chemistry^", edited by J W F McOmie, Plenum Press (1973), and ^'Protective Groups in Organic Synthesis^', 2nd edition, T W Greene & P G M Wutz, Wiley-lnterscience (1991 ).

Thus, it will be appreciated by those skilled in the art that, although protected derivatives of compounds of the disclosure may not possess pharmacological activity as such, they may be administered, for example parenteral^ or orally, and thereafter metabolised in the body to form compounds of the disclosure which are pharmacologically active. Such derivatives are therefore examples of "prodrugs". All prodrugs of the described compounds are included within the scope of the disclosure.

TRPV-1 Receptor Antagonist In some embodiments of the invention, use of a TRPV-1 receptor modulator or antagonist is contemplated. The class of TRPV-1 receptor modulators, particularly inhibitors, includes, for example, an active agent disclosed herein and an anti-TRPV-1 antibody which modulates, particularly inhibits, TRPV-1 function.

The TRPV-1 receptor is a member of the TRP superfamily, which includes for example TRPM proteins, TRPC proteins and other members of the TRPV family e.g. TRPV-2 and TRPV-3. Thus, whenever reference is made herein to "TPRV-I", the reader will understand that the teaching may be applied to other members of the TRP protein superfamily and the disclosure of the specification extends accordingly. Therefore a "TRPV-1 antagonist" disclosed herein may be used to modulate, e.g. inhibit other transient receptor potential proteins. However, in embodiments the invention is restricted to subject matter relating to the TRPV-1 receptor itself.

The term "anti-TRPV-1 antibody" includes, although is not limited to, antibody and antibody fragments which bind to TRPV-1. In particular, an anti-TRPV-1 antibody modulates e.g. inhibits the function of TRPV-1. Typically, an antibody is a protein which including one or more polypeptides substantially encoded by immunoglobulin genes. The recognized immunoglobulin genes include the kappa, lambda, alpha (IgA), gamma (IgGI, lgG2, lgG3, lgG4), delta (IgD), epsilon (IgE) and mu (IgM) constant region genes, as well as the myriad immunoglobulin variable region genes. Antibodies also exist in a variety of other forms including, for example, Fv, Fab, and

(Fab¹) 2, as well as bifunctional hybrid antibodies and single chains (e. g. , Lanzavecchia et al.,

Eur. J. Immunol. 17: 105,1987 ; Huston et al., Proc. Natl. Acad. Sci. U. S. A., 85: 5879-5883,

1988; Bird et al., Science 242 : 423-426,1988 ; Hood et al., Immunology, Benjamin, N. Y. , 2nd.ed.

, 1984; Hunkapiller and Hood, Nature 323: 15-16,1986).

In one embodiment, the anti-TRPV-1 antibody can be a chimeric antibody. Chimeric antibodies are antibodies whose light and heavy chain genes have been constructed, typically by genetic engineering, from immunoglobulin variable and constant region genes belonging to different species. In one example, a therapeutic chimeric antibody is thus a hybrid protein composed of the variable or antigen-binding domain from a mouse antibody and the constant or effector domain from a human antibody although other mammalian species can be used, or the variable region can be produced by molecular techniques. Methods of making chimeric antibodies are well known in the art, e. g. see U. S. Patent No. 5,807, 715, which is herein incorporated by reference.

Also contemplated by the invention is an anti-TRPV-1 antibody which is a "humanized" antibody. A humanized antibody is an immunoglobulin including a human framework region and one or more CDRs from a non-human (such as a mouse, rat, or synthetic) immunoglobulin. The non-human immunoglobulin providing the CDRs is termed a "donor" and the human immunoglobulin providing the framework is termed an "acceptor." In one embodiment, all the CDRs are from the donor immunoglobulin in a humanized immunoglobulin. Constant regions need not be present, but if they are, they must be substantially identical to human immunoglobulin constant regions, i. e. , at least about 85-90%, such as about 95% or more identical. Hence, all parts of a humanized immunoglobulin, except possibly the CDRs, are substantially identical to corresponding parts of natural human immunoglobulin sequences. A "humanized antibody" is an antibody comprising a humanized light chain and a humanized heavy chain immunoglobulin. A humanized antibody binds to the same antigen as the donor antibody that provides the CDRs.

The acceptor framework of a humanized immunoglobulin or antibody may have a limited number of substitutions by amino acids taken from the donor framework. Humanized or other monoclonal antibodies can have additional conservative amino acid substitutions which have substantially no effect on antigen binding or other immunoglobulin functions. Exemplary conservative substitutions are those such as gly, ala; val, ile, leu; asp, glu; asn, gin ; ser, thr; lys, arg; and phe, tyr (see U. S. Patent No. 5,585, 089, which is incorporated herein by reference). Humanized immunoglobulins can be constructed by means of genetic engineering, e. g., see U. S. Patent No. 5,225, 539 and U. S. Patent No. 5,585, 089, which are herein incorporated by reference. In one embodiment, the anti-TRPV-1 antibody is a human antibody which is an antibody wherein the light and heavy chain genes are of human origin. Human antibodies can be generated using methods known in the art. Human antibodies can be produced by immortalizing a human B cell secreting the antibody of interest. Immortalization can be accomplished, for example, by EBV infection or by fusing a human B cell with a myeloma or hybridoma cell to produce a trioma cell. Human antibodies can also be produced by phage display methods (see, e. g. Dower et al. , PCT Publication No. W091/17271; McCafferty et al., PCT Publication No. W092/001047; and Winter, PCT Publication No. W092/20791, which are herein incorporated by reference), or selected from a human combinatorial monoclonal antibody library (see the Morphosys website). Human antibodies can also be prepared by using transgenic animals carrying a human immunoglobulin gene (e. g., see Lonberg et al. PCT Publication No. W093/12227 ; and Kucherlapati, PCT Publication No. WO91/10741, which are herein incorporated by reference.)

Also included in the present disclosure, are monoclonal anti-TRPV-1 antibodies. Monoclonal antibodies are antibodies produced by a single clone of B- lymphocytes or by a cell into which the light and heavy chain genes of a single antibody have been transfected. Monoclonal antibodies are produced by methods known to those of skill in the art, for instance by making hybrid antibody- forming cells from a fusion of myeloma cells with immune spleen cells.

In one embodiment, the anti-TRPV-1 antibody is an antibody fragment. It has been shown that fragments of a whole antibody can perform the function of binding antigens. Various fragments of antibodies have been defined, including Fab, (Fab')2, Fv, single domain antibodies and single- chain Fv (scFv). These antibody fragments are defined as follows: (1) Fab, the fragment that contains a monovalent antigen-binding fragment of an antibody molecule produced by digestion of whole antibody with the enzyme papain to yield an intact light chain and a portion of one heavy chain or equivalently by genetic engineering. The Fab fragment therefore contains VL, VH, CL and CH1 domains; (2) Fab', the fragment of an antibody molecule obtained by treating whole antibody with pepsin, followed by reduction, to yield an intact light chain and a portion of the heavy chain; two Fab¹ fragments are obtained per antibody molecule; (3) (Fab¹) 2, the fragment of the antibody obtained by treating whole antibody with the enzyme pepsin without subsequent reduction or equivalents by genetic engineering; (4) F(Ab') 2, a dimer of two FAb' fragments held together by disulfide bonds(5) Fv, a genetically engineered fragment containing the variable region of the light chain and the variable region of the heavy chain expressed as two chains; (6) single domain antibodies; antibodies whose complementary determining regions are part of a single domain polypeptide; and (7) single chain antibody ("scFV"), a genetically engineered molecule containing the variable region of the light chain, the variable region of the heavy chain wherein the VH domain and the VL domain are linked by a peptide linker which allows the two domains to associate to form an antigen binding site (Bird etal, Science, 242, 423-426,1988 ; Huston et al, PNAS USA, 85, 5879-5883,1988) ; (8) the dAb fragment (Ward.E. S. etal., Nature 341,544-546 (1989) ) which consists of a VH domain; (9) bispecific single chain Fv dimers (PCT/US92/09965) and(10)"diabodies", multivalent or multispecific fragments constructed by gene fusion(W094/13804 ; P. Holliger et al, Proc. Natl. Acad. Sci. USA 90 6444-6448,1993). Fv.scFv or diabody molecules may be stabilised by the incorporation of disulphide bridges linking the VH and VL domains (Y. Reiter etal, Nature Biotech, 14, 1239-1245,1996). Minibodies comprising ascFv joined to a CH3 domain may also be made (S. Hu etal, Cancer Res., 56, 3055-3061 ,1996). . Methods of making these fragments are routine in the art. Other antibody fragments are also considered.

In one embodiment, the TRPV-1 receptor antagonist is an aptamer. Aptamers have been defined as artificial nucleic acid ligands that can be generated against amino acids, drugs, proteins and other molecules. They are isolated from complex libraries of synthetic nucleic acids by an iterative process of adsorption, recovery and re-amplification.

RNA aptamers are nucleic acid molecules with affinities for specific target molecules. They have been likened to antibodies because of their ligand binding properties. They may be considered as useful agents for a variety of reasons. Specifically, they are soluble in a wide variety of solution conditions and concentrations, and their binding specificities are largely undisturbed by reagents such as detergents and other mild denaturants. Moreover, they are relatively cheap to isolate and produce. They may also readily be modified to generate species with improved properties. Extensive studies show that nucleic acids are largely non-toxic and non-immunogenic and aptamers have already found clinical application. Furthermore, it is known how to modulate the activities of aptamers in biological samples by the production of inactive dsRNA molecules in the presence of complementary RNA single strands (Rusconi et al., 2002).

It is known from the prior art how to isolate aptamers from degenerate sequence pools by repeated cycles of binding, sieving and amplification. Such methods are described in US 5,475,096, US 5,270,163 and EP0533 38 and typically are referred to as SELEX (Systematic Evolution of Ligands by EX-ponential Enrichment). The basic SELEX system has been modified for example by using Photo-SELEX where aptamers contain photo-reactive groups capable of binding and/or photo cross-linking to and/or photo-activating or inactivating a target molecule. Other modifications include Chimeric-SELEX, Blended-SELEX, Counter-SELEX, Solution-SELEX, Chemi-SELEX, Tissue-SELEX and Transcription-free SELEX which describes a method for ligating random fragments of RNA bound to a DNA template to form the oligonucleotide library. However, these methods even though producing enriched ligand-binding nucleic acid molecules, still produce unstable products. In order to overcome the problem of stability it is known to create enantiomeric "spiegelmers" (see for example WO 01/92566). The process involves initially creating a chemical mirror image of the target, then selecting aptamers to this mirror image and finally creating a chemical mirror image of the SELEX selected aptamer. By selecting natural RNAs, based on D-ribose sugar units, against the non-natural enantiomer of the eventual target molecule, for example a peptide made of D-amino acids, a spiegelmer directed against the natural L-amino acid target can be created. Once tight binding aptamers to the non-natural enantiomer target are isolated and sequenced, the Laws of Molecular Symmetry mean that RNAs synthesised chemically based on L-ribose sugars will bind the natural target, that is to say the mirror image of the selection target. This process is conveniently referred to as reflection-selection or mirror selection and the L-ribose species produced are significantly more stable in biological environments because they are less susceptible to normal enzymatic cleavage, i.e.they are nuclease resistant.

The class of TRPV-1 receptor antagonists also includes an active agent disclosed herein. In one embodiment, the TRPV-1 receptor antagonist is dexbrompheniramine or a structural variant thereof.

It is re-emphasised at this point that reference to "TRPV-1 receptor" herein includes reference to other members of the TRP superfamily, e.g. TRPM proteins, TRPC proteins and other members of the TRPV family e.g. TRPV-2 and TRPV-3. Thus, a "TRPV-1 antagonist" disclosed herein may be used to modulate, e.g. inhibit other transient receptor potential proteins. Nonetheless TRPV-1 receptor is a particular receptor disclosed herein.

Methods and Uses The present invention provided methods for the treatment of a disease or condition that would benefit from inhibition of a calcium ion channel receptor, comprising administering an effective amount of an active agent as defined herein.

In one embodiment, the method further comprises administering at least one other pharmaceutically active agent. In one embodiment, the other pharmaceutically active agent (also referred to herein as "therapeutic agent") is selected from a group which includes, although is not limited to, an analgesic, a steroid, a corticosteroid, an agent which is indicated for the treatment of epilepsy, an agent which is indicated for the treatment of urinary tract disorders, an agent which is indicated for the treatment of bowel disorders, an anti-inflammatory drug, an anti-depressant, and other pharmaceutically active agents as defined herein under the heading Products. The selection of the at least one therapeutic agent will be determined by the nature of the disorder to be treated. The active agent and the at least one other pharmaceutically active agent ("therapeutic agent") can be administered as a fixed combination. Alternatively, or in addition, the active agent and the at least one other pharmaceutically active agent can be administered as components of separate products. The present invention also provides a use of dexbrompheniramine, or a structural variant thereof, for the manufacture of a medicament for the treatment of diseases or conditions that would benefit from inhibition of a calcium ion channel receptor polypeptide encoded by a nucleic acid molecule selected from the group consisting of:

i) a nucleic acid molecule comprising a nucleic acid sequence as represented in Figure 1;

ii) a nucleic acid molecule that hybridizes to a nucleic acid molecule in (i) above and which encodes a calcium ion channel receptor;

iii) a nucleic acid molecule comprising a nucleic acid sequence which is degenerate as a result of the genetic code to the sequences defined in (i) and (ii) above.

According to an aspect of the invention there is provided dexbrompheniramine, or a structural variant thereof, for use in the treatment of diseases or conditions that would benefit from calcium ion receptor polypeptide inhibition. In one embodiment, the diseases or conditions would benefit from TRPV-1 inhibition.

In one embodiment of the invention said nucleic acid molecule hybridizes under stringent hybridisation conditions to the sequences described in (i), (ii) and (iii) above.

Hybridization of a nucleic acid molecule occurs when two complementary nucleic acid molecules undergo an amount of hydrogen bonding to each other. The stringency of hybridization can vary according to the environmental conditions surrounding the nucleic acids, the nature of the hybridization method, and the composition and length of the nucleic acid molecules used.

Calculations regarding hybridization conditions required for attaining particular degrees of stringency are discussed in Sambrook et al., Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2001); and Tijssen, Laboratory Techniques in Biochemistry and Molecular Biology— Hybridization with Nucleic Acid Probes Part I,

Chapter 2 (Elsevier, New York, 1993). The T_m is the temperature at which 50% of a given strand of a nucleic acid molecule is hybridized to its complementary strand. The following is an exemplary set of hybridization conditions and is not limiting:

Very High Stringency (allows sequences that share at least 90% identity to hybridize)

Hybridization: 5x SSC at 65°C for 16 hours

Wash twice: 2x SSC at room temperature (RT) for 15 minutes each

Wash twice: 0.5x SSC at 65°C for 20 minutes each

High Stringency (allows seguences that share at least 80% identity to hybridize)

Hybridization: 5x-6x SSC at 65°C-70°C for 16-20 hours

Wash twice: 2x SSC at RT for 5-20 minutes each

Wash twice: 1x SSC at 55°C-70°C for 30 minutes each

Low Stringency (allows sequences that share at least 50% identity to hybridize)

Hybridization: 6x SSC at RT to 55°C for 16-20 hours

Wash at least twice: 2x-3x SSC at RT to 55°C for 20-30 minutes each.

Thus, the present disclosure provides use of an active agent as defined herein to manufacture a medicament to treat pain. Administration of the active agent can alleviate the pain suffered by the patient. In one embodiment, there is provided a method for reducing or controlling pain, comprising administering an effective amount of an active agent as defined herein or both a said active agent and at least one other pharmaceutically active agent as defined herein.

In an embodiment of the invention said disease or condition is selected from the group consisting of: chronic pain, neuropathic pain, dental pain, post operative pain, rheumatoid pain, osteoarthritic pain, back pain, visceral pain, cancer pain, neuralgia, migraine, neuropathies, pain relating to diabetic neuropathy, sciatica, HIV related neuropathy, post herpetic neuralgia, fibromyalgia, pain associated with nerve fibre injury, pain associated with ischaemia, pain associated with neurodegeneration, pain associated with stroke, post stroke pain, pain associated with multiple sclerosis, pain which is secondary to inflammatory disorders, pain associated with inflammatory bowel disease, pain associated with cystitis, pain associated with burns and pain associated with psoriasis. This paragraph provides basis for claims specific to any one of the listed diseases, i.e. each recited disease or disorder may be included in a claim directed solely to a product, method or use relating to that, and only that, disease or disorder. In a further embodiment of the present invention, there is provided a method of reducing or controlling epilepsy comprising administering an effective amount of any TRPV-1 receptor antagonist, whether one disclosed herein or another one, to a patient who has epilepsy. The present invention contemplates a method of reducing the number of seizures suffered by a patient suffering from epilepsy. Also included is the use of a TRPV-1 receptor antagonist for the manufacture of a medicament for treating epilepsy. In one embodiment, the TRPV-1 receptor antagonist is an active agent as disclosed herein. In particular embodiments, the term "TRPV-1" in this paragraph does not include reference to other TRP proteins than TRPV-1. The TRPV-1 receptor is considered to mediate glutamatergic synaptic input to neurons (Xing and Li, J. Neurophysiol 2006 Oct 25). Antagonism of the TRPV-1 receptor by a TRPV-1 receptor antagonist as disclosed herein will result in a decrease in the neuronal activity of the neurons which is contemplated for the treatment of epilepsy and epileptic events. The invention therefore includes a method of inhibiting neuronal activity, comprising administering an effective amount of a TRPV-1 receptor antagonist of the disclosure. Also disclosed is a method of modulating, particularly inhibiting glutamatergic synaptic input to neurons, comprising administering an effective amount of a TRPV-1 receptor antagonist of the disclosure. In particular embodiments, the term "TRPV-1" in this paragraph does not include reference to other TRP proteins than TRPV-1.

The TRPV-1 receptor has been identified in the urinary tract of humans and it has been disclosed as being involved in detecting bladder distension (Birder Vascul, Pharmacol 29 Jun. 2006). In an embodiment of the present invention, there is provided a method of treating a urinary tract disorder comprising administering an effective amount of a TRPV-1 receptor antagonist as disclosed herein to a patient suffering from a urinary tract disorder. The TRPV-1 receptor antagonist e.g. an active agent as disclosed herein, can be administered alone or in combination with at least one other pharmaceutically active agent (also referred to herein as "therapeutic agent"). In one embodiment, the urinary tract disorder is, for example, bladder over-activity. Overactive bladder (OAB) is the most common term currently used in clinical medicine to describe a complex of lower urinary tract symptoms (LUTS) with or without incontinence. The symptoms often include urgency, frequency, nocturia, troublesome or incomplete emptying, and pain. In particular embodiments, the term "TRPV-1" in this paragraph does not include reference to other TRP proteins than TRPV-1.

In one embodiment of the present invention, there is provided use of a TRPV-1 receptor antagonist as disclosed herein in the manufacture of a medicament for the treatment of urinary tract disorders. In one embodiment, the urinary tract disorder is bladder over-activity. In particular embodiments, the term "TRPV-1" in this paragraph does not include reference to other TRP proteins than TRPV-1.

It has been suggested that TRPV1 is involved in faecal urgency and rectal hypersensitivity (Chan et al Lancet 2003 Feb 1;361(9355):385-91).

In one embodiment of the present invention, there is provided a method of treating a bowel disorder comprising administering an effective amount of a TRPV-1 receptor antagonist of the disclosure, as defined herein, to a patient suffering from a bowel disorder. The present invention also provides the use of a TRPV-1 receptor antagonist e.g. an active agent as disclosed herein, for the manufacture of a medicament to treat a bowel disorder. In one embodiment, the bowel disorder is selected from irritable bowel syndrome, inflammatory bowel syndrome, faecal urgency, faecal incontinence, rectal hypersensitivity and combinations thereof. Other bowel disorders may also be treated by the use of dexbrompheniramine and are encompassed by the methods, uses and products of the present invention. In particular embodiments, the term "TRPV-1" in this paragraph does not include reference to other TRP proteins than TRPV-1.

Included also is a method of treating urinary and/or faecal incontinence, comprising administering an effective amount of a TRPV-1 receptor antagonist. The disclosure also provides a method for reducing or preventing bed-wetting, comprising administering an effective amount of a TRPV-1 receptor antagonist e.g. an active agent, both disclosed herein. In particular embodiments, the term "TRPV-1" in this paragraph does not include reference to other TRP proteins than TRPV-1.

As well as being expressed by neuronal cells, it has been shown that expression of TRPV1 is up regulated in airways smooth muscle in disease, for example, in patients who have chronic cough

(Mitchell et al. Exp. Lung Res 2005 Apr 31(3):295-306). It has also been shown that TRPV-1 knockout mice develop less joint inflammation than their wild-type counterparts, suggesting a role for

TRPV-1 in the development of joint inflammation (Barton et al Exp. MoI. Pathol 2006 Oct. 81(2) 166-

170.) It is also believed that TRPV-1 is expressed by for example keratinocytes (Denda et al, Biochem, Biophys Res. Commun 2001 285(5) pp1250-52).

In one embodiment, the present disclosure provides a method of treating an inflammatory condition or disorder in a patient comprises treating the patient with an effective amount of a TRPV-1 receptor antagonist disclosed herein. The present disclosure also provides use of a TRPV-1 receptor antagonist, e.g. an active agent disclosed herein, for the manufacture of a medicament to treat an inflammatory condition or disorder. In particular embodiments, the term "TRPV-1" in this paragraph does not include reference to other TRP proteins than TRPV-1.

A number of inflammatory conditions could be treated by inhibiting TRPV1 induced inflammation. In one embodiment, the inflammatory condition is selected from conditions relating to neurogenic inflammation, conditions relating to joint inflammation e.g. arthritis, rheumatoid arthritis, hyperinflammatory conditions, sepsis, vascular inflammation, respiratory inflammation e.g. asthma, intestinal inflammation, conditions relating to chronic inflammation, conditions relating to acute inflammation, nephritis, systemic lupus, erythematosus, inflammatory bowel disease, asthma, Crohn's disease, rheumatoid arthritis, glomerulonephritis, vasculitis and sarcoidosis. In particular embodiments, the term "TRPV-1" in this paragraph does not include reference to other TRP proteins than TRPV-1.

In one embodiment, the inflammatory condition is asthma. In one embodiment, the inflammatory condition is arthritis. In a further embodiment, the inflammatory condition is rheumatoid arthritis.

According to a further aspect of the invention there is provided the use of dexbrompheniramine, or a structural variant thereof, in the treatment of disease conditions that result from the over- expression of a nucleic acid molecule wherein said nucleic acid molecule selected from the group consisting of:

i) a nucleic acid molecule comprising a nucleic acid sequence as represented in

Figure 1;

In an embodiment of the invention said disease condition is an inflammatory disease condition that results from over-expression of a calcium ion channel receptor.

According to a further aspect of the invention there is provided the use of an active agent disclosed herein for the manufacture of a medicament for the treatment of a cough that is not caused by post nasal drip syndrome. The present invention also provides a method of treating or alleviating a cough that is not caused by post-nasal drip syndrome in a patient, wherein the method comprises treating the patient with an effective amount of an active agent selected from dexbrompheniramine, or a structural variant thereof.

In an embodiment of the invention the cough is an acute viral cough. In one embodiment of the invention the cough is the result of gastro-oesophageal reflux. In a further embodiment of the invention the cough is the result of asthma.

Included in the disclosure is the use of active agents described herein for the manufacture of a medicament for treating a disease other than cough. Sometimes, this does not apply to active agents other than dexbrompheniramine or, alternatively, other than pheniramines as a class. In an embodiment, the patient is human.

According to a further aspect of the invention there is provided a method to provide analgesia to a subject in need of pain relief, comprising administering an active agent disclosed herein to the subject.

According to an aspect of the invention there is provided a method to treat a cough wherein said cough is not caused by post nasal drip syndrome comprising administering an active agent disclosed herein to a subject in need of treatment.

In one method of the present invention, the cough is an acute viral cough. In a further method of the invention, the cough is the result of gastro-oesophageal reflux. In a yet further method of the invention, the cough is the result of asthma. In one class of methods of the present invention the subject is human. In an alternative method of the invention the subject is a non-human mammal, for example a non-human primate. In an alternative method of the invention the non-human mammal is a livestock species, for example a cow, horse, pig or sheep. In an alternative method of the invention the non-human mammal is a companion animal, for example a dog, cat or rabbit. In one method of the invention the subject is bird species.

According to a further aspect of the invention there is provided a method to provide analgesia to a subject in need of pain relief comprising topically applying a wound dressing according to the invention to a wound.

In one method of the invention the wound is a burn or scald. In an alternative method of the invention the wound is a contusion. In a further method of the invention the wound is an ulcer, for example a diabetic ulcer. In a method of the invention the wound is a post-operative wound. Products

The present disclosure also provides pharmaceutically useful products comprising a TRPV-1 receptor antagonist, e.g. an active agent disclosed herein, for treating conditions and disorders which would benefit from inhibition of a calcium ion channel receptor. In one embodiment, the active agent is dexbrompheniramine or a structural variant thereof. In one embodiment, the products are for the treatment of disorders and conditions which would benefit from inhibition of a TRPV receptor. The TRPV receptor is for example TRPV-1. In one embodiment, the product comprises the active agent and at least one other pharmaceutically active agent (also referred to herein as "therapeutic agent"). According to an embodiment of the invention, the product is a pharmaceutical composition comprising a TRPV-1 receptor antagonist disclosed herein, for example an active agent disclosed herein, and at least one other pharmaceutically active agent. In one embodiment, the product comprises dexbrompheniramine and at least one pharmaceutically active agent. In one embodiment, the product does not contain pseudoephidrine. According to a further embodiment of the present invention, there is provided a pharmaceutical composition comprising dexbrompheniramine or a structural variant thereof and at least one therapeutic agent which is not pseudoephedrine or dextromethorphan. In one embodiment, the invention includes a pharmaceutical composition in unit dosage form (e.g. tablet or capsule) wherein each unit comprises an active agent of the disclosure in an amount of from about 6mg to about 24mg. The invention also includes a pharmaceutical composition which is for inhaled administration. The amount of active agent in the product can be, for example, about any of the following: 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21 mg, 22mg, 23mg, and 24mg. In other embodiments, the amount of active agent, e.g. dexbrompheniramine may be differ from the dosage indicated above, for example, the amount of active agent may be from about 1mg to about 100mg, including about any of the following: 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 95mg and 100mg.

In one aspect of the present invention, there is provided a combination of an active agent of the disclosure and one or more other pharmaceutically active agents. In one embodiment, the combination can be used to treat pain. In one embodiment, the combination is a fixed combination i.e. comprised within a single product. In an alternative embodiment, the combination comprises separate products but is for co-administration, as for example in the case of a package comprising a separate dosage form for each pharmaceutically active agent. The active agent may be supplied in dosage forms as indicated above.

In an embodiment of the invention the other therapeutic agent is a steroid. In one embodiment, the steroid is a corticosteroid, although the present invention also encompasses other steroids as therapeutic agents. In one embodiment, the product comprises a steroid, for example, a corticosteroid. A product according to this embodiment may be used in methods to treat or alleviate cough as described herein. In one embodiment, the cough is not caused by post-nasal drip syndrome. Products comprising an active agent disclosed herein and a steroid can be used to treat inflammatory disorders. Such inflammatory disorders include, although are not limited to, those described herein, for example, asthma and inflammatory bowel syndrome.

In one embodiment of the invention, the product comprises the active agent and at least one other therapeutic agent which is an analgesic. In this embodiment, the product can be used to treat pain. Analgesics are well known in the art and relates to a diverse group of drugs that are used to relieve pain. Analgesic drugs work in various ways on the peripheral and central nervous system and include paracetamol, non-steroidal anti-inflammatory drugs (for example, sulindac, suliπdac suifide, sulindac sulfone, aspirin, indomethacin, ibuprofen, meclofenamic acid, flurbiprofen, naproxen or piroxican), and narcotic drugs such as morphine. In one embodiment, the analgesic is selected from the class of non-steroidal anti-inflammatory drugs. For example, the therapeutic agent can be aspirin. In other embodiments, the analgesic can be paracetamol. The amount of paracetamol per dose can be for example, about any of the following: about 500mg to about 1000mg, and may be for example 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or IOOOmg per dosage form. In one embodiment, the therapeutic agent is aspirin. The amount of aspirin per dosage may be for example about 300 to about 1200mg, including, for example, about any of the following:from 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150 and 1200mg.

In one embodiment, in which the product can be used to treat pain, e.g. depression in combination with pain, the other therapeutic agent is an anti-depressant. In one embodiment, the antidepressant is a tricyclic anti-depressant, for example although not limited to, amitriptyline and nortriptyline. Other tricylic anti-depressants may be used in the products of the disclosure.

In one embodiment, in which the product can be used to treat pain, e.g. depression in combination with pain, the other therapeutic agent is amitriptyline. The amount of amitriptyline per dose can be for example from about 75mg to about 200mg, including for example about any of the following: 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 and 200mg.

In one embodiment, in which the product can be used to treat pain, the other therapeutic agent is an opiate. Thus, in one embodiment the combination is a combination of dexbrompheniramine and an opiate. In one embodiment, the therapeutic agent is selected from a class of morphinomimetics. Other embodiments include a pharmaceutical composition comprising dexbrompheniramine and an opiate. Examples of opiates which are encompassed by the present invention include morphine and codeine. Opiates other than those described herein are encompassed by the present invention.

In one embodiment, in which the product can be used to treat pain, the other therapeutic agent is codeine. The amount of codeine can be for example from about 15mg to 60mg per dosage form e.g. about any of the following: 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg and 60mg.

In one embodiment, in which the product can be used to treat pain, the other therapeutic agent can be morphine wherein the amount of morphine per dosage form may be for example from about 5mg to about 200mg, for example, about any of the following: 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 and about 200mg. In one embodiment, in which the product can be used to treat pain, the other therapeutic agent is selected from gabapentin and pregabalin. In one embodiment, the other therapeutic agent is gabapentin. The amount of gabapentin or pregabalin per dosage can be for example from about 300 to about 1200mg, including for example, about any of the following: 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150 and 1200mg.

In an embodiment, in which the product can be used to treat pain, e.g. migraine, the other therapeutic agent may be selected from the class of triptan drugs. The class of triptan compounds include, for example, sumatriptan, which is currently licensed for treatment of migraines. In one embodiment of the present invention, there is provided a combination of an active agent e.g. dexbrompheniramine, and sumatriptan. Also included in the present disclosure, is a pharmaceutical composition comprising dexbrompheniramine and sumatriptan. The present disclosure also encompasses pharmaceutical compositions comprising an active agent e.g. dexbrompheniramine and other triptan compounds e.g. zolmitriptan or sumatriptan.

In one embodiment, in which the product can be used to treat pain, the other therapeutic agent is sumatriptan. The amount of sumatriptan per dosage form is from about 50mg to about 300mg for example, about any of the following: 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290 and 300mg.

In one embodiment, the other therapeutic agent is an anti-epileptic drug, for example, sodium valproate or carbamazepine, lamotrigine, oxcarbazepine, topiramate, gabapentin, levetiracetam, phenytoin, tiagabine and vigabatrin. In a particular embodiment, the therapeutic agent is carbamazepine. The amount of carbamazepine per dosage form can be from about 10Omg to about 1200 mg, e.g. about any of the following: 200, 300, 400, 500, 600, 700, 800, 900, 1000, HOOmg and 1200mg.

In an embodiment, the other therapeutic agent is phenytoin. The amount of phenytoin per dosage form can be from about 150mg to about 500mg, e.g., about any of the following: 150, 200, 250, 300, 350, 400, 450 and 500mg.

In one embodiment, the other therapeutic agent is gabapentin. For the treatment of urinary tract disorders, the active agent may be administered solely or in combination with at least one other therapeutic agent. In one embodiment, the other therapeutic agent is a urinary anti-spasmodic. In one embodiment, the other therapeutic agent is selected from darifenacin, emepronium, flavoxate, meladrazine, oxybutynin, propiverine, solifenacin, terodiline, tolterodine, trospium and combinations thereof. In one embodiment, the other therapeutic agent is selected from oxybutynin, tolterodine and combinations thereof. Use of other urinary anti-spasmodics in combination with an active agent disclosed herein is encompassed by the present invention.

In one embodiment, the other therapeutic agent is oxybutynin. The amount of oxybutynin per dosage can be from about 2.5 to about 20mg, including for example, about any of the following: 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or20mg.

In one embodiment, the other therapeutic agent is tolterodine. The amount of tolterodine per dosage can be from about 1 to about 4mg e.g., about any of the following: 1 , 2, 3 or 4mg.

In one embodiment, the other therapeutic agent can be an anti-inflammatory agent. In one embodiment, the other therapeutic agent can be a bowel-specific anti-inflammatory agent e.g. licensed for use to treat inflammatory conditions of the bowel. In one embodiment, the other therapeutic agent is selected from, for example, mesalazine and hyoscine (also referred to as scopolamine). Scopolamine may be in the form of scopolamine hydrobromide.

In one embodiment, the other therapeutic agent is mesalazine. The amount of mesalazine per dosage can be from about 2 to about 4grammes e.g , about any of the following. 2, 2.5, 3, 3.5 or 4grammes.

In an embodiment, the other therapeutic agent is hyoscine. The amount of hyoscine per dosage can be from about 30mg to about 80mg e.g. about any of the following: 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 or 80mg. In one embodiment, the product comprises a combination of an active agent as described herein and at least two other therapeutic agents. The other therapeutic agents are typically therapeutic agents as defined herein.

In one embodiment, in which the product can be used to treat inflammatory disorders, the product comprises the active agent and other therapeutic agents such as montelukast and prednisolone.

The amount of montelukast per product in this embodiment can be from about 5mg to about 15mg e.g. , about any of the following: 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15mg. In an embodiment, the amount of montelukast per product is about 10mg. The dosage of prednisolone in the product can be from about 2mg to about 60mg e.g. about any of the following: 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or about 60mg.

In one embodiment, in which the product can be used to treat inflammatory disorders for example rheumatoid arthritis, the product can comprise the active agent, aspirin, ibuprofen, and leflunomide. The amount of aspirin comprised within the product is typically as detailed earlier. The amount of ibuprofen contained within the product may be from about 200mg to about 1800mg, including for example about any of the following: 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700 and 1800mg. The amount of leflunomide per product can be from about 10mg to about 20mg e.g. about any of the following: 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or about 20mg.

In one embodiment, in which the product can be used to treat asthma, the other therapeutic agent is anti-asthma drug. In one embodiment, the other therapeutic agent is selected from a class of drugs which includes, although is not limited to, leukotriene receptor antagonists e.g. montelukast and salts and prodrugs thereof (e.g. montelukast sodium), pranlukast and salts and prodrugs thereof, and zafirlukast and salts and prodrugs thereof. In one embodiment, the other therapeutic agent is selected from a class of drugs (known and future) which includes, although is not limited to, corticosteroids. In one embodiment, the corticosteriodal drug is selected from prednisolone and prednisone. In one embodiment, the method comprises administering a combination of the active agent as defined herein and at least two therapeutic agents. In a particular embodiment, the combination comprises dexbrompheniramine, a leukotriene receptor antagonist and a corticosteroid. An exemplary combination is, for example, dexbrompheniramine, montelukast and prednisolone. The skilled person will understand that other combinations of dexbrompheniramine and other therapeutic agents for use in the treatment of an inflammatory disorder is envisaged and encompassed by the present invention.

The combinations and pharmaceutical compositions as described herein can be used to treat, reduce or alleviate pain. A product which comprises the active agent and at least one therapeutic agent which is an analgesic can be used in methods for the reduction and/or alleviation of pain including, although in no way limited to, the treatment of pain in relation to inflammatory disorders. The product may also be used to treat other types of pain as described herein.

In some embodiments, the disorders disclosed herein can be treated by co-administration of the active agent in combination with a therapeutic agent, wherein the active agent and the therapeutic agent are not present in the same product. In these embodiments, the therapeutic agent may be administered in the dosage amounts indicated above. Co-administration of the active agent and the therapeutic agent can be simultaneous or sequential. The present disclosure also includes use of a product comprising the active agent and an analgesic in methods for treating inflammatory disorders and/ or conditions.

In an embodiment of the invention the products, medicaments and combined composition include a carrier, adjuvant or excipient. The present disclosure also includes use of a product comprising the active agent and an analgesic in methods for treating cough in a patient. In one embodiment, the product comprises the active agent selected from dexbrompheniramine and structural variants thereof and an analgesic selected from codeine, morphine, dextromethorphan and guaiphensin.

According to a further aspect of the invention there is provided a combined pharmaceutical composition comprising dexbrompheniramine or a structural variant thereof and at least one analgesic.

In an embodiment of the invention, the active agent is administered with at least one therapeutic agent, either in combination in the medicament or in combination as separate products. The administration may be simultaneous or sequential administration.

In an embodiment of the invention said therapeutic agent is a steroid; preferably a corticosteroid. In a particular embodiment of the invention said product, medicament or composition is provided as a topical formulation, e.g. a cream adapted for topical application.

When administered, the products, active agents, compositions and medicaments of the present invention are administered as pharmaceutically acceptable preparations. Such preparations may routinely contain pharmaceutically acceptable concentrations of excipients, diluents, and/or carriers e.g. salt, buffering agents, preservatives, compatible carriers and optionally other therapeutic agents.

The products and medicaments of the invention can be administered by any conventional route, including injection or by gradual infusion over time. The administration may, for example, be oral, intravenous, intraperitoneal, intramuscular, intracavity, subcutaneous, inhalation, nasal or transdermal. Medicaments may be administered by aerosol e.g. by inhalation. Techniques for preparing aerosol delivery systems are well known to those of skill in the art. Generally, such systems should utilize components which will not significantly impair the biological properties of the medicaments. Those of skill in the art can readily determine the various parameters and conditions for producing aerosols without resort to undue experimentation.

In one embodiment, the product is for oral administration. Solid dosage . forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active agent is typically mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or one or more: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycol, for example.

Suitably, oral formulations contain a dissolution aid. The dissolution aid is not limited as to its identity so long as it is pharmaceutically acceptable. Examples include nonionic surface active agents, such as sucrose fatty acid esters, glycerol fatty acid esters, sorbitan fatty acid esters (e.g. sorbitan trioleate), polyethylene glycol, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, methoxypolyoxyethylene alkyl ethers, polyoxyethylene alkylphenyl ethers, polyethylene glycol fatty acid esters, polyoxyethylene alkylamines, polyoxyethylene alkyl thioethers, polyoxyethylene polyoxypropylene copolymers, polyoxyethylene glycerol fatty acid esters, pentaerythritol fatty acid esters, propylene glycol monofatty acid esters, polyoxyethylene propylene glycol monofatty acid esters, polyoxyethylene sorbitol fatty acid esters, fatty acid alkylolamides, and alkylamine oxides; bile acid and salts thereof (e.g. chenodeoxycholic acid, cholic acid, deoxycholic acid, dehydrocholic acid and salts thereof, and glycine or taurine conjugate thereof); ionic surface active agents, such as sodium laurylsulfate, fatty acid soaps, alkylsulfonates, alkylphosphates, ether phosphates, fatty acid salts of basic amino acids; triethanolamine soap, and alkyl quaternary ammonium salts; and amphoteric surface active agents, such as betaines and aminocarboxylic acid salts. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, and/or in delayed fashion. Examples of embedding compositions include polymeric substances and waxes.

The active compounds may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients. The active agents may be in finely divided form, for example it may be micronised.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active agents, the liquid dosage forms may contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyi alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof. Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents. Suspensions, in addition to the active agents, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth and mixtures thereof. The products and medicaments of the invention are administered in effective amounts. An "effective amount" is that amount of a medicament that alone, or together with further doses, produces the desired response. Such amounts will depend, of course, on the particular condition being treated, the severity of the condition, the individual patient parameters including age, physical condition, size and weight, the duration of the treatment, the nature of concurrent therapy (if any), the specific route of administration and like factors within the knowledge and expertise of the health practitioner. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is generally preferred that a maximum dose of the individual components or combinations thereof be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art, however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons.

In an alternative embodiment, the product is for inhaled administration. Dosage forms for topical administration of an active agent of this invention include powders, sprays, ointments and inhalants. The active agent is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which may be required. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention. The products e.g. medicaments used in the foregoing methods preferably are sterile and contain an effective amount of an active agent e.g. dexbrompheniramine or its structural variants as defined herein for producing the desired response in a unit of weight or volume suitable for administration to a patient. The response can, for example, be measured by determining the signal transduction enhanced or inhibited by the product comprising an active agent disclosed herein e.g. dexbrompheniramine or its structural variants via a reporter system, by measuring downstream effects such as gene expression, or by measuring the physiological effects of an active agent disclosed herein e.g. dexbrompheniramine or its structural variants, such as regression of disease symptoms. Other assays will be known to one of ordinary skill in the art and can be employed for measuring the level of the response. Actual dosage levels of active ingredients in the pharmaceutical compositions and products of this disclosure may be varied so as to obtain an amount of the active agent(s) that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration (referred to herein as a "therapeutically effective amount"). The selected dosage level will depend upon the activity of the particular active agent, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the active agent at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

The doses of an active agent disclosed herein e.g. dexbrompheniramine or its structural variants administered to a subject can be chosen in accordance with different parameters, in particular in accordance with the mode of administration used and the state of the subject. Other factors include the desired period of treatment. In the event that a response in a subject is insufficient at the initial doses applied, higher doses (or effectively higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits.

In general, doses of the active agent e.g. dexbrompheniramine and its structural variants are formulated and administered in doses typically between about 1mg and 36mg. Particularly, doses of the active agent e.g. dexbrompheniramine and its structural variants are from about 6 to about 24mg.ln one embodiment, which is not limiting, the dose is from about 6mg to aboutabout 12mg, according to any standard procedure in the art. Other protocols for the administration of products comprising the active agent e.g. dexbrompheniramine and its structural variants will be known to one of ordinary skill in the art, in which the dose amount, schedule of injections, sites of injections, mode of administration and the like vary from the foregoing. Administration of the active agent e.g. dexbrompheniramine compositions to mammals other than humans, (e.g. for testing purposes or veterinary therapeutic purposes), is carried out under substantially the same conditions as described above. A subject, as used herein, is a mammal, preferably a human, and including a non-human primate, cow, horse, pig, sheep, goat, dog, cat or rodent.

When administered, the products e.g. medicaments of the invention are applied in pharmaceutically-acceptable amounts and in pharmaceutically-acceptable compositions. The term "pharmaceutically acceptable" j_s employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. The term "pharmaceutically acceptable" means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredients. Such preparations may routinely contain salts, buffering agents, preservatives, compatible carriers, and optionally other therapeutic agents. When used in medicine, the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically-acceptable salts thereof and are not excluded from the scope of the invention. Such pharmacologically and pharmaceutically-acceptable salts include, but are not limited to, . those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, citric, formic, malonic, succinic, and the like. Also, pharmaceutically-, acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts. . .

The active agent e.g. dexbrompheniramine and its structural variants compositions may be combined, if desired, with a pharmaceutically-acceptable carrier. The term "pharmaceutically- acceptable carrier" as used herein means one or more compatible solid or liquid fillers, diluents or encapsulating substances which are suitable for administration into a human: The term "carrier" denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions also are capable of being co-mingled with the molecules of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy.

The products e.g. pharmaceutical compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well-known in the art of pharmacy. All methods include the step of bringing the active agent into association with a carrier which constitutes one or more accessory ingredients. In general, the products e.g. compositions are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.

Products, including compositions, which are suitable for oral administration may be presented as discrete units, such as capsules, tablets, lozenges, each containing a predetermined amount of the active compound. Other compositions include suspensions in aqueous liquids or non-aqueous liquids such as syrup, elixir or an emulsion.

Products, including compositions, which are suitable for parenteral administration conveniently comprise a sterile aqueous or non-aqueous preparation of dexbrompheniramine or a structural variant thereof, which is preferably isotonic with the blood of the recipient. This preparation may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation also may be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or di-glycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables. Carrier formulation suitable for oral, subcutaneous, intravenous, intramuscular, etc. administrations can be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA. According to a further aspect of the invention there is provided a wound dressing that includes dexbrompheniramine, or a structural variant thereof. In one embodiment of the invention said wound dressing is a bandage or plaster. In ann embodiment of the invention said wound dressing is a hydrogel. Hydrogels are also included within the scope of the invention. Hydrogels are amorphous gels or sheet dressings which are crosslinked and which typically consist of a polymer, a humectant and water in varying ratios. Hydrogels are known in the art and are commercially available. Hydrogels/sheets function to maintain a moist wound environment and can be removed without trauma to a wound bed. Examples of commercially available hydrogels are Tegagel¹"¹, Nu-Gel^tm or FlexiGer.

According to a further aspect of the invention there is provided a screening assay for the identification of agents that antagonise the activity of a calcium ion receptor comprising:

i) forming a preparation comprising a polypeptide encoded by a nucleic acid molecule selected from the group consisting of:

a) a nucleic acid molecule comprising a nucleic acid sequence as represented in Figure 1;

b) a nucleic acid molecule that hybridizes to a nucleic acid molecule in (i) above and which encodes a calcium ion channel receptor;

c) a nucleic acid molecule comprising a nucleic acid sequence which is degenerate as a result of the genetic code to the sequences defined in (i) and (ii) above and a candidate agent to be tested;

ii) determining the effect, or not, of the candidate agent on the activity of said calcium ion receptor.

In a preferred method of the invention the effect of the candidate agent is compared in the presence of an agonist that activates said calcium ion receptor. Preferably said agonist is capsaicin or resiniferatoxin. In a preferred method of the invention the calcium ion receptor is expressed by a cell, preferably a mammalian cell. In a preferred method of the invention the mammalian cell is a human cell.

In a further method of the invention said cell is transfected with a nucleic acid molecule encoding a polypeptide that is a calcium ion channel receptor. Preferably the receptor is encoded by a nucleic acid molecule as represented in Figure 1. In a yet further preferred method of the invention the candidate agent is based on the structure presented in Figure 4. According to a further aspect of the invention there is provided a method to determine the ligand binding activity of a molecule to associate with a calcium ion channel receptor polypeptide comprising the steps of:

i) providing computational means to perform a fitting operation between the molecule and a polypeptide defined by the amino acid sequence in Figure 2; and ii) analysing the results of the fitting operation to quantify the association between the molecule and the calcium ion channel receptor polypeptide.

The rational design of binding entities for proteins is known in the art and there are a large number of computer programs that can be utilised in the modelling of 3-dimensional protein structures to determine the binding of chemical entities to functional regions of proteins and also to determine the effects of mutation on protein structure. This may be applied to binding entities and also to the binding sites for such entities. The computational design of proteins and/or protein ligands demands various computational analyses which are necessary to determine whether a molecule is sufficiently similar to the target protein or polypeptide. Such analyses may be carried out in current software applications, such as the Molecular Similarity application of QUANTA (Molecular Simulations Inc., Waltham, Mass.) version 3.3, and as described in the accompanying User's Guide, Volume 3 pages. 134-135. The Molecular Similarity application permits comparisons between different structures, different conformations of the same structure, and different parts of the same structure. Each structure is identified by a name. One structure is identified as the target (i.e., the fixed structure); all remaining structures are working structures (i.e., moving structures). When a rigid fitting method is used, the working structure is translated and rotated to obtain an optimum fit with the target structure.

The person skilled in the art may use one of several methods to screen chemical entities or fragments for their ability to associate with a target. The screening process may begin by visual inspection of the target on the computer screen, generated from a machine-readable storage medium. Selected fragments or chemical entities may then be positioned in a variety of orientations, or docked, within that binding pocket. Useful programs to aid the person skilled in the art in connecting the individual chemical entities or fragments include: CAVEAT (P. A. Bartlett et al, "CAVEAT: A Program to Facilitate the Structure- Derived Design of Biologically Active Molecules". In Molecular Recognition in Chemical and Biological Problems", Special Pub., Royal Chem. Soc, 78, pp. 182-196 (1989)). CAVEAT is available from the University of California, Berkeley, California. 3D Database systems such as MACCS-3D (MDL Information Systems, San Leandro, California). This is reviewed in Y. C. Martin, "3D Database Searching in Drug Design", J. Med. Chem., 35, pp. 2145-2154 (1992); and HOOK (available from Molecular Simulations, Burlington, Mass.). These citations are incorporated by reference. Once the ligand has been optimally selected or designed, as described above, substitutions may then be made in some of its atoms or side groups in order to improve or modify its binding properties. Generally, initial substitutions are conservative, i.e., the replacement group will have approximately the same size, shape, hydrophobicity and charge as the original group. The computational analysis and design of molecules, as well as software and computer systems therefor are described in US Patent No 5,978,740 which is included herein by reference.

Examples

EXAMPLE 1

Primers were purchased from either Sigma Genosys, Pampisford, Cambridgeshire, UK or MWG Biotechnology, Ebersberg, Germany. The rapid DNA ligation kit was obtained from Roche, Lewes, East Sussex, UK. The Quick Change site directed mutagenesis kit and competent E.coli were supplied by Stratagene, Amsterdam, The Netherlands. Penicillin/streptomycin, foetal calf serum (FCS), Dulbecco's Modified Eagle Medium (DMEM), sodium pyruvate, geneticin (G418), LipofectAMINE and the mammalian expression vector pcDNA3 were all obtained from Invitrogen, Paisley, UK. Fluo-3 acetoxymethyl ester was purchased from Invitrogen, Paisley, UK. The rabbit anti-capsaicin receptor polyclonal antibody was obtained from Chemicon International, Hampshire, UK. All other reagents were obtained from Sigma Aldrich unless stated otherwise. Cloning and Expression of rTRPVI and h TRPV1

Using a PCR technique, reading frames for wt-rTRPV1 and wt-hTRPV1 were cloned from a rat dorsal root ganglia cDNA library or MRC5 cDNA respectively, before ligation into the mammalian expression vector pcDNA3 (Invitrogen). The cloned PCR products were sequenced and compared to the published sequences, accession number AF029310 and AY131289 respectively. The LipofectAMINE^® method was employed for transfection of rTRPVI and hTRPVI into Human Embryonic Kidney cells (HEK293) according to the manufacturers protocol (Gibco). To create a permanently expressing cell line, wt-rTRPV1 transfected HEK cells were subcloned in geneticin (0.6 mg ml^"1) containing medium (DMEM containing 10 % FCS, 100 U ml^"1 penicillin, 100 μg ml^"1 streptomycin, and 250 ng ml^"1 amphotericin B) and propagated for two weeks to allow selection. To obtain a rTRPVI permanently expressing single cell line, transfected cells were plated in 96 well plates (1 cell per well) and colonies grown from single cells were subsequently tested for capsaicin responsiveness by measuring increases in intracellular calcium (see Measurement of Intracellular Calcium). The final clones selected, were taken through three further rounds of single cell cloning to ensure the cell lines were derived from a single cell. Example 2- Measurement of Intracellular Calcium

Calcium signalling was performed using methods based on those by Compton et al (J. Biol. Chem 275, pp39207-39212). Cells at 90% confluence in 75 cm² (approximately 9x10⁶ cells, BD falcon) were washed and harvested with PBS (without calcium or magnesium). Cells were pelleted and resuspended in 1 ml of normal culture medium containing 0.25 mM sulphinpyrazone and 25 μg of Fluo-3 acetoxymethyl ester (Fluo-3 AM) in DMF. The cells were then incubated at room temperature for 25 minutes whilst gently shaking, to allow the fluorescent probe to be taken up by the cells. The cells were then washed by centrifugation to remove excess Fluo-3 AM and resuspended in Calcium Assay Buffer (CAB) (150 mM sodium chloride, 250 μM sulphinpyrazone, 3 mM potassium chloride, 10 mM glucose, 20 mM HEPES and 280 mM calcium chloride (CaCI₂6H₂O), pH7.4).

Increases in intracellular calcium levels were measured at room temperature using a fluorospectrometer (Photon Technology International). The fluorospectrometer was set to emit an excitation wavelength of 480 nm and record light emitted with a wavelength of 530 nm. Concentration-effect curves were constructed for each test agonist by adding increasing concentrations of the agonist to separate cell containing cuvettes in half log increments. The increase in fluorescence measured at 530 nm was expressed as a percentage of the maximum fluorescence signal after the addition of 6 μM calcium ionophore (A23187). For inhibition of capsaicin responses, cells were incubated in CAB containing 100μM antihistamine for 4 minutes before the addition of capsaicin or resiniferatoxin.

Dexbrompheniramine Maleate Inhibits hTRPV1-HEK activation by capsaicin and resiniferatoxin. hTRPVI was successfully cloned from MRC5 cDNA and permanently expressed in HEK293 cells. By measuring agonist triggered increases in intracellular calcium, hTRPVI -HEK cells were characterised. The hTRPVI -HEK cells responded in a concentration dependent manner to capsaicin from 300 pM, reaching a maximum by 300 nM with an EC₅₀ of 5.5 nM (Figure 5). hTRPVI -HEK cells also responded in a concentration dependant manner to resiniferatoxin from 3 pM, reaching a maximum by 3 nM with an EC₅₀ of 85 pM (Figure 6). In the mock transfected cell line, the two specific TRPV1 agonists, capsaicin and resiniferatoxin had no observable effect on intracellular calcium levels up to the maximum concentration tested (30 μM and 30 nM respectively, data not shown). Pre-incubation with dexbrompheniramine maleate (4 minutes, 100μM) caused the EC₅₀ values for the hTRPVI -HEK capsaicin and resiniferatoxin concentration effect curves to rise (Figures 5A and B).

Example 3

Dexbrompheniramine Maleate Inhibits rTRPV1-HEK activation by capsaicin and resiniferatoxin. To ensure the antagonism observed in hTRPV1-HEK cells was not species specific, rTRPVI was cloned from rat dorsal root ganglia and permanently expressed in HEK293 cells (rTRPVI -HEK) and Pro5 cells (rTRPV1-Pro5). Again using agonist triggered increases in intracellular calcium, rTRPV1-HEK cells were characterised. In the rTRPV1-HEK cell line, a concentration-effect curve was observed in response to both resiniferatoxin and capsaicin. Resiniferatoxin induced an increase in intracellular calcium from as low as 30 pM, reaching maximal response at 3 nM with an EC₅₀ value of ~168 pM (Figure 6B). Capsaicin induced an increase in intracellular calcium from as low as 10 nM, reaching maximal response at 30 μM with an EC₅Q value of -424 nM (Figure 6A). Like in hTRPV1-HEK cells, pre-incubation with dexbrompheniramine maleate (100 μM) right- shifted the concentration effect curves for capsaicin and resiniferatoxin with EC₅₀ values rising to 762nM and 2.5nM respectively. rTRPV1-Pro5 also responded to capsaicin in a concentration dependent manor from as low as 3 nM reaching a maximum by 300 nM with an EC₅₀ of 20 nM. Following incubation with dexbrompheniramine (100 μM), the rTRPV1-Pro5 capsaicin concentration effect curve showed a slight rightward shift and a reduction in maximal response. The cells responded to capsaicin from 30 nM reaching maximal response at 300 nM with an EC₅₀ of 2OnM.

Example 4

Histamine does not Activate hTRPVL

To determine whether the dexbrompheniramine maleate inhibition of TRPV1 was histamine dependent, the effect of histamine on TRPV1 was investigated. Histamine activated mock transfected and hTRPVI transfected HEK cells equally, from 1μM reaching a maximum at around 100 μM with an EC₅₀ of μM (Figure 7A). Histamine (30 μM) had no additive effect on the capsaicin concentration effect curve (Figure 7B). Example 5

Fexofenadine, Diphenhydramine and Chlorpheniramine

In order to determine whether other antihistamines could antagonise hTRPVI activation by capsaicin and resiniferatoxin, the effect of two further H1 antagonists on hTRPV1-HEK activation were investigated. Following preincubation of hTRPVI -HEK with diphenhydramine hydrochloride (100 μM), the cells responded to capsaicin from 300 pM, reaching a maximum by 30 nM. Diphenhydramine hydrochloride (100 μM) caused a slight reduction in the maximum response to capsaicin and a decrease in EC50 value (3.1 nM) compared to non treated cells (Figure 8A). Fexofenadine also had little effect on hTRPV1-HEK activation by capsaicin. hTRPV1-HEK cells pre-exposed to fexofenadine responded to capsaicin from 1 nM reaching a maximum by 300 nM. Fexofenadine (100 μM) caused a very slight drop in maximal response and EC₅₀ (3.8 nM, Figure 8B).

Preincubation with chlorpheniramine caused a greater reduction in maximal capsaicin response. Following incubation with chlorpheniramine, hTRPVI -HEK cells responded to capsaicin from 300 pM, reaching a maximum by 300 nM with an increase in EC₅₀ value (8.8 nM) compared to non treated cells (Figure 8C).

Example 6

Cultured Rat Dorsal Root Ganglia Neurons

Adult Sprague-Dawley rats were terminally anaesthetized and decapitated. The dorsal root ganglia (DRG) were rapidly removed and placed in collagenase, trypsin and DNase type IV (2 mg/ml, 1 mg/ml, 0.2 mg/ml respective, dissolved in DMEM) for 55 min at 37°C. Ganglia were then placed in 2 ml of cold DMEM supplemented with 10% fetal bovine serum (FBS, heat inactivated), 10% horse serum, 2 mM L-glutamine, 100 U/m! penicillin and 100 mg/ml streptomycin. The ganglia were dissociated into single cells by several passages through a series of syringe needles (23G down to 25G). Finally, the complex of medium and ganglia cells were sieved through a 40 μm filter to remove debris and topped up with 8 ml of DMEM medium and centrifuged. The final cell pellet were re-suspended in DMEM medium (supplemented with 100 ng/ml mouse Nerve Growth Factor (mouse-NGF-7S) and cytosine-b-D-arabino-furanoside free base (ARA-C) 2.5 mM (van der Stelt M et al., 2005). Cells were plated on poly-L-lysine (8.3 mM) and laminin (5 mM) coated 25 mm glass cover slips and kept for 2 days at 37°C in a humidified incubator gassed with 5% CO₂ and air. Measurement of changes in [Ca²⁺J₁

DRG neurons were loaded with Fura-2-AM-ester (3 μM) in Ca²⁺ buffer solution of the following composition (mM): CaCI₂ 1.4; KCI 5.4; MgSO₄ 0.4; NaCI 135; D-glucose 5; HEPES 10 with BSA 0.1%, at pH 7.4, for 35 min at 37⁰C, washed twice with the Ca²⁺ buffer solution and transferred to a chamber on the stage of Nikon eclipse TE300 microscope. The dye was excited at 340 and 380 nm to indicate relative [Ca²⁺]j changes by the F₃₄₀ZF_38O ratio recorded with a dynamic image analysis system (Laboratory Automation 2.0, RCS, Florence, Italy). Various stimuli or their respective vehicles were directly added to the chamber. Cells were pretreated with DXB (30- 300 μM) or its vehicle (phosphate buffer solution) 10 min prior to the challenge with capsaicin (0.1 μM). At the end of each experiment ionomicyn (5 μM) was added to chamber. Variation in [Ca²⁺]) was expressed as percentage of the maximum calcium mobilization induced by ionomycin (see Figure 9). Example 6 indicates the action of dexbrompheniramine on TRPV1 in an alternative cell system.

Example 7

Clinical Effects of Dexbrompheniramine

Dexbrompheniramine was administered to 79 chronic cough patients suffering from treatment resistant chronic cough of a wide variety of causes including gastro-oesophageal reflux, asthma and idiopathic (not PNDS). Cough was abolished in 50 out of 79 and mean cough scores reduced from 7.6 out of 10 to 4.8. The subject matter of the following paragraphs also forms part of the present invention:

1. The use of dexbrompheπiramine, or a structural variant thereof, for the manufacture of a medicament for the treatment of diseases or conditions that would benefit from inhibition of a calcium ion channel receptor polypeptide encoded by a nucleic acid molecule selected from the group consisting of.

i) a nucleic acid molecule comprising a nucleic acid sequence as represented in

Figure 1;

2. Dexbrompheniramine, or a structural variant thereof, for use in the treatment of diseases or conditions that would benefit from calcium ion channel receptor polypeptide inhibition.

3. Use according to paragraph 1 or 2 wherein dexbrompheniramine is provided as dexbrompheniramine maleate.

4. Use according to any of paragraphs 1-3 wherein said disease or condition is a disease or condition that results in pain and administration of dexbrompheniramine alleviates said pain.

5. Use according to paragraph 4 wherein said disease or condition is selected from the group consisting of: chronic pain, neuropathic pain, post operative pain, rheumatoid pain, osteoarthritic pain, back pain, visceral pain, cancer pain, neuralgia, migraine, neuropathies, diabetic neuropathy, sciatica, HlV related neuropathty, post herpetic neuralgia, fibromyalgia, nerve fibre injury, ischaemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, inflammation, inflammatory disorders, inflammatory bowel disease, cystitis, burns and psoriasis. 6. Use according to any of paragraph 1-5 wherein said medicament includes at least one further therapeutic agent.

7. Use according to paragraph 6 wherein said therapeutic agent is a steroid.

8. Use according to paragraph 7 wherein said steroid is a corticosteroid.

9. Use according to any of paragraphs 1-8 wherein said medicament is combined with at least one analgesic.

10. A combined pharmaceutical composition comprising dexbrompheniramine, or a structural variant thereof and at least one therapeutic agent.

11. A preparation according to paragraph 10 wherein said agent is a steroid.

12. A preparation according to paragraph 11 wherein said steroid is a corticosteroid.

13. A preparation according to paragraph 7 wherein said pharmaceutical composition comprises dexbrompheniramine and an analgesic.

14. A preparation according to paragraph 13 wherein said analgesic is a non-steroidal antiinflammatory drug.

15. A medicament or combined preparation according to any of paragraph 1-14 wherein said medicament or preparation includes a carrier, adjuvant or excipient. 16. The use of dexbrompheniramine, or a structural variant thereof, for the manufacture of a medicament for the treatment of a cough that is not caused by post nasal drip syndrome.

17. Use according to paragraph16 wherein said cough is an acute viral cough.

18. Use according to paragraph 16 wherein said cough is the result of gastro-oesophageal reflux.

19. Use according to paragraph 16 wherein said cough is the result of asthma.

20. Use according to any of paragraphs 1-15 wherein said medicament or preparation is provided as a cream adapted for topical application.

21. A wound dressing that includes dexbrompheniramine, or a structural variant thereof.

22. A dressing according to paragraph 21 wherein dressing is a bandage or plaster.

23. A dressing according to paragraph 21 wherein said wound dressing is a hydrogel.

24. A method to administer analgesia to a subject in need of pain relief comprising administering a medicament or pharmaceutical composition according to any of paragraphs 1-15 to said subject.

25. A method to treat a cough wherein said cough is not caused by post nasal drip syndrome comprising administering a medicament or pharmaceutical composition according to any of paragraphs 1-15 to a subject in need of treatment.

26. A method according to paragraph 25 wherein said cough is an acute viral cough.

27. A method according to paragraph 25 wherein said cough is the result of gastro- oesophageal reflux.

28. A method according to paragraph 25 wherein said cough is the result of asthma.

24. A method according to any of paragraphs 24-28 wherein said subject is human.

30. A method according to any of paragraphss 24-28 wherein said subject is a non-human mammal.

31. A method according to paragraph 30 wherein said non-human mammal is a livestock species.

32. A method according to paragraph 30 wherein said non-human mammal is a companion animal.

33. A method according to any of paragraphs 24-28 wherein said subject is bird species. 34. A method to administer analgesia to a subject in need of pain relief comprising topically applying a wound dressing according to any of paragraphs 21-23 to a wound.

35. A method according to paragraph 34 wherein said wound is a burn or scold.

36. A method according to paragraph 34 wherein said wound is a contusion.

37. A method according to paragraph 34 wherein said wound is an ulcer.

38. A method according to paragraph 34 wherein said wound is a post-operative wound.

39. A screening assay for the identification of agents that antagonise the activity of a calcium ion receptor comprising:

i) forming a preparation comprising a polypeptide encoded by a nucleic acid molecule selected from the group consisting of: a) a nucleic acid molecule comprising a nucleic acid sequence as represented in Figure 1;

ii) determining the effect, or not, of said candidate agent on the activity of said calcium ion receptor.

40. A method according to paragraph 39 wherein the effect of said candidate agent is compared in the presence of an agonist that activates said calcium ion receptor.

41. A method according to paragraph 39 or 40 wherein said calcium ion receptor is expressed by a cell.

42. A method according to paragraph 41 wherein said cell is a mammalian cell.

43. A method according to paragraph 42 wherein said mammalian cell is a human cell.

44. A method according to any of paragraphs 39-43 wherein said cell is transfected with a nucleic acid molecule encoding a polypeptide that is a calcium ion channel receptor.

45. A method according to paragraph 44 wherein said polypeptide receptor is encoded by a nucleic acid molecule as represented in Figure 1.

46. A method according to any of paragraphs 39-45 wherein said candidate agent is based on the structure presented in Figure 4.

47. A method to determine the ligand binding activity of a molecule to associate with a calcium ion channel receptor polypeptide comprising the steps of:

i) providing computational means to perform a fitting operation between said molecule and a polypeptide defined by the amino acid sequence in Figure 2; and ii) analysing the results of said fitting operation to quantify the association between the molecule and the calcium ion channel receptor polypeptide.

48. The use of dexbrompheniramine, or a structural variant thereof, in the treatment of disease conditions that result from the over-expression of a nucleic acid molecule wherein said nucleic acid molecule selected from the group consisting of:

i) a nucleic acid molecule comprising a nucleic acid sequence as represented in

Figure 1 ;

49. Use according to paragraph 48 wherein said disease condition is an inflammatory disease condition that results from over-expression of a calcium ion channel receptor. 50. A screening assay for the identification of an agent having potential activity for treating a disorder which would benefit from inhibition of a member of the TRP protein superfamily, comprising determining or measuring the effect, or not, of a candidate agent on the activity of the member of the superfamily.

51. A screening assay for the identification of an agent having potential activity for treating epilepsy, a urinary tract disorder, a bowel disorder or pain, comprising determining or measuring the effect, or not, of a candidate agent on the activity of the member of the superfamily.

Claims

1. Use of an active agent selected from dexbrompheniramine and structural variants thereof, for the manufacture of a medicament for the treatment of a disease or condition that would benefit from inhibition of a calcium ion channel receptor.

2. The use of claim 1 , wherein the calcium ion channel receptor is TRPV1.

3. The use of claim 1 or claim 2, wherein the active agent is a histamine H₁ receptor antagonist of the alkylamine class.

4. The use of claim 1 or claim 2, wherein the active agent is a pheniramine or a prodrug or pharmaceutically acceptable salt thereof.

5. The use of claim 1 or claim 2, wherein the active agent is pheniramine which is unsubstituted or substituted by one or more substituents selected from the group consisting of trifluoromethyl and species having 1, 2 or 3 non-hydrogen atoms and optionally one or more hydrogen atoms, or a prodrug or pharmaceutically acceptable salt thereof.

6. The use of claim 5 or claim 6 wherein the pheniramine is a D-pheniramine.

7. The use of claim 5 or claim 6 wherein the one or more substituents are selected from the group consisting of halogen, hydroxy, methyl, trifluoromethyl, formyl (-CHO), methoxy, amino, methylamino, dimethylamino, amidino, hydroxylamino, cyano, thiol and methylthio.

8. The use of claim 7 wherein the one or more substituents are selected from chlorine and bromine.

9. The use of claim 8 wherein the one or more substituents are bromine.

10. The use of any of claims 4 to 9 wherein the pheniramine is substituted by a single substituent.

11. The use of any of claims 4 to 10 wherein the pheniramine is substituted at the 4-position of its phenyl group.

12. The use of claim 1 wherein the active agent has the formula

wherein X is O or CH₂,

A and B are each the same or different and an aromatic or heteroaromatic 6-membered ring, A and B each independently unsubstituted or substituted unsubstituted or substituted by one or more substituents selected from the group consisting of trifluoromethyl and species having 1, 2 or 3 non-hydrogen atoms and optionally one or more hydrogen atoms, and

* indicates a chiral centre of (R) or (S) configuration.

13. The use of claim 12 wherein the one or more substituents are selected from the group consisting of halogen, hydroxy, methyl, trifluoromethyl, formyl (-CHO), methoxy, amino, methylamino, dimethylamino, amidino, hydroxylamino, cyano, thiol and methylthio.

14. The use of claim 13 wherein the one or more substituents are selected from chlorine and bromine.

15. The use of claim 14 wherein the one or more substituents are bromine.

16 The use of any of claims 12 to 15 wherein exactly one of A and B is substituted by a single substituent.

17. The use of any of claims 12 to 16 wherein at least one of A and B is phenyl.

18. The use of any of claims 12 to 16 wherein at least one of A and B is substituted phenyl.

19. The use of any of claims 12 to 18 wherein at least one of A and B is substituted at its A- position.

20. The use of any of claims 12 to 19 wherein one of A and B is substituted or unsubstituted phenyl and the other of A and B is substituted or unsubstituted pyridinyl.

21. The use of claim 20 wherein the pyridinyl group is pyridin-2-yl.

22. The use of claim 20 or claim 21 wherein the pyridinyl group is unsubstituted.

23. The use of any of claims 19 to 21 wherein the phenyl group is substituted solely at the A- position.

24. The use of claim 22 wherein the substituent is bromine.

25. The use of claim 22 wherein the substituent is chlorine.

26. The use of any of claims 11 to 25 wherein the chiral centre is of (S)-configuration.

27. The use of any of claims 11, 17 and 26 wherein neither of A and B is substituted.

28. The use of claim 1 wherein the active agent is selected from pheniramine, chlorpheniramine, dexchlorpheniramine, brompheniramine, dexbrompheniramine and triprolidine and prodrugs and pharmaceutically acceptable salts thereof.

29. The use of claim 1 wherein the active agent is dexbrompheniramine or a prodrug or pharmaceutically acceptable salt thereof.

30. The use of any of claims 1 to 29, wherein the medicament is for administration with at least one other pharmaceutically active agent.

31. The use of any of claims 1 to 29, wherein the medicament comprises at least one other pharmaceutically active agent.

32. The use of claim 30 or claim 31, wherein the at least one other pharmaceutically active agent is an analgesic and/ or an anti-inflammatory agent and/or an anti-depressant, optionally wherein the analgesic is selected from codeine, morphine, aspirin, paracetamol, gabapentin, sumtriptan and amitriptyline.

33. The use of any of claims 1 to 29 or claim 32, wherein the medicament or a combination of the medicament and the at least one other pharmaceutically active agent is for the treatment of pain, wherein said treatment reduces or alleviates pain in a subject.

34. The use of claim 30 or claim 31, wherein the at least one other pharmaceutically active agent is an anti-epilepsy drug, optionally wherein the anti-epilepsy drug is selected from carbamazepine, gabapentin and phenytoin.

35. The use of any of claims 1 to 29 or claim 34, wherein the medicament or a combination of the medicament and the at least one other pharmaceutically active agent is for the treatment of epilepsy.

36. The use of claim 30 or claim 31, wherein the at least one other pharmaceutically active agent is a urinary anti-spasmodic, wherein the urinary anti-spasmodic is selected from darifenacin, emepronium, flavoxate, meladrazine, oxybutynin, propiverine, solifenacin, terodiline, tolterodine and trospium.

37. The use of any of claims 1 to 29 or claim 36, wherein the medicament or a combination of the medicament and the at least one other pharmaceutically active agent is for the treatment of urinary tract disorders e.g. bladder over-activity.

38. The use of claim 30 or claim 31, wherein the at least one other pharmaceutically active agent is an anti-inflammatory agent for the treatment of bowel disorders, wherein the anti- inflammatory is selected from mesalazine and hyoscine.

39. The use of any of claims 1 to 29 or claim 38, wherein the medicament or a combination of the medicament and the at least one other pharmaceutically active agent is for the treatment of bowel disorders e.g. irritable bowel syndrome or inflammatory bowel syndrome.

40. The use of any of claims 1 to 29 or claim 30 or claim 31, wherein the medicament or a combination of the medicament and the at least one other pharmaceutically active agent is for the treatment of an inflammatory disorder.

41. The use of claim 40, wherein the inflammatory disorder is selected from asthma, arthritis, rheumatoid arthritis, inflammatory bowel disorder and combinations thereof.

42. The use of claim 30 or claim 31, wherein the at least one other pharmaceutically active agent is selected from codeine, morphine, dextromethorphan and guaiphenesin.

43. The use of any of claims 1 to 29 or claim 42, wherein the medicament or a combination of the medicament and the at least one other pharmaceutically active agent is for the treatment of cough, that is not caused by post nasal drip syndrome.

44. Use according to claim 43, wherein said cough is selected from an acute viral cough, a cough which is the result of gastro-oesophageal reflux and a cough which is the result of asthma.

45. The use of any preceding claim wherein the calcium ion channel receptor comprises a calcium ion channel receptor polypeptide encoded by a nucleic acid molecule selected from the group consisting of: i) a nucleic acid molecule comprising a nucleic acid sequence as represented in Figure 1; ii) a nucleic acid molecule that hybridizes to a nucleic acid molecule in (i) above and which encodes a calcium ion channel receptor; iii) a nucleic acid molecule comprising a nucleic acid sequence which is degenerate as a result of the genetic code to the sequences defined in (i) and (ii) above.

46. A product for use as a pharmaceutical comprising an active agent as defined in any of claims 1 to 29 and at least one other pharmaceutically active agent, wherein the at least one other pharmaceutically active agent is not pseudoephidrine, phenylephrine, or dextromethorphan.

47. The product of claim 46, wherein the active agent is dexbrompheniramine.

48. The product of claim 46 or claim 47, wherein the product comprises from about 6 to about 24mg of the active agent.

49. The product of any of claims 46 to 48, wherein the at least other pharmaceutically active agent is selected from codeine, morphine, dextromethorphan, guaiphenesin, amitriptyline, aspirin, paracetamol, gabapentin, sumtriptan, carbamazepine, phenytoin, oxybutynin, tolterodine, mesalazine, hyoscine, montelukast, prednisolone, ibuprofen and leflunomide.

50. A screening assay for the identification of agents that antagonise the activity of a calcium ion receptor comprising:

a) a nucleic acid molecule comprising a nucleic acid sequence as represented in Figure 1 ;

51. The assay of claim 50 wherein the effect of said candidate agent is compared in the presence of an agonist that activates said calcium ion receptor.

52. The assay of claim 50 or claim 51 wherein said calcium ion receptor is expressed by a cell, wherein optionally said cell is a mammalian cell, wherein further optionally the mammalian cell is a human cell.

53. The assay of any of claims 50 to 52 wherein said cell is transfected with a nucleic acid molecule encoding a polypeptide that is a calcium ion channel receptor.

54. The assay of any of claims 50 to 53 wherein said polypeptide receptor is encoded by a nucleic acid molecule as represented in Figure 1.

55. The assay of any of claims 50 to 54, wherein said candidate agent is based on the structure presented in Figure 4.

56. A screening assay for the identification of an agent having potential activity for treating a disorder which would benefit from inhibition of a member of the TRP protein superfamily, comprising determining or measuring the effect, or not, of a candidate agent on the activity of the member of the superfamily.

57. A screening assay for the identification of an agent having potential activity for treating epilepsy, a urinary tract disorder, a bowel disorder or pain, comprising determining or measuring the effect, or not, of a candidate agent on the activity of the member of the superfamily.

58. Use of a compound of formula (III) or a prodrug or pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a disorder which would benefit from inhibition of a member of the TRP protein superfamily:

D

-(W)₁- (CH₂)_m—R¹⁰ (III) wherein: the symbol * designates a chiral centre of (R)- or (S)- configuration; D and E are the same or different and are each a substituted or unsubstituted ring moiety, and wherein D and E are optionally joined together as part of a fused ring system;

W is O, S(O)_t where t is 0, 1 or 2, or CH₂, I is 0 or 1 , m is 0, 1 ,2, 3 or 4, e.g. 0, 1 or 2,

R¹⁰ is a group of Formula (IV):

wherein V is a bond, -NR¹³- or, when not linked to SO or SO₂, is -C(O)-;

R¹³ is selected from R¹⁸, -OR¹⁹, -C(O)R¹⁸, -C(O)OR¹⁸, -OC(O)R¹⁸, -N(R¹⁸)R¹⁹, - C(O)N(R¹⁹)R²⁰, -S(O)₁R¹⁸ and -C(R¹⁸J₃;

R¹⁴ and R¹⁵ are the same or different and selected from R¹⁸, -OR¹⁸, -C(O)R¹⁸, -C(O)OR¹⁸, ' -OC(O)R¹⁸, -N(R¹⁸)R¹⁹, -C(O)N(R¹⁹JR²⁰, -S(O),R¹⁸ and -C(R¹⁸)₃; or R¹⁴ and R¹⁵ taken together form =NR²⁰, =O or =S;

R¹⁶ and R¹⁷ are the same or different and selected from hydrogen, C_1-6 alkyl, -OR²¹ and -NR¹⁸R¹⁹; or R¹⁶ and R¹⁷ together form a ring which is unsubstituted or substituted;

R¹⁸ and R¹⁹ are the same or different and selected from hydrogen, R²¹, hydrocarbyl optionally su ibbssttiituted with 1, 2, 3, 4 or 5 R²¹; and heterocyclyl optionally substituted with 1 , 2, 3, 4 or 5 R²¹;

R²⁰ is hydrogen or C_1-6 alkyl; and each R²¹ is independently selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, oxo, amidino, -B(OH)₂, =NR¹², -OR¹², -C(O)R¹², -C(O)OR¹², -OC(O)R¹², -N(R¹²)R¹³, - C(O)N(R¹²)R¹³, -S(O)|R¹², -C(R¹²J₃ and R¹⁴.

59. Use of a compound as defined in claim 58 or a prodrug or pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating for treating a neural disorder, epilepsy, a urinary tract disorder, a bowel disorder or pain.