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WO2008005407A2 - Récepteurs associés à une amine de trace dans l'épithélium olfactif - Google Patents

Récepteurs associés à une amine de trace dans l'épithélium olfactif Download PDF

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WO2008005407A2
WO2008005407A2 PCT/US2007/015310 US2007015310W WO2008005407A2 WO 2008005407 A2 WO2008005407 A2 WO 2008005407A2 US 2007015310 W US2007015310 W US 2007015310W WO 2008005407 A2 WO2008005407 A2 WO 2008005407A2
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taar
subject
receptor modulator
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olfactory epithelium
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WO2008005407A3 (fr
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Stephen D. Liberles
Linda Buck
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Fred Hutchinson Cancer Center
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Fred Hutchinson Cancer Center
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose

Definitions

  • the present invention concerns products, formulations and methods that are indicated by the discovery of trace amine-associated receptors (TAARs) in the olfactory epithelium.
  • TAARs trace amine-associated receptors
  • the first step in odor perception is the detection of odorants by G protein-coupled odorant receptors (ORs) on olfactory sensory neurons (OSNs) in the nasal olfactory epithelium (OE) (Buck & Axel (1991) Cell 65:175-87; Kandel, et al. (2000) Principles of Neural Science, McGraw-Hill, New York; Buck (2000) Cell 100:61 1-8).
  • OSNs transmit signals to the brain, thereby generating odor perceptions (Kandel, et al. (2000) Principles of Neural Science, McGraw-Hill, New York; Shepherd, et al. (2004) In: The Synaptic Organization of the Brain, ed. Shepherd, G.
  • Each OSN expresses a single functional OR gene (Malnic, et al. (1999) Cell 96:713-23) and OSNs with the same OR are randomly dispersed within one OE zone (Vassar, et al. (1993) Cell 74:309-18; Ressler, et al. (1993) Cell 73:597-609). Consistent with their ability to detect and discriminate diverse odorants, mammals have as many as 1000 different ORs that vary in protein sequence (Zhang & Firestein (2002) Nat. Neurosci. 5:124- 33; Young & Trask (2002) Hum. MoI. Genet.
  • MHC major histocompatibility complex
  • the present invention provides, in a method of administering a TAAR receptor modulator to a subject, the improvement comprising topically administering an effective amount of said TAAR receptor modulator to the olfactory epithelium of said subject.
  • a further aspect of the invention is a method of treating a subject in need thereof, comprising topically administering an effective amount of a TAAR receptor modulator to the olfactory epithelium of said subject.
  • a further aspect of the invention is a topical formulation for the administration of a
  • TAAR receptor modulator to the olfactory epithelium of a subject comprising, consisting of, or consisting essentially of a TAAR receptor modulator in combination with a topical carrier composition.
  • the formulation (and the corresponding carrier) may be in any suitable form, including but not limited to pharmaceutical, cosmetic, fragrance, perfume, etc.
  • a further aspect of the invention is a delivery device containing a topical formulation as described above.
  • a further aspect of the invention is a method of repelling an animal, comprising applying to a subject or a site from which said animal is to be repelled an effective amount of a TAAR receptor modulator.
  • a further aspect of the invention is a repellant formulation comprising an effective amount of a TAAR receptor modulator in a suitable carrier.
  • a further aspect of the invention is a delivery device containing a repellant formulation as described above.
  • a further aspect of the invention is a method of attracting an animal, comprising applying to a subject or a site from which said animal is to be attracted an effective amount of a TAAR receptor modulator.
  • a further aspect of the invention is a attractant formulation comprising an effective amount of a TAAR receptor modulator in a suitable carrier.
  • a further aspect of the invention is a delivery device containing an attractant formulation as described above.
  • a further aspect of the present invention is the use of an active agent or TAAR receptor modulator as described herein for the preparation of a medicament, fragrance, formulation or the like useful for carrying out a method as described herein.
  • an active agent or TAAR receptor modulator as described herein for the preparation of a medicament, fragrance, formulation or the like useful for carrying out a method as described herein.
  • Figure 1 shows that TAARs are specifically expressed in subsets of OSNs.
  • Figure IA Digoxigenin-labeled cRNA probes for different mouse Taar genes were hybridized to coronal sections of mouse OE. Each Taar probe hybridized to mRNA in a small percentage of OSNs scattered in selected OE regions. The Taarld probe hybridizes with 5 different Taar7 subfamily members and labels more OSNs, as well as more OE regions, than the others. Scale bar 1 mm.
  • FIG. IB qPCR analysis was performed in triplicate (+/- s.d.) using primers specific for 9 mouse Taar genes, two mouse OR genes (OR-M5 (MOR255-2) and OR-EG (MORI 74-9)) and actin, and cDNAs prepared from various mouse tissues (A- heart, B- spleen, C- intestine, D-liver, E-brain, F-vomeronasal organ, G- OE, H- taste papillae, I- olfactory bulb, J- testis, K- OE (repeat). Y-axis for each graph is cDNA copies per 10 ng RNA. All of the Taar genes except Taarl appear to be selectively expressed in the OE (filled bars).
  • FIG. 2 shows that each Taar gene defines a unique subset of OSNs.
  • OE sections were hybridized with differentially labeled pairs of probes visualized as green versus red fluorescence signals.
  • Probes for different Taars label different OSNs ( Figures IA and IB), while probes for the same Taar label the same cells ( Figure 1C).
  • Figure ID In transgenic mice expressing mOR28 in 50-90% of OSNs, different OSNs are labeled for MOR28 and Taar ⁇ ( Figure ID) and in non-transgenic mice, different OSNs hybridize to a K20 (MOR227-2) OR probe and a mixed Taar probe (Figure IE).
  • OSNs labeled by a Taar7f probe are also labeled by a Ga 0If probe ( Figure IF).
  • Scale bars Figure IA, 250 urn, Figure 1B-1F, 50 um.
  • FIG 3 shows that TAARs recognize volatile amines.
  • HEK293 cells were co- transfected with TAAR and CRE-SEAP (secreted alkaline phosphatase fused to cAMP response elements) expression vectors, incubated with different compounds, and then assayed for SEAP activity. Triplicate results are shown +/- s.d. for compounds recognized by the indicated TAARs.
  • Figure IA The different TAARs displayed different ligand specificities, but all recognized volatile amines. Test compounds were used at 5 ⁇ M (D), 10 ⁇ M (B, C, E), or 20 ⁇ M (F, G, H).
  • Figure IB Dose-response experiments show selectivity of mTAAR5 for a tertiary amine and of mTAAR3 for several primary amines, but not the corresponding alcohols.
  • Figure 4 shows that mTAAR5 is activated by urine from sexually mature male mice.
  • HEK293 cells were co-transfected with mTAAR5 and CRE-SEAP expression vectors, incubated with diluted urine from different sources, and then assayed for SEAP activity. Triplicate results are shown +/- s.d.
  • mTAAR5 -expressing cells responded strongly to male mouse urine, but only weakly to female mouse urine, and not at all to human urine (Figure IA).
  • Urine from both BALB/c and C57BL/6 strain male mice produced responses (Figure IA).
  • the activating substance(s) in male mouse urine was not evident until puberty (at ⁇ 1 month of age) ( Figure IB).
  • Differences in mTAAR5 responses to urine from male, female, and prepubescent mice are emphasized by experiments using different concentrations of urine from each (Figure 1C).
  • Male mouse urine is about 30- fold more effective than female urine.
  • Subjects as used herein include human subjects, as well as animal subjects such as dogs or cats for veterinary purposes, as well as other animal (typically mammalian) subjects such as sheep, cows, horse, pig, goat, deer, coyote, wolf, etc. for animal attractant and repellent purposes.
  • animal subjects or animals may be male or female and at any stage of development, including but not limited to neonate, infant, juvenile, adolescent, adult, and geriatric subjects.
  • Trace amine associated receptor refers to a family of G-protein coupled receptors, some of which bind and are activated by biogenic trace amines, and some of which were previously known as “octopamine receptors”. Examples of trace amine associated receptors are summarized in Table 1.
  • PNR putative neurotransmitter receptor
  • trace amine associated receptors or TAARs Additional examples of trace amine associated receptors or TAARs are set forth by
  • TAAR receptor modulators are known, or can be identified by binding assays with the receptors described above in accordance with known techniques or variations thereof that will be apparent to those skilled in the art in light of the present disclosure.
  • a TAAR modulator of the invention may be a compound identified or produced by the process of screening a candidate compound (such as an amine compound) for activity in binding (particularly specific binding) to a TAAR receptor, the presence of binding of said candidate compound indicating said candidate compound is a TAAR receptor modulator.
  • Binding may be determined by any suitable technique, including competitive binding assays in which the binding of a known (and, e.g., detectably labelled) binding partner of the TAAR receptor is displaced, assays in which the TAAR receptor is coupled to a native or alternate downstream effector molecule such as an enzyme ⁇ e.g., through the G protein in a cell or cell membrane preparation, such as described in U.S. Patent No.
  • the screening assay is carried out by contacting the compound to be screened to the TAAR receptor in volatilized or gas form.
  • an "artificial nose" may be created, in like manner as previously described
  • TAAR receptor utilized as the receptor molecule or that is immobilized on the substrate to form an individual sensor element.
  • individual sensor elements carrying a particular TAAR receptor may be utilized individually, or utilized in combination with other sensor elements carrying other TAAR receptors, or indeed other sensory/binding molecules.
  • Active agents that may be used to carry out the present invention are, in general, TAAR receptor modulators (particularly TAAR receptor agonists but in some embodiments also including TAAR receptor antagonists).
  • Such compounds are generally ligands which compete for binding with the endogenous ligand (if known) or other specific binding partner of a TAAR.
  • Such compounds generally include amines such as tertiary amines and amino acid derivatives. Particular examples include but are not limited to tyramine, ⁇ - phenethylamine and analogs or derivatives thereof, octopamine, dopamine, and thyronamine and analogs or derivatives thereof. See, e.g., Lewin (2006) AAPS J. 8:E128-45; Scanlan, et al., Thyronamine derivatives and analogs and methods of use thereof, U.S. Patent No.
  • active compounds include thyronamine analogs of formula:
  • Ri and R 2 are: H, lower alkyl, cyclic alkyl, or benzyl; Y and Z are: CH 2 , CHR, C(R) 2 , CHOH, or CHOR; R 3 , R 4 , R 5 , and R 7 are: H, I, Br, Cl, F, CH 3 , CF 3 , CN, OCH 3 , CH 2 CH 3 , or CH(CH 3 ) 2 ; R 6 is: OH, H, SH, F, CF 3 , lower alkyl, NH 2 , NHR, or N(R) 2 ; X is: O, S, SO, SO 2 , NH, NR, CH 2 , CHR, C(R) 2 , or CH 2 O; and R is lower alkyl. See U.S. Patent No. 6,
  • agonists include, but are not limited to:
  • N,N-dimethyloctylamine (1-3 uM); N,N,O-trimethylserotonin, otherwise known as 5-methoxy, N,N-dimethyltryptamine (1-3 uM) (a natural metabolite of serotonin found in urine); N,N-dimethylphenylethylamine (3 uM); N-methylpyrrolidine; and N 5 N- dimethylbutylamine;
  • Taar7f N,N-dimethyloctylamine; N,N dimethylcyclohexylamine; and N- methylpyrrolidine.
  • TAAR7 subfamily members are activated by tertiary amines, including but not limited to (for mTAAR7b, MTAAR7e; MTAAR:
  • tertiary amines are example active agents of the present invention.
  • examples of tertiary amines include but are not limited to compounds of the formula:
  • each R is independently selected from alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, or arylalkyl.
  • Alkyl as used herein alone or as part of another group, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.
  • Lower alkyl as used herein, is a subset of alkyl, in some embodiments preferred, and refers to a straight or branched chain hydrocarbon group containing from 1 to 4 carbon atoms.
  • Representative examples of lower alkyl include, but are not limited to, methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, and the like.
  • akyl or “loweralkyl” is intended to include both substituted and unsubstituted alkyl or loweralkyl unless otherwise indicated and these groups may be substituted with groups selected from halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocyclolalkyloxy, mercapto, alkyl-S(O) m , haloalkyl-S(O) m , alkenyl-S(O) m , alkynyl-S(O) m , cycloalkyl,
  • alkenyl refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms (or in loweralkenyl 1 to 4 carbon atoms) which include 1 to 4 double bonds in the normal chain.
  • alkenyl include, but are not limited to, vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4- pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2,4-heptadiene, and the like.
  • alkenyl or “loweralkenyl” is intended to include both substituted and unsubstituted alkenyl or loweralkenyl unless otherwise indicated and these groups may be substituted with groups as described in connection with alkyl and loweralkyl above.
  • Alkynyl refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms (or in loweralkynyl 1 to 4 carbon atoms) which include 1 triple bond in the normal chain.
  • Representative examples of alkynyl include, but are not limited to, 2-propynyl, 3-butynyl, 2- butynyl, 4-pentynyl, 3- pentynyl, and the like.
  • alkynyl or “loweralkynyl” is intended to include both substituted and unsubstituted alkynyl or loweralknynyl unless otherwise indicated and these groups may be substituted with the same groups as set forth in connection with alkyl and loweralkyl above.
  • Haloalkyl as used herein alone or as part of another group, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, and the like.
  • Cycloalkyl as used herein alone or as part of another group, refers to a saturated or partially unsaturated cyclic hydrocarbon group containing from 3, 4 or 5 to 6, 7 or 8 carbons (which carbons may be replaced in a heterocyclic group as discussed below).
  • Representative examples of cycloalkyl include, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. These rings may be optionally substituted with additional substituents as described herein such as halo or loweralkyl.
  • the term "cycloalkyl” is generic and intended to include heterocyclic groups as discussed below unless specified otherwise.
  • Heterocyclic group refers to an aliphatic (e.g., fully or partially saturated heterocyclo) or aromatic (e.g., heteroaryl) monocyclic- or a bicyclic-ring system.
  • Monocyclic ring systems are exemplified by any 5 or 6 membered ring containing 1, 2, 3, or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur. The 5 membered ring has from 0-2 double bonds and the 6 membered ring has from 0-3 double bonds.
  • monocyclic ring systems include, but are not limited to, azetidine, azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine, oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrazine,
  • Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system as defined herein.
  • Representative examples of bicyclic ring systems include but are not limited to, for example, benzimidazole, benzothiazole, benzothiadiazole, benzothiophene, benzoxadiazole, benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxine, 1,3- benzodioxole, cinnoline, indazole, indole, indoline, indolizine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine, purine, pyranopyridine, quinoline, quinoliz
  • These rings include quatemized derivatives thereof and may be optionally substituted with groups selected from halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocyclolalkyloxy, mercapto, alkyl-S(O) m , haloalkyl-S(O) m , alkenyl- S(O) m , alkynyl-S(O) m , cycloaIkyl-S(O) m , cycloalkylalkyl-S(O) m , ary
  • Aryl refers to a monocyclic carbocyclic ring system or a bicyclic carbocyclic fused ring system having one or more aromatic rings.
  • Representative examples of aryl include, azulenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like.
  • aryl is intended to include both substituted and unsubstituted aryl unless otherwise indicated and these groups may be substituted with the same groups as set forth in connection with alkyl and loweralkyl above.
  • Arylalkyl refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of arylalkyl include, but are not limited to, benzyl, 2- phenylethyl, 3-phenylpropyl, 2-naphth-2-ylethyl, and the like.
  • the active agents are topically administered to the olfactory epithelium of a subject.
  • Topical administration to the olfactory epithelium as used herein means the pharmacological activity of the active compound is at the olfactory epithelium, which then in turn acts by electrochemical signalling to other regions of the brain, and not by transport and binding of the active agents to TAAR receptors beyond the olfactory epithelium and elsewhere in the central nervous system.
  • the active agents are delivered to the olfactory epithelium in a relatively low dose, and/or in a formulation that would effectively prevent the active agents from being systemically administered to the subject or administered to regions of the central nervous system beyond the olfactory epithelium (e.g., free of membrane permeabilizing agents).
  • Suitable carrier compositions and delivery devices are known (see, e.g., U.S. Patent No. 6,824,762 to Haslwanter, et al. and U.S. Patent No. 6,780,398 to Akutsu, et al.).
  • the active agents are administered to the olfactory epithelium of the subject volatilized as a gas (for example, by topically applying a formulation containing the active agent to the skin of, or an article such as a garment worn by, the subject).
  • the active agent is administered to the olfactory epithelium of a subject in the form of fine, solid or liquid, respirable particles (e.g., particles having a size of five microns or less), which particles may optionally include a carrier composition.
  • respirable particles e.g., particles having a size of five microns or less
  • the active agent is administered to the olfactory epithelium of a subject in the form of non-respirable particles (e.g., particles having a size greater than five or ten microns), or as a spray or droplets in combination with a suitable carrier such as an aqueous carrier.
  • a suitable carrier such as an aqueous carrier.
  • the amount of the active agent in the formulation may be quite low, e.g., from 0.01, 0.001, 0.0001 or 0.00001 percent by weight or less; and up to 0.001, 0.01, or 0.1 percent by weight).
  • the amount of active agents in the carrier composition can be quite low, for example, at least about 50 ng/ml, at least about 100 ng/ml, preferably at least about 500 ng/ml, and up to about 1 or 2 ⁇ g/ml. Higher amounts can be utilized when the formulation is applied to a site remote from the olfactory epithelium in a manner such that the active agent reaches the olfactory epithelium in volatilized, or small respirable particle form.
  • disorders that can be treated by the active agents described herein, or with which the active agents described herein can be used as an aid in combination with other treatment regimens include but are not limited to: mood disorders or mood disturbances in general, affective disorders in general, depression, anxiety, stress such as post-traumatic stress disorder, obsessive-compulsive disorders, bulimia, hypertension, anorexia nervosa, panic, social phobia, stuttering, sleep disorders such as insomnia, chronic fatigue, alcohol abuse, appetite disorders, obesity (e.g., as an aid to weight loss), agoraphobia, impaired memory, smoking (e.g., as an aid to smoking cessation), nicotine withdrawal symptoms, premenstrual syndromes such as disturbances of mood and/or appetite associated therewith, and/or depressed mood and/or carbohydrate craving associated therewith, appetite disturbances, disturbances which contribute to recidivism associated with nicotine withdrawal, circadian rhythm disorder, borderline personality disorder, hypochondriasis, late luteal phase dysphoric disorder,
  • active agents are provided in the in the fragrance composition of the subject invention at a concentration of at least about 50 ng/ml, more commonly at least about 100 ng/ml, preferably at least about 500 ng/ml, more preferably at least about 1 ⁇ g/ml, up to about 1 or 2 mg/ml or more.
  • Active compounds as described herein may be incorporated into therapeutic or non- therapeutic fragrance compositions or perfumes, and used in like manner as described in U.S. Patent No. 5,278,141 to Berliner and U.S. Patent No. 5,272,134 to Kirk.
  • such compositions include a mixture of a variety of substances, and may include natural materials of vegetable or animal origin, wholly or partly artificial compounds, or mixtures thereof. Dissolved in alcohol, these mixtures of various volatile fragrant substances release their scents into the air at normal temperatures.
  • compact and cream perfumes are produced by mixing up to 25% fragrance oil with solids such as paraffin or other waxes. The mixtures may be provided in liquid form or in an aerosol container with a suitable aerosol propellant.
  • active agents are provided in the in the fragrance composition of the subject invention at a concentration of at least about 50 ng/ml, more commonly at least about 100 ng/ml, preferably at least about 500 ng/ml, more preferably at least about 1 ⁇ g/ml, up to about 1 or 2 mg/ml or more.
  • Active compounds described herein can be used in attractant and repellent
  • Activity of a particular TAAR receptor modulator as an attractant or repellent will depend upon the species and/or sex of the animal, with active agents that are active as an attractant for some animals being inactive, or active as a repellent, for other animals.
  • Formulations suitable as attractants and repellents can be in any physical form, including both liquid and solid (such as bait granules, collars, building materials, etc.).
  • the formulations can generally comprise the active compound in a suitable effective amount, which may be a relatively small amount given the sensitivity of the TAAR receptors on the olfactory epithelium (e.g., from 0.01, 0.001 , 0.0001 or 0.00001 percent by weight or less, up to 0.1, 1 or 10 percent by weight, or more).
  • identification of the active agents described herein enables the preparation of formulations that contain the active agents in highly concentrated form as compared to what might otherwise be found in the natural state (e.g., from 0.001, 0.01, or 0.1 or percent by weight, up to 1, 10, 20, or 40 percent by weight, or more, or more).
  • the active compounds can be applied to a site, such as a building, building material, collar, article of clothing, trap, or the like, from which the animal is to be attracted or from which the animal is to be repelled.
  • the active compounds can be applied to a body of water, or a particular location in a body of water, to which the animal is to be attracted or from which the animal is to be repelled.
  • Example 1 Identification of a Second Family of Receptors in the Olfactory Epithelium
  • the mammalian olfactory system detects chemicals sensed as odors as well as social cues that stimulate innate responses. Odorants are detected in the nasal olfactory epithelium by the odorant receptor family, whose —1000 members allow discrimination of myriad odorants. It has now been found that a second family of receptors are present in the mouse olfactory epithelium. Genes encoding these receptors, called "trace amine-associated receptors" (TAARs), are present in human, mouse, and fish. Like odorant receptors, individual mouse TAARs are expressed in unique subsets of neurons dispersed in the epithelium. Strikingly, at least three mouse TAARs recognize volatile amines found in urine.
  • TAARs trace amine-associated receptors
  • OE cells were treated with a fluorescent ⁇ - galactosidase substrate, fluorescein di-( ⁇ -galactopyranoside) (Fiering, et al. (1991) Cytometry 12:291-301), wherein labeled cells were isolated by fluorescence-activated cell sorting.
  • a fluorescent ⁇ - galactosidase substrate fluorescein di-( ⁇ -galactopyranoside)
  • labeled cells were isolated by fluorescence-activated cell sorting.
  • cDNA was prepared, which was then used in real-time PCR (qPCR) reactions with primers matching GPCRs not previously implicated in odor, pheromone, or taste detection (Vassilatis, et al. (2003) Proc. Natl. Acad. Sci. USA 100:4903- 8).
  • cDNAs encoding individual GPCRs were quantified using standard curves obtained from qPCR reactions with titrations of mouse genomic DNA.
  • TAARs are unrelated to ORs, with their closest relatives being receptors for biogenic amines, such as serotonin and dopamine.
  • mouse TAARl is 33% identical to the mouse 5HT-4 serotonin receptor, but only 16% identical to the most closely related mouse OR (MORI 20-3), and it lacks sequence motifs characteristic of ORs.
  • TAARs have been proposed to function as receptors for trace amines (e.g., tyramine, octopamine) in the brain (Borowsky, et al. (2001) Proc. Natl. Acad. ScL USA 98:8966-71), no evidence for Taar gene expression was obtained in any tissue except the OE, including the brain, even though high level expression of several biogenic amine receptors was detected in brain. It could be that TAARs are expressed in small subsets of brain neurons below the detection level of these assays ( ⁇ 100 copies of mRNA per cell in 60,000 brain cells).
  • the Taarl gene is reportedly expressed in mouse and human brain and the Taar9 gene in human pituitary (and skeletal muscle; Vanti, et al. (2003) Genomics 82:531-6), but qPCR reactions with 50-fold more mouse brain cDNA (detection threshold: -100 copies of mRNA per cell in 1200 cells) also failed to reveal the expression of either Taarl or Taar9 in mouse brain. Consistent with these results, no ESTs were listed for any mouse Taar gene in the NCBI Unigene database and, except for two ESTs from stomach ⁇ Taarl) and eye (Taar2), all ESTs listed for human Taar genes came from sequence collections derived in part from genomic DNA.
  • TAARs may be expressed primarily or exclusively in the OE.
  • the expression of some TAARs in small subsets of cells in other tissues cannot be excluded.
  • Zebrafish reportedly has 57 intact Taar genes (Gloriam, et al. (2005) MoI. Phylogenet.
  • each mouse Taar gene in the OE was examined by in situ hybridization (Montmayeur, et al. (2001) Nat. Neurosci. 4:492-8). Similar to results obtained with OR probes (Vassar, et al. (1993) Cell 74:309-18; Ressler, et al. (1993) Cell 73:597-609), every Taar probe except a Taar] probe labeled a small subset of OSNs that were scattered in the OE in a seemingly random fashion (Figure IA). The labeled neurons were confined to certain OE zones, which differed among Taars, another feature characteristic of OR gene expression (Vassar, et al.
  • Each Taar probe was specific for one Taar gene (see below) except the Taar7 and Taar ⁇ probes, which are likely to hybridize with all of the highly related members of the Taar7 or Taar ⁇ subfamilies, respectively (Taar7a, b, d, e, and / or Taar8a, b, and c). Expression of each T ⁇ r, except Taarl, was seen in both male and female mice by qPCR as well as in situ hybridization.
  • OSNs labeled with probes for Taar2, Taar ⁇ , or Taar9 showed the same double-labeling with a Ga 0 If probe ( Figure 2F) as those labeled with an OR probe. This indicates that, like ORs (Jones, et al. (1989) Science 244:790-5), TAARs may transduce signals by coupling to Ga 0 If, thereby elevating intracellular cAMP.
  • HEK293 cells were transfected with expression vectors encoding individual mouse and human TAARs (mTAARs and hTAARs).
  • the cells were co-transfected with the cAMP reporter gene, CRE-SEAP, which expresses secreted alkaline phosphatase (SEAP) in response to cAMP owing to its cAMP response elements (CRE) (Durocher, et al. (2000) Anal.
  • each TAAR was tested with 30 odorant mixtures containing a total of 210 odorants (each at 2-5 ⁇ M) with diverse structures and perceived odor qualities. Consistent with reports that hTAARl and rat TAAR4 respond to small organic amines (Borowsky, et al. (2001) Proc. Natl. Acad. Sci. USA 98:8966-71), several previously unknown TAAR ligands were identified, and all were amines. Each TAAR was subsequently tested with 81 additional amines, bringing the total number of amines tested to 94.
  • mTAAR5 and mTAAR7f both responded to ' tertiary amines, mTAAR5 to trimethylamine (0.3 ⁇ M EC 50 ) and mTAAR7f to N- methylpiperidine (20 ⁇ M EC 50 ). Consistent with previous reports that hTAARl and rat TAAR4 both recognize ⁇ -phenylethylamine (Borowsky, et al. (2001) Proc. Natl. Acad. ScL USA 98:8966-71), this compound activated hTAARl, mTAARl (0.1 ⁇ M EC 50 ), and mTAAR4 (1 ⁇ M EC 50 ).
  • mTAAR3 responded to isoamylamine and cyclohexylamine, but not to the corresponding alcohols, isoamylalcohol and cyclohexanol ( Figure 3B).
  • mTAAR5 was potently activated by trimethylamine, the related compounds, methylamine, dimethylamine, and tetramethylammonium chloride failed to activate mTAAR5 at even 1000-fold higher concentrations ( Figure 3B).
  • mTAARs did not respond to the corresponding amino acids: phenylalanine for ⁇ -phenylethylamine (mTAARl, mTAAR4); leucine for isoamylamine (mTAAR3); and N,N-dimethylglycine for trimethylamine (mTAAR5).
  • mTAARl phenylalanine for ⁇ -phenylethylamine
  • mTAAR3 leucine for isoamylamine
  • mTAAR5 N,N-dimethylglycine for trimethylamine
  • mTAAR4 recognizes ⁇ -phenylethylamine, a compound whose elevation in urine is correlated with increases in stress and stress responses in both rodents and humans (Paulos & Tessel (1982) Science 215:1127-9; Snoddy, et al. (1985) Pharmacol. Biochem. Behav. 22:497-500; Grimsby, et al. (1997) Nat. Genet.
  • mTAAR3 and mTAAR5 detect compounds (isoamylamine and trimethylamine, respectively) that are enriched in male versus female mouse urine (Gavaghan et al. (2006) J. Proteome Res. 5:378-84; Nishimura, et al. (1989) J. Exp. Zool. 251:300-5). Furthermore, isoamylamine in male urine is reported to act as a pheromone, accelerating puberty onset in female mice by one criterion (Nishimura, et al. (1989) J. Exp. Zool. 251:300-5), though not by another (Price & Vandenbergh (1992) J. Exp. Zool. 264:42-5).
  • HEK293 cells expressing each mTAAR were treated with dilutions of mouse urine.
  • mouse urine generally inhibited responses in the SEAP assay when diluted even 100-fold, making it difficult or impossible to detect TAAR responses to low abundance urinary compounds.
  • a response to male mouse urine was observed for mTAAR5 with an EC 50 corresponding to a 30,000- fold dilution of urine ( Figure 4).
  • male urine could be diluted about 30-fold more than female urine to elicit a similar response.
  • the urine of males did not activate mTAAR5 until the males had reached puberty at about one month of age.
  • the mTAAR5 activator appeared to be highly volatile as it strongly activated several adjacent wells in a multiwell plate containing mTAAR5-expressing cells.
  • the activator may well be trimethylamine, a highly volatile compound that was identified as an mTAAR5 ligand. If so, based on these data, trimethylamine would be present in male urine at about 9 mM. This is consistent with NMR analysis indicating that trimethylamine is at least as abundant in male mouse urine as creatinine, which is present at 3-5 mM (Gavaghan et al. (2006) J. Proteome Res. 5:378-84).
  • mice could in principle determine the gender and sexual status of other mice.
  • TAARs chemosensory receptors expressed in the nasal olfactory epithelium. These receptors, called TAARs, are expressed in a small subpopulation of neurons that appear to lack ORs, indicating that these neurons use TAARs rather than ORs to detect chemosensory stimuli. Similar to ORs, different mTAARs are expressed in different neurons, and those with the same TAAR are scattered in selected OE regions. OSNs expressing TAARs co-express Ga 0If , the G protein to which ORs couple, and TAARs can increase cAMP levels when activated by ligands in heterologous cells, indicating that they activate the same cAMP second messenger pathway in OSNs as ORs.
  • TAAR3, mTAAR4, mTAAR5, and mTAAR7f all recognize small molecule amines and, furthermore, that each of these receptors detects a unique set of amine ligands.
  • mTAAR ligands are derivatives of naturally occurring amino acids, ⁇ -phenylethylamine, an mTAAR4 ligand, is decarboxylated phenylalanine, and isoamylamine, a ligand for mTAAR3, is decarboxylated leucine.
  • Trimethylamine, the mTAAR5 ligand could be derived in vivo from either choline or N,N-dimethylglycine, while N-methylpiperidine, which activates mTAAR7f, could be derived from either lysine or homoproline.
  • mTAARs detect compounds found in mouse urine, a rich source of social cues, such as pheromones (Halpern & Martinez-Marcos (2003) Prog. Neurobiol. 70:245-318; Novotny (2003) Biochem. Soc. Trans. 31 :117-22).
  • ⁇ - phenylethylamine which is detected by mTAAR4, is elevated in urine in response to stress while isoamylamine and trimethylamine, which activate mTAAR3 and mTAAR5, respectively, are both highly enriched in male versus female mouse urine.
  • Isoamylamine also reportedly acts as a pheromone, inducing puberty acceleration in young female mice (Nishimura, et al. (1989) J. Exp. Zool. 251 :300-5).
  • mTAAR5 is activated by extremely dilute mouse urine from sexually mature males, but not females or prepubescent males.
  • Example 5 Materials and Methods Visualization of ⁇ -Galactosidase Activity in OE.
  • C57BL6/J mice were perfused intracardially with fixative (1% formaldehyde, 0.2% glutaraldehyde, 2 mM MgCl 2 , 5 mM EGTA, and 0.02% NP-40 in phosphate-buffered saline (pH 7.4) (PBS)).
  • fixative 1% formaldehyde, 0.2% glutaraldehyde, 2 mM MgCl 2 , 5 mM EGTA, and 0.02% NP-40 in phosphate-buffered saline (pH 7.4) (PBS)
  • Cryostat sections through the OE were incubated with the fixative for 30 minutes at room temperature, washed 3 times for 5 minutes at room temperature with PBS containing 0.02% NP-40, and then incubated overnight at 37°C with 1 mg/ml X-gal (Sigma, St.
  • OSN Isolation OE tissue dissected from adult C57BL/6 mice (Jackson Laboratories, Bar Harbor, ME) was minced, incubated with trypsin/EDTA solution (GIBCO-BRL, Rockville, MD) containing 20 units/ml DNase (Roche, Indianapolis, IN) for 10 minutes at 37 0 C, and then centrifuged (228 x g, 5 minutes, 4°C). Pelleted tissue was triturated in phenol red-free DMEM (GIBCO-BRL) plus 4% fetal bovine serum (Sigma) ('culture media') using a pasteur pipet.
  • Dissociated cells were next diluted 1:1 with 2 mM fluorescein di( ⁇ - galactopyranoside) in water, incubated for 2 minutes at 4°C, diluted 10-fold with culture media containing 1.5 ⁇ M propidium iodide, and then incubated for 2 hours at 4°C.
  • Cells labeled with fluorescein, but not propidium iodide were isolated using a VANTAGE cell sorter (BD Biosciences, San Jose, CA). qPCR.
  • qPCR was conducted in 384-well plates using 5 ⁇ l reactions containing cDNA from ⁇ 25-50 OSNs or from 10 ng tissue RNA, SYBR green indicator (Invitrogen), and ROX internal reference dye (Invitrogen), using the protocol (Wittwer, et al.
  • Digoxigenin- and fluorescein-labeled riboprobes were prepared as described previously (Montmayeur, et al. (2001) Nat. Neurosci. 4:492-8) using linearized PCR4-TOPO vectors containing Taar gene inserts (see below) as transcription templates.
  • Fourteen ⁇ m coronal OE sections from 3-4 week old male or female C57BL/6 mice were hybridized with labeled antisense or sense cRNA probes, and hybridized probes visualized by immunostaining, as described previously (Montmayeur, et al. (2001) Nat. Neurosci.
  • Taar coding regions were PCR-amplified from OE cDNA, cloned into the PCR4-TOPO vector (Invitrogen), and sequenced for verification. Coding region segments were then transferred to the pcDNA3.1 plasmid vector (Invitrogen) either with or without a sequence encoding the first 20 amino acids of bovine rhodopsin attached to the 5' end of the Taar coding region.
  • SEAP assays were performed in 96-well plates according to established methods (Clipstone & Crabtree (1992) Nature 357:695-7) with the following minor modifications. Each well contained 100,000 HEK293 cells (ATCC, Manassas, VA) that were transfected with 20 ng TAAR plasmid and 20 ng CRE-SEAP reporter plasmid (BD Biosciences) using LIPOFECTAMINETM reagent (Invitrogen), and then incubated for 48 hours at 37°C in serum-free media with or without test compounds.
  • ATCC Manassas, VA
  • Plates were next incubated at 65-70 0 C for 2 hours, and an aliquot of supernatant from each well was then incubated with an equal volume of 1.2 mM 4-methylumbelliferyl phosphate (Sigma) in 2 M diethanolamine bicarbonate, pH 10.0 for 2-5 minutes at room temperature. Fluorescence was measured using a CYTOFLUORTM 4000 multi-well plate reader (Applied Biosystems). Mouse urine was obtained by holding an EPPENDORF tube under a handled animal. Antibiotics were added to cells incubated with urine to prevent bacterial contamination.
  • Mix 1 (carboxylic acids): butyric acid, isobutyric acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, propionic acid.
  • Mix 2 (carboxylic acids): adipic acid, benzoic acid, p-Xoh ⁇ c acid, tiglic acid, valeric acid, isovaleric acid, pimelic acid.
  • lactones, musks pentadecanolide, 16-hexadecanolide, ambrettolide (IFF), muscone (IFF), d-octanolactone (Lancaster), undecanoic g-lactone, 6-methylcoumarin.
  • Mix 5 (alcohols): geraniol, 4-(4-hydroxyphenyl)-2-butanone, 2-phenylethanol, furfuryl alcohol, thymol, 2-ethyl-4-(2,2,3)-trimethylcyclopent-3-enylbut-2-en-l-ol (Acros Organics, Geel, Belgium), guaiacol, 2-methoxy-4-methylphenol.
  • Mix 7 (alcohols, ethers): benzyl alcohol, /7-cresol, 1-undecanol, 3,7-dimethyl-3- octanol, Pamplefleur (IFF), Phenafleur (IFF), 2-isobutoxynaphthalene.
  • Mix 8 ethers: 4-methylanisole, Orange flower ether (IFF), butyl ethyl ether, ambroxide, safrole, rose oxide (Fluka, Buchs, Switzerland), anisole, dibutyl ether.
  • Mix 9 camphor: 1,8-cineole, camphor, isoborneol, borneol, fenchone, camphene.
  • esters hexyl-2-furoate, cedramber (IFF), cyclacet (IFF), piconia (IFF), patchomint (IFF), talia (IFF), dihydro myrcenyl acetate (IFF), vanoris (IFF).
  • Mix 11 esters: terpinyl acetate (Fluka), fraistone (IFF), fructone (IFF), methyl anthranilate, 2-phenoxyethyl propionate, verdox (IFF), isopropyl hexanoate (TCI America, Portland, OR), isobornyl acetate.
  • Mix 12 (esters): ethyl acetate, butyl acetate, ethyl butyrate, butyl butyrate, amyl acetate, isoamyl acetate, butyl hexanoate.
  • Mix 14 (alcohols and alkanes): hexanol, heptanol, fer/-butanol, methanol, butanol, hexane, octane, decane.
  • Mix 15 (aromatics): /ra «_?-stilbene, ethylbenzene, butylbenzene, toluene, benzene, diethylbenzenes.
  • Mix 21 non-aromatic rings: cyclohexanol, apo patchone (IFF), 2-cyclohexylethanol, coniferan (IFF), iso cyclemone E (IFF), 4-ter/-butyl cyclohexanol, 2-terrtmtyl cyclohexanone (Fluka), pinene, cyclohexane.
  • Mix 22 aromatic, nitrogen containing: indole, 3-methylindole, pyridine, pyrazine,
  • ketones ionone, irone (Fluka), 4-phenyl-2-butanone, jasmone, 4-phenyl-3- buten-2-one, 3, 4-hexanedione.
  • Mix 25 (other): p-anisaldehyde, eugenol, piperonal, isoeugenol, methyl salicylate, 3- hydroxy-2-methyl-4-pyrone, vanillin, ethylvanillin.
  • Mix 26 (other): glycine, phenylalanine, adenine, isoleucine, pyrrolidine.
  • Mix 27 (androstenones): trans-androsterone, androsterone, 5a-androst-16-en-3a-ol, 5a-androst-16-en-3-one, 1, 3, 5(10), 16-estratetraen-3-ol (Steraloids, Newport, RI), 5a- androsten-3b-ol-17-one sulfate (Steraloids), 4,16-androstadien-3-one (Steraloids).
  • Mix 28 (others): salsolinol, creatine, 2-aminobutyric acid, 2,5-dihydro-2,4,5- trimethylthiazole (Phero Tech, Inc., Delta, BC).
  • MHC peptide SYFPEITHI (SEQ ID NO: 37).
  • Mouse phero mones 2,5-dimethylpyrazine, dehydro-brevicomin, 2-(sec-butyl)-4,5- dihydrothiazole, lactol form of 6-hydroxy-6-methyl-3-heptanone. Amines tested: 2-phenylethylamine.
  • AMPA AMPA, amphetamine, ephinephrine, norepinephrine, norephedrine, 2- amino-3 -phenyl- 1 -propanol.
  • Mix A2 histamine, dopamine, serotonin.
  • Mix A3 tryptamine, octopamine, tyramine.
  • Mix A4 methylamine, dimethylamine, trimethylamine, carnitine, dibutylamine, diisopropylamine.
  • Mix A6 balanine, GABA, 4-aminobenzoic acid.
  • Mix A7 heptylamine, hexylamine, butylamine, propylamine, ethylamine.
  • Mix A9 b-alanine amide, cysteamine, ethanolamine, l-amino-2-propanol, 3- (methylthio)-propylamine.
  • Mix AlO on mTAARl, mTAAR4, mTAAR5 only: phe-ala, phe-gly-gly, N,N- dimethylphenylalanine, N,N-dimethylphenethylamine.
  • Mix A12 choline chloride, carnitine, homovanillic acid.
  • Mix A13 5-hydroxyindoleacetic acid, 6-hydroxydopamine, 5-aminoindole.
  • Mix Al 4 3-methoxytyramine, 3-hydroxy-4-methoxyphenethylamine, 3,4- dimethoxyphenethylamine.
  • Mix A15 6-methoxytryptamine, 5-methoxytryptamine, N-methyltryptamine.
  • Mix A25 2'-aminoacetophenone, 3'-aminoacetophenone, 4'-aminoacetophenone.
  • Mix A26 quinoline, quinaldine.
  • TAAR Response Summary Shown below are the compounds that elicited SEAP responses in HEK293 cells expressing individual TAARs. The EC50 for each compound is shown in parentheses (n.d., not determined). mTAARl and hTAARl had similar ligand profiles: 2-phenylethylamine (100 nM), tyramine (n.d.), 2-methylbutylamine (n.d.), 3-(methylthio)-propylamine (n.d.), hexylamine
  • mTAAR3 isoamylamine (10 mM), cyclohexylamine (20-30 mM), 2- methylbutylamine (100 mM), isobutylamine (>300 mM), 3 -(methyl thio)-propylamine (n.d.).
  • mTAAR4 2-phenylethylamine (1 mM), N,N-dimethyl-2-phenylethylamine (n.d.), at least one component of mix Al 6 (see below) (n.d.).
  • mTAAR5 trimethylamine (300 nM), dimethylethylamine (700 nM), N- methylpiperidine (n.d.).
  • mTAAR7f N-methylpiperidine (20 mM).

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Abstract

La présente invention concerne des procédés d'utilisation de modulateurs de récepteurs associés à une amine de trace (TAAR) et de formulations contenant lesdits modulateurs utiles en tant qu'agents attractifs et répulsifs pour animaux, et pour traiter des conditions pathologiques telles que le stress, l'anxiété, la dépression ou des troubles sociaux chez des sujets qui en ont besoin.
PCT/US2007/015310 2006-07-03 2007-06-29 Récepteurs associés à une amine de trace dans l'épithélium olfactif Ceased WO2008005407A2 (fr)

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EP2470181A1 (fr) * 2009-08-26 2012-07-04 Allergan, Inc. Procédé de traitement de troubles compulsifs par les agonistes du récepteur alpha-2b adrénergique
EP2720536A4 (fr) * 2011-06-16 2015-04-01 Harvard College Nouveaux agents de lutte contre les rongeurs et utilisation de ces agents
CN105941405A (zh) * 2016-07-15 2016-09-21 中国农业科学院油料作物研究所 一种5-羟色胺在缓解油菜干旱胁迫中的应用
EP3253423A4 (fr) * 2015-02-05 2018-07-04 Monell Chemical Senses Center Procédé de blocage de la perception de mauvaises odeurs
US10301263B2 (en) 2014-09-10 2019-05-28 Royal Holloway And Bedford New College Anticonvulsant compound
US10390536B2 (en) 2013-03-14 2019-08-27 National Center for Scientific Research “Demokritos” Methods, compounds and compositions for repelling insects and/or arachnids
CN115400109A (zh) * 2022-09-29 2022-11-29 首都医科大学附属北京安定医院 酪胺及其衍生物在制备治疗抑郁症药物中的应用
CN118308458A (zh) * 2024-06-06 2024-07-09 汉王科技股份有限公司 嗅觉受体在识别氨中的用途和检测氨的方法

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US5827551A (en) * 1996-04-23 1998-10-27 Berkley Inc. Fish attractant
US7321065B2 (en) * 2003-04-18 2008-01-22 The Regents Of The University Of California Thyronamine derivatives and analogs and methods of use thereof

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2470181A1 (fr) * 2009-08-26 2012-07-04 Allergan, Inc. Procédé de traitement de troubles compulsifs par les agonistes du récepteur alpha-2b adrénergique
EP2720536A4 (fr) * 2011-06-16 2015-04-01 Harvard College Nouveaux agents de lutte contre les rongeurs et utilisation de ces agents
US10390536B2 (en) 2013-03-14 2019-08-27 National Center for Scientific Research “Demokritos” Methods, compounds and compositions for repelling insects and/or arachnids
US10301263B2 (en) 2014-09-10 2019-05-28 Royal Holloway And Bedford New College Anticonvulsant compound
EP3253423A4 (fr) * 2015-02-05 2018-07-04 Monell Chemical Senses Center Procédé de blocage de la perception de mauvaises odeurs
CN105941405A (zh) * 2016-07-15 2016-09-21 中国农业科学院油料作物研究所 一种5-羟色胺在缓解油菜干旱胁迫中的应用
CN105941405B (zh) * 2016-07-15 2018-11-20 中国农业科学院油料作物研究所 一种5-羟色胺在缓解油菜干旱胁迫中的应用
CN115400109A (zh) * 2022-09-29 2022-11-29 首都医科大学附属北京安定医院 酪胺及其衍生物在制备治疗抑郁症药物中的应用
CN118308458A (zh) * 2024-06-06 2024-07-09 汉王科技股份有限公司 嗅觉受体在识别氨中的用途和检测氨的方法

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