WO2002053139A2

WO2002053139A2 - Excitatory amino acid receptor antagonist and 5-ht1f agonist combination: a method for the treatment of neurological disorders

Info

Publication number: WO2002053139A2
Application number: PCT/US2001/045863
Authority: WO
Inventors: Kirk Willis Johnson
Original assignee: Eli Lilly and Co
Current assignee: Eli Lilly and Co
Priority date: 2001-01-05
Filing date: 2001-12-20
Publication date: 2002-07-11
Anticipated expiration: 2003-07-05
Also published as: WO2002053139A3; WO2002053139A8; AU2002241565A1

Abstract

The present invention relates to a method of treating a neurological disorder, particularly migraine, comprising administering to a patient an effective amount of an excitatory amino receptor antagonist in combination with a 5HT1f agonist.

Description

EXCITATORY AMINO ACID RECEPTOR ANTAGONIST AND 5-HT1F

AGONIST COMBINATION: A METHOD FOR THE TREATMENT OF

NEUROLOGICAL DISORDERS

BACKGROUND OF THE INVENTION

The diverse physiological activity exhibited by the neurotransmitter serotonin (5-HT) is mediated by at least seven receptor classes: 5-HTι, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7. The most heterogeneous of these classes appears to be 5- HTi, subclassified as: 5-HTiA, 5-HTIB, 5-HTιc, 5-HTID (Hamon et al, NeuropsychopharmacoL, 3(5/6), 349-360 (1990)) and 5-HTIE (Leonhardt et al.J.

Neurochem., 53(2), 465-471 (1989)). A human gene which expresses an additional 5- HTi subclass, 5-HTiF, was isolated by Kao and coworkers (Proc. Natl. Acad. Sci. USA, 90, 408-412 (1993)). This 5-HTIF receptor has been όhown to exhibit a pharmacological profile distinct from any serotonergic receptor yet described.

Theories regarding the pathophysiology of migraine have been dominated since 1938 by the work of Graham and Wolff (Arch. Neurol. Psychiatry, 39, 737-63 (1938)). They proposed that the cause of migraine headache is vasodilatation of extracranial vessels. This view is supported by knowledge that ergot alkaloids and sumatriptan contract cephalic vascular smooth muscle and are effective in the treatment of migraine. Sumatriptan is a hydrophilic agonist at 5-HT-l-like receptors and does not cross the blood-brain barrier (Humphrey, et al, Ann. NYAcad. Set, 600, 587-600 (1990)). Recently several new series of compounds said to be useful for the treatment of migraine have been described in WO94/03446, WO93/11106, WO92/13856, EP0438230 and WO91/18897. Each of these series of compounds has been developed to optimize the 5-HTι-like mediated vasoconstrictive activity of sumatriptan. Sumatriptan's contraindications, coronary vasospasm, hypertension and angina, however, are also products of its vasoconstrictive activity (Maclntyre, P.D., et al, British Journal of Clinical Pharmacology, 34, 541-546 (1992); Chester, A.H., et al, Cardiovascular Research, 24, 932-937 (1990); Conner, I.E., et al., European Journal of Pharmacology, 161, 91-94 (1990)).

While this vascular mechanism for migraine has gained wide acceptance, there is not total agreement as to its validity. Moskowitz has shown, for example, that the occurrence of migraine headaches is independent of changes in vessel diameter (Cephalalgia, 12, 5-7, (1992)). Furthermore, Moskowitz has proposed that currently unknown triggers stimulate trigeminal nerves which innervate vasculature within cephalic tissue, giving rise to release of vasoactive neuropeptides from axons on the vasculature and transmission of painful signals into the brain stem. These released neuropeptides then initiate a series of events leading to neurogenic inflammation, a consequence of which is pain. This neurogenic inflammation is blocked by sumatriptan and ergot alkaloids at a dose similar to that required to treat acute migraine in humans. While this blockade of neurogenic protein extravasation, one aspect of neurogenic inflammation, is believed to be mediated by 5-HTID receptors, the effective dosages of 5-HTID selective compounds do not correlate with in vitro binding at the 5-HTID binding site. The lack of correlation suggests that a receptor subtype other than 5-HTID may mediate the effects of sumatriptan (Neurology, 43(suppl. 3), S16-S20 (1993)). In addition, it has been reported that 0-2, H3, μ-opioid and somatostatin receptors may also be located on trigeminovascular fibers and may block neurogenic plasma extravasation (Matsubara et al, Eur. J. Pharmacol, 224, 145-150 (1992)). Weinshank et al. have reported that sumatriptan and several ergot alkaloids have a high affinity for the 5-HTIF receptor, suggesting a role for the 5- HTIF receptor in migraine (WO93/14201). Furthermore, United States Patent No. 5,698,571 has disclosed that administration of an agonist of the 5-HTiF receptor provides an effective treatment of migraine and related disorders without attending vasoconstricitve effects.

The transmission of nerve impulses in the mammalian central nervous system (CNS) is controlled by the interaction between a neurotransmitter, that is released by a sending neuron, and a surface receptor on a receiving neuron, which causes excitation of this receiving neuron. L-Glutamate, which is the most abundant neurotransmitter in the CNS, mediates the major excitatory pathways in mammals, and is referred to as an excitatory amino acid (EAA). The receptors that respond to glutamate are called excitatory amino acid receptors (EAA receptors). See Watkins & Evans, Ann. Rev. Pharmacol. Toxicol., 21, 165 (1981); Monaghan, Bridges, and Cotman, Ann. Rev. Pharmacol. Toxicol, 29, 365 (1989); Watkins, Krogsgaard-Larsen, and Honore, Trans. Pharm. Sci., 11, 25 (1990). The excitatory amino acids are of great physiological importance, playing a role in a variety of physiological processes, such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation, and sensory perception.

Excitatory amino acid receptors are classified into two general types; "ionotropic" and "metabotropic". "Ionotropic" receptors are directly coupled to the opening of cation channels in the cell membrane of neurons. This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists N-methyl-D-aspartate (ΝMDA), -amino-3-hydroxy- 5-methylisoxazole-4-propionic acid (AMPA), and kainic acid (KA). Molecular biological studies have established that AMPA receptors are composed of subunits (GluRi - GIUR4), which can assemble to form functional ion channels. Five kainate receptors have been identified which are classified as either High Affinity (KA1 and KA2) or Low Affinity (GIUR5, GluRg, and GluR ). Bleakman et al., Molecular

Pharmacology, 49, No.4, 581,(1996). The "metabotropic" excitatory amino acid receptors are G-protein or second messenger-linked receptors. This type of receptor is coupled to multiple second messenger systems that lead to enhanced phosphoinositide hydrolysis, activation of phospholipase D, increases or decreases in cAMP formation, and changes in ion channel function. Schoepp and Conn, Trends in Pharmacol. Sci., 14, 13 (1993). Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways, but also to participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990).

The excessive or inappropriate stimulation of excitatory amino acid receptors leads to neuronal cell damage or loss by way of a mechanism known as excitotoxicity. This process has been suggested to mediate neuronal degeneration in a variety of neurological disorders and conditions. The medical consequences of such neuronal degeneration makes the abatement of these degenerative neurological processes an important therapeutic goal.

Excitatory amino acid excitotoxicity has been implicated in the pathophysiology of numerous neurological disorders. For example, excitotoxicity has , been linked with the etiology of cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord lesions resulting from trauma or inflammation, perinatal hypoxia, cardiac arrest, and hypoglycemic neuronal damage. In addition, excitotoxicity has been implicated in chronic neurodegenerative conditions including Alzheimer's Disease, Huntington's Chorea, inherited ataxias, AIDS-induced dementia, amyotrophic lateral sclerosis, idiopathic and drug-induced Parkinson's Disease, as well as ocular damage and retinopathy. Other neurological disorders implicated with excitotoxicity and/or glutamate dysfunction include muscular spasticity including tremors, drug tolerance and withdrawal, brain edema, convulsive disorders including epilepsy, depression, anxiety and anxiety related disorders such as post-traumatic stress syndrome, tardive dyskinesia, and psychosis related to depression, schizophrenia, bipolar disorder, mania, and drug intoxication or addiction. In addition, it has also been reported that excitatory amino acid excitotoxicity participates in the etiology of acute and chronic pain states including severe pain, intractable pain, neuropathic pain, and post-traumatic pain. (WO 98/45270) The use of a neuroprotective agent, such as an excitatory amino acid receptor antagonist, is believed to be useful in treating or preventing these disorders and/or reducing the amount of neurological damage associated with these disorders. For example, studies have shown that AMPA receptor antagonists are neuroprotective in focal and global ischemia models. The competitive AMPA receptor antagonist

NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[ ]quinoxaline) has been reported effective in preventing global and focal ischemic damage. Sheardown et al, Science,

247, 571 (1900); Buchan et al, Neuroreport, 2, 473 (1991); LePeillet et al, Brain

Research, 571, 115 (1992). The noncompetitive AMPA receptor antagonists GKYI

52466 has been shown to be an effective neuroprotective agent in rat global ischemia models. LaPeillet et al, Brain Research, 571, 115 (1992). European Patent

Application Publication No. 590789A1 and United States Patents No. 5,446,051 and

5,670,516 disclose that certain decahydroisoquinoline derivative compounds are

AMPA receptor antagonists and, as such, are useful in the treatment of a multitude of disorders conditions, including pain and migraine headache. WO 98/45270 discloses that certain decahydroisoquinoline derivative compounds are selective antagonists of the iGluR5 receptor and are useful for the treatment of various types of pain, including; severe, chronic, intractable, and neuropathic pain. Excitatory amino acid receptor antagonists may also be useful as analgesic agents.

Recently, it has been reported that all five members of the kainate subtype, of ionotropic glutamate receptors, are expressed on rat trigeminal ganglion neurons. In particular, high levels of GIUR5 and KA2 have been observed. (Sahara et al, The

Journal of N euro science, 17(17), 6611 (1997)). Simmons et al. reported that the kainate GIUR5 receptor subtype mediates the nociceptive response to formalin in a rat model of persistent pain. (Neuropharmacology, 37, 25 (1998). Further, WO98/45270 previously disclosed that antagonists selective for the iGluR5 receptor are useful for the treatment of pain, including; severe, chronic, intractable, and neuropathic pain.

Noteworthy is the observation that kainate receptors have not previously been implicated in the etiology of migraine headache. In particular, selective iGluR5 receptor antagonists have not been previously reported as being useful for the treatment of migraine.

Surprisingly, and in accordance with this invention, Applicants have discovered that combining an excitatory amino acid receptor antagonist, such as a selective antagonist of the iGluR5 receptor, with an agonist of the 5HT_]^f receptor, provides a synergistic and efficacious response in an animal model of neurogenic inflammation and, thus, could be useful for the treatment of migraine. Such a combination could address a long felt need for a safe and effective treatment for migraine, without attending side effects. The treatment of neurological disorders is hereby furthered.

SUMMARY OF THE INVENTION

The present invention provides a method of treating a neurological disorder or a neurodegenerative disease, comprising administering to a patient in need thereof an effective amount of an excitatory amino acid receptor antagonist, in combination with an effective amount of a 5HTi receptor agonist.

More specifically, the present invention provides a method of treating a neurological disorder or a neurodegenerative disease, comprising administering to a patient in need thereof an effective amount of a selective iGluR5 receptor antagonist, in combination with an effective amount of a 5HTif receptor agonist.

Even more specifically, the present invention provides a method of treating migraine, comprising administering to a patient in need thereof an effective amount of a selective iGluR5 receptor antagonist in combination with an effective amount of a 5HTif receptor agonist.

In addition, the present invention provides a method of treating a neurological disorder or a neurodegenerative disease comprising administering to a patient in need thereof an effective amount of a compound which possesses the combined activities of a selective iGluR5 receptor antagonist and a 5HTι f receptor agonist.

Li addition, the present invention provides a pharmaceutical composition comprising a selective iGluR5 receptor antagonist and a 5HTif receptor agonist, in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients.

The present invention further provides the use of a selective iGluR5 receptor antagonist in combination with a 5HTif receptor agonist for the manufacture of a medicament for treating a neurological disorder.

DESCRIPTION OF DRAWINGS

Figure 1 is a comparison of dose-response curves for Compound I (382884) and Compound II (344864) when administered intravenously, either individually, or in combination, in the rat model of dural protein extravasation. This figure depicts the dose of each compound administered and the resulting effect on extravasation ratio. This figure also depicts the ID50 values for Compound II when administered alone, and when administered in combination with a dose of Compound I which produced no change in extravasation ratio when administered individually.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a method for the treatment of a neurological disorder or neurodegenerative disease. Specifically, the present invention provides a method for the treatment of migraine which can be demonstrated by a particular mechanism of action, inhibition of neurogenic dural protein extravasation. By treating a migraineur with an excitatory amino acid receptor antagonist, such as a selective iGluR5 receptor antagonist, in combination with a 5HTif receptor agonist, or a single compound possessing the combined activities of a selective iGluR5 receptor antagonist and a 5HTif receptor agonist, the neurogenic extravasation which mediates migraine is inhibited without the attending side effects of agents designed to optimize the 5-HTi-like mediated vasoconstrictive activity of sumatriptan.

The term "pharmaceutically acceptable salt" as used herein, refers to salts of the compounds employed in the present invention which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds employed in the methods of the present invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts.

It will be understood by the skilled reader that most or all of the compounds used in the present invention are capable of forming salts, and that the salt forms of pharmaceuticals are commonly used, often because they are more readily crystallized and purified than are the free bases. In all cases, the use of the pharmaceuticals described herein as salts is contemplated in the description herein, and often is preferred, and the pharmaceutically acceptable salts of all of the compounds employed in the methods of the present invention are included in the names of them.

Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as /7-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne- 1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, -hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, napththalene-2- sulfonate, mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid.

Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. The potassium and sodium salt forms are particularly preferred.

It should be recognized that the particular counterion forming a part of any salt employed in the methods of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.

As used herein the term "iGluR5" refers to the kainate ionotropic glutamate receptor, subtype 5, of the larger class of excitatory amino acid receptors.

As used herein, the term "selective iGluR5 antagonist" or "selective iGluR5 receptor antagonist" refers those excitatory amino acid receptor antagonists which selectively bind to the iGluR5 kainate receptor subtype, relative to the iGluR.2 AMPA receptor subtype. Preferably, the selective iGluR5 antagonist for use according to the method of the present invention has a binding affinity at least 10 fold greater for iGluR5 than for iGluR2, more preferably at least 100 fold greater. It is further understood that any selective iGluR5 antagonist, as appreciated by one of ordinary skill in the art, is included within the scope of the methods of the present invention. Such selective iGluR5 receptor antagonists are readily available to, or are readily prepared by, one of ordinary skill in the art following recognized procedures. Examples of selective iGluR5 receptor antagonists include, but are not limited to, the compounds provided in WO 98/45270, the entire contents of which is herein incorporated by reference.

The selective iGluR5 antagonists for use according to the methods of the present invention may be a single compound or a combination of compounds capable of functioning as a selective iGluR5 receptor antagonist. For example, it may be a combination of a compound capable of functioning as an antagonist at the iGluR5 receptor and one or more other glutamate receptors, in combination with one or more compounds capable of blocking its actions at the iGluR2 receptor. It is understood, however, that the selective iGluR antagonist for use in the methods of the present invention, is preferably a single compound.

As used herein, the term "5HTi agonist" refers to a full or partial agonist which may be composed of one or more agents which, individually or together, are selective agonists of 5-HTIF receptors relative to other serotonin receptors which produce unwanted effects like vasoconstriction. It is understood, however, that the 5HTι f agonist for use in the methods of the present invention, is preferably a single compound. A compound which is a partial agonist at the 5-HTIF receptor must exhibit sufficient agonist activity to inhibit neurogenic meningeal extravasation at an acceptable dose. While a partial agonist of any intrinsic activity may be useful for the method of this invention, partial agonists of at least about 50% agonist effect (E_maχ) are preferred and partial agonists of at least about 80% agonist effect (E_maχ) are more preferred. Full agonists at the 5-HTIF receptor are most preferred. Examples of 5HTif agonists include, but are not limited to, the compounds described in United

States Patents No. 5,698,571; 5,708,187; and 5,814, 653, the entire contents of which are all herein incorporated by reference.

It is further understood that the selective iGluR5 antagonists, and the 5HTlf receptor agonists, employed in the methods of the present invention may exist as pharmaceutically acceptable salts and, as such, that the use of such salts are included within the scope of the present invention.

It should be understood by the skilled artisan that compounds useful for the methods of the present invention may be available for prodrug formulation. As used herein, the term "prodrug" refers to a compound which has been structurally modified such that in vivo the prodrug is converted, for example, by hydrolytic, oxidative, reductive, or enzymatic cleavage into the parent compound (e.g. the carboxylic acid (drug), or as the case may be the parent dicarboxylic acid). Such prodrugs may be, for example, metabolically labile mono- or di-ester derivatives of the parent compounds having a carboxylic acid group. It is to be understood that the present invention includes any such prodrugs, such as metabolically labile ester or diester derivatives of compounds useful in the methods of the present invention. In all cases, the use of the compounds described herein as prodrugs is contemplated, and often is preferred, and thus, the prodrugs of the compounds employed are encompassed in the names of the compounds herein. Preferred prodrugs include, for example, the diester derivatives of Compound I. Conventional procedures for the selection and preparation of suitable prodrugs are well known to one of ordinary skill in the art. As used herein the term "neurological disorder" refers a disorder of the nervous system including but not limited to cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, global and focal cerebral ischemia, spinal cord lesions resulting from trauma or inflammation, perinatal hypoxia, hypoxia-induced nerve cell damage resulting from cardiac arrest, hypoglycemic neuronal damage, neonatal distress, and the like. Other neurological disorders contemplated include muscular spasticity including tremors, drug tolerance and withdrawal, brain edema, convulsive disorders including epilepsy, depression, anxiety and anxiety related disorders such as post-traumatic stress syndrome, tardive dyskinesia, and psychosis related to depression, schizophrenia, bipolar disorder, mania, and drug intoxication or addiction, and acute and chronic pain states including severe pain, intractable pain, neuropathic pain, and post-traumatic pain.

As used herein the term "neurodegenerative disease" refers to Alzheimer's Disease, Huntington's Chorea, inherited ataxias, AIDS-induced dementia, amyotrophic lateral sclerosis(ALS), idiopathic and drug-induced Parkinson's Disease, ocular damage and retinopathy, and the like. These Neurodegenerative diseases are chronic conditions. The term "chronic" means a deteriorating condition of slow progress and long continuance. As such, a chronic neurodegenerating condition is treated when it is diagnosed and continued throughout the course of the disease.

As used herein the term "migraine" refers a neurological disorder characterized by recurrent attacks of head pain (which are not caused by a structural brain abnormalitiy such as those resulting from tumor or stroke), gasrointestinal disturbances, and possibly neurological symptoms such as visual distortion. Characteristic headaches of migraine usually last one day and are commonly accompanied by nausea, emesis, and photophobia.

Migraine may be a "chronic" or "acute" condition. The term "chronic", as used herein, means a condition of slow progress and long continuance. As such, a chronic condition is treated when it is diagnosed and treatment continued throughout the course of the disease. Conversely, the term "acute" means an exacerbated event or attack, of short course, followed by a period of remission. Thus, the treatment of migraine contemplates both acute events and chronic conditions. In an acute event, compound is administered at the onset of symptoms and discontinued when the symptoms disappear. As described above, a chronic condition is treated throughout the course of the disease.

As used herein the term "patient" refers to a mammal, such a mouse, gerbil, guinea pig, rat, dog or human. It is understood that the preferred patient is a human.

As used herein, the terms "treating" or "to treat" each mean to alleviate symptoms, eliminate the causation either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder. As such, the methods of this invention encompass both therapeutic and prophylactic administration.

As used herein the term "effective amount" refers to the amount or dose of the compound, upon single or multiple dose administration to the patient, either alone or in combination with another agent, which provides the desired effect in the patient under diagnosis or treatment.

An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount or dose of compound administered, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of mammal; its size, age, and general health; the specific neurological disorder involved; the degree of or involvement or the severity of the neurological disorder; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.

A typical daily dose will contain from about 0.001 mg/kg to about 100 mg/kg of each compound used in the present adjunctive therapy. Preferably, daily doses will be about 0.05 mg/kg to about 50 mg/kg, more preferably from about 0.1 mg/kg to about 25 mg/kg.

The adjunctive therapy of the present invention is carried out by administering an excitatory amino acid receptor antagonist, particularly a selective iGluR5 antagonist, together with a 5HTlf receptor agonist in any manner which provides effective levels of the particular compounds in the body at the same time. The excitatory amino acid receptor antagonist and the 5HTlf receptor agonist may be administered together, in a single dosage form, or may be administered separately. Oral administration is a preferred route, however, oral administration is not the only route, nor even the only preferred route. For example, other routes of administration include, but are not limited to, transdermal, percutaneous, intravenous, intramuscular, intranasal, buccal, pulmonary, sublingual, or intrarectal routes of administration. Further, one of the compounds may be administered by one route, such as oral, and the other may be administered by the transdermal, percutaneous, intravenous, intramuscular, intranasal, buccal, pulmonary, sublingual, or intrarectal route, in particular circumstances. The route of administration may be varied in any way, limited by the physical properties of the compounds and the convenience of the patient and the caregiver. The adjunctive combination may be administered as a single pharmaceutical composition, and so pharmaceutical compositions incorporating both compounds are important embodiments of the present invention. Such compositions may take any physical form that is pharmaceutically acceptable, but orally usable pharmaceutical compositions are particularly preferred. Such adjunctive pharmaceutical compositions contain an effective amount of each of the compounds, which effective amount is related to the daily dose of the compounds to be administered. Each adjunctive dosage unit may contain the daily doses of all compounds, or may contain a fraction of the daily doses, such as one-third of the doses. Alternatively, each dosage unit may contain the entire dose of one of the compounds, and a fraction of the dose of the other compounds. In such case, the patient would daily take one of the combination dosage units, and one or more units containing only the other compounds. The amounts of each compound to be contained in each dosage unit depends on the identity of the compounds chosen for the therapy, and other factors such as the indication for which the adjunctive therapy is being given.

The compositions are preferably formulated in a unit dosage form, each dosage containing from about 1 mg to about 500 mg of each compound individually or in a single unit dosage form, more preferably about 5 mg to about 300 mg (for example 25 mg). The term "unit dosage form" refers to a physically discrete unit suitable as unitary dosages for a patient, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient.

The inert ingredients and manner of formulation of the adjunctive pharmaceutical compositions are conventional, except for the presence of the combination of the present invention. The usual methods of formulation used in pharmaceutical science may be used here. All of the usual types of compositions may be used, including tablets, chewable tablets, capsules, solutions, parenteral solutions, intranasal sprays or powders, troches, suppositories, transdermal patches and suspensions. In general, compositions contain from about 0.5% to about 50% of the compounds in total, depending on the desired doses and the type of composition to be used. The amount of the compounds, however, is best defined as the "effective amount", that is, the amount of each compound which provides the desired dose to the patient in need of such treatment. The activity of the adjunctive combinations do not depend on the nature of the composition, so the compositions are chosen and formulated solely for convenience and economy. Any of the combinations may be formulated in any desired form of composition.

Capsules are prepared by mixing the compound with a suitable diluent and filling the proper amount of the mixture in capsules. The usual diluents include inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.

Tablets are prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and disintegrators as well as the compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

Tablets are often coated with sugar as a flavor and sealant. The compounds may also be formulated as chewable tablets, by using large amounts of pleasant- tasting substances such as mannitol in the formulation, as is now well-established practice. Instantly dissolving tablet-like formulations are also now frequently used to assure that the patient consumes the dosage form, and to avoid the difficulty in swallowing solid objects that bothers some patients.

A lubricant is often necessary in a tablet formulation to prevent the tablet and punches from sticking in the die. The lubricant is chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.

Tablet disintegrators are substances which swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins and gums. More particularly, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose, for example, may be used, as well as sodium lauryl sulfate.

Enteric formulations are often used to protect an active ingredient from the strongly acid contents of the stomach. Such formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in acid environments, and soluble in basic environments. Exemplary films are cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate.

When it is desired to administer the combination as a suppository, the usual bases may be used. Cocoa butter is a traditional suppository base, which may be modified by addition of waxes to raise its melting point slightly. Water-miscible suppository bases comprising, particularly, polyethylene glycols of various molecular weights are in wide use, also. Transdermal patches have become popular recently. Typically they comprise a resinous composition in which the drugs will dissolve, or partially dissolve, which is held in contact with the skin by a film which protects the composition. Many patents have appeared in the field recently. Other, more complicated patch compositions are also in use, particularly those having a membrane pierced with innumerable pores through which the drugs are pumped by osmotic action.

"Prodrugs" have also become preferred recently, thus, it should also be understood by the skilled artisan that some of the compounds useful for the methods of the present invention are available for prodrug formualtion. "Prodrug" as used herein, includes metabolically labile ester or diester derivatives of the functional parent acid compounds (drugs) employed in the methods of, the present invention. When administered to a patient, the prodrug undergoes enzymatic and/or chemical hydrolytic cleavage in such a manner that the parent carboxylic acid (drug), or as the case may be the parent dicarboxylic acid, is released. In all cases, the use of the compounds described herein as prodrugs is contemplated, and often is preferred, and thus, the prodrugs of the compounds employed are encompassed in the names of the compounds herein.

The following table provides an illustrative list of formulations suitable for use with adjunctive therapy employed in the present invention. "Active Ingredient" as it is used in the following table means either a 5HTlf agonist or a selective iGluR5 antagonist, or in the alternative, a single compound possessing the activities of a 5HTlf agonist and a selective iGluR5 antagonist. The following is provided only to illustrate the invention and should not be interpreted as limiting the present invention in any way.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

Quantity (mg/capsule)

Active Ingredient 250

Starch, dried 200

Magnesium stearate JO

Total 460 mg The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.

Formulation 2 A tablet is prepared using the ingredients below:

Quantity (mg/tablet)

Active Ingredient 250

Cellulose, microcrystalline 400 Silicon dioxide, fumed 10

Stearic acid 5

Total 665 mg

The components are blended and compressed to form tablets each weighing 665 mg.

Formulation 3

An aerosol solution is prepared containing the following components:

Weight %

Active Ingredient 0.25

Ethanol 29.75

Propellant 22 70.00 (Chlorodifluoromethane)

Total 100.00

The active compound is mixed with ethanol and the mixture added to a portion of the Propellant 22, cooled to -30°C and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container.

Formulation 4

Tablets each containing 60 mg of active ingredient are made as follows:

Active Ingredient 60 : mg

Starch 45 : mg

Microcrystalline cellulose 35 mg

Polyvinylpyrrolidone 4.0 mg

Sodium carboxymethyl starch 4.5 mg

Magnesium stearate 0.5 mg

Talc 1.0 mg

Total 150 mg

The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50°C and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.

Formulation 5

Capsules each containing 80 mg medicament are made as follows:

Active Ingredient 80 mg

Starch 59 mg

Microcrystalline cellulose 59 mg

Magnesium stearate 2 mg

Total 200 mg

The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 45 sieve, and filled into hard gelatin capsules in 200 mg quantities.

Formulation 6

Suppositories each containing 225 mg of active ingredient may be made as follows:

Active Ingredient 225 mg

Saturated fatty acid glycerides 2,000 mg

Total 2,225 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.

Formulation 7

Suspensions each containing 50 mg of medicament per 5 ml dose are made as follows:

Active Ingredient 50 mg

Sodium carboxymethyl cellulose 50 mg

Syrup 1.25 ml Benzoic acid solution 0.10 ml Flavor q.v.

Color q.v.

Purified water to total 5.0 ml

The medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.

Formulation 8

An intravenous formulation may be prepared as follows:

Active Ingredient 100 mg

Mannitol 100 mg

5 N Sodium hydroxide 200 ml Purified water to total 5 ml

It is understood by one of ordinary skill in the art that the above procedures can be applied to a method of treating a neurological disorder or a neurodegenerative disease comprising administering to a patient in need thereof, an effective amount of a selective iGluR5 receptor antagonist in combination with an effective amount of a 5HTi receptor agonist. It is further understood that the above procedures can also be applied to a method of treating a neurological disorder or a neurodegenerative disease comprising administering to a patient in need thereof an effective amount of a compound which possesses the combined activities of a selective iGluR5 receptor antagonist and a 5HTlf receptor agonist.

The following examples illustrate the methods of the present invention as well as the panel of compounds employed to demonstrate the principles of the invention . The reagents and starting materials are readily available to one of ordinary skill in the art. These examples are intended to be illustrative only and are not to be construed so as to limit the scope of the invention in any way. As used herein, the following terms have the meanings indicated: "i.v." refers to intravenously; "p.o." refers to orally; "i.p." refers to intraperitoneally; "eq" or "equiv." refers to equivalents; "g" refers to grams; "mg" refers to milligrams; "L" refers to liters; "mL" refers to milliliters; "μL" refers to microliters; "mol" refers to moles; "mmol" refers to millimoles; "psi" refers to pounds per square inch; "mm Hg" refers to millimeters of mercury; "min" refers to minutes; "h" or "hr" refers to hours; "°C" refers to degrees Celsius; "TLC" refers to thin layer chromatography; "HPLC" refers to high performance liquid chromatography; "R_f" refers to retention factor; "R_t" refers to retention time; "δ" refers to part per million down-field from tetramethylsilane; "THF" refers to tetrahydrofuran; "DMF" refers to N,N-dimethylformamide; "DMSO" refers to dimethyl sulfoxide; "aq" refers to aqueous; "EtOAc" refers to ethyl acetate; "iPrOAc" refers to isopropyl acetate; "MeOH" refers to methanol; "MTBE" refers to tert-butyl methyl ether; "RT" refers to room temperature; "Kj" refers to the dissociation constant of an enzyme-antagonist complex and serves as an index of ligand binding; and "ID50" and "ID 100" ^ref^{er t0} doses of an administered therapeutic agent, or combination of agents, which produce, respectively, a 50 % and 100% reduction in a physiological response.

Example I

The following compounds are representative of the excitatory amino acid receptor antagonists and the 5HTlf agonists, useful in the methods of the present invention. These compounds are intended to be illustrative only, and are under no circumstances to be interpreted as limiting the methods of the present invention in any way.

Compound I (382884)

3S, 4aR, 6S, 8aR-6-(((4-carboxy) phenyl) methyl) -1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a - decahydroisoquinoline-3-carboxylic acid

Those skilled in the art will recognize Compound I (382884) as an excitatory amino acid receptor antagonist, selective for the iGluR5 receptor subtype. Compound

I may be prepared by following recognized general procedures as described in United States Patent No. 5,446,051 (Issued August 29, 1995), and more specifically as described in WO 98/45270 (published October 15, 1998), the entire contents of which are both herein incorporated by reference.

Compound II (344864)

Those skilled in the art will recognize Compound U (344864) as an agonist of the 5-HTIF receptor. Compound II may be prepared by following recognized general procedures as described in United States Patents No. 5,708,187 and 5,814,653, the entire contents of which are both herein incorporated by reference.

Example II

To establish that a compound is a 5HTlf receptor agonist or a selective iGluR5 receptor antagonist and, thus, useful in the methods of the present invention, the ability of the compound to bind to the 5HTlf receptor or the iGluR5 receptor may be determined according to the following procedures. A. 5HT1F Receptor Binding The ability of the compounds employed in the present invention to bind to the 5HT1F receptor subtype can be measured essentially as described in N. Adham, et al, Proceedings of the National Academy of Sciences (USA), 90, 408-412 (1993), as taught in United States Patents No. 5,708,187, the entire contents of which is herein incorporated by reference. For comparison purposes, the binding affinities of compounds to other serotonin receptors can also be determined essentially as described below except that different cloned receptors are employed in place of the 5-HTIF receptor clone described herein.

Membrane Preparation

Membranes are prepared from transfected Ltk- cells which are grown to 100% confluency. The cells are washed twice with phosphate-buffered saline, scraped from the culture dishes into 5 mL of ice-cold phosphate-buffered saline, and centrifuged at 200 x g for 5 minutes at 4°C. The pellet is resuspended in 2.5 mL of ice-cold Tris buffer (20 mM Tris HC1, pH=7.4 at 23°C, 5 mM EDTA) and homogenized with a Wheaton tissue grinder. The lysate is subsequently centrifuged at 200 x g for 5 minutes at 4°C to pellet large fragments which are discarded. The supernatant is collected and centrifuged at 40,000 x g for 20 minutes at 4°C. The pellet resulting from this centrifugation is washed once in ice-cold Tris wash buffer and resuspended in a final buffer containing 50 mM Tris HC1 and 0.5 mM EDTA, pH=7.4 at 23°C. Membrane preparations are kept on ice and utilized within two hours for the radioligand binding assays. Protein concentrations are determined by the method of Bradford (Anal. Biochem., 72, 248-254 (1976)).

Radioligand Binding

[^H 5-Hr] binding is performed using slight modifications of the 5-HTID assay conditions reported by Herrick-Davis and Titeler (J. Neurochem., 50, 1624-1631 (1988)) with the omission of masking ligands. Radioligand binding studies are achieved at 37°C in a total volume of 250 μL of buffer (50 mM Tris, 10 mM MgCl2,

0.2 mM EDTA, 10 DM pargyline, 0.1% ascorbate, pH=7.4 at 37°C) in 96 well microtiter plates. Saturation studies are conducted using [3H]5-HT at 12 different concentrations ranging from 0.5 nM to 100 nM. Displacement studies are performed using 4.5-5.5 nM [3H]5-HT. The binding profile of drugs in competition experiments is accomplished using 10-12 concentrations of compound. Incubation times are, for example, 30 minutes for both saturation and displacement studies based upon initial investigations which determine equilibrium binding conditions. Nonspecific binding is defined in the presence of.iDM 5-HT. Binding is initiated by the addition of 50 DL membrane homogenates (10-20 Dg). The reaction is terminated by rapid filtration through presoaked (0.5% poylethyleneimine) filters using 48R Brandel Cell Harvester (Gaithersburg, MD). Subsequently, filters are washed for 5 seconds with ice cold buffer (50 mM Tris HC1, pH=7.4 at 4°C), dried and placed into vials containing 2.5 mL Readi-Safe (Beckman, Fullerton, CA) and radioactivity is measured using a Beckman LS 5000TA liquid scintillation counter. The efficiency of counting of [3H]5-HT averages between 45-50%. Binding data is analyzed by computer-assisted nonlinear regression analysis (Accufit and Accucomp, Lunden Software, Chagrin Falls, OH). IC50 values are converted to Kj values using the Cheng-Prusoff equation

(Biochem. Pharmacol, 22, 3099-3108 (1973). All experiments are performed in triplicate.

As was reported by R.L. Weinshank, et al., WO93/14201, the 5-HTIF receptor is functionally coupled to a G-protein as measured by the ability of serotonin and serotonergic drugs to inhibit forskolin stimulated cAMP production in NIH3T3 cells transfected with the 5-HTIF receptor. Adenylate cyclase activity is determined using standard techniques. A maximal effect is achieved by serotonin. An E_max is determined by dividing the inhibition of a test compound by the maximal effect and determining a percent inhibition. N. Adham, et al, supra,; R.L. Weinshank, et al., Proceedings of the National Academy of Sciences (USA), 89,3630-3634 (1992)), and the references cited therein.

Measurement of cAMP formation

Transfected NIH3T3 cells (estimated Bmax from one point competition studies=488 fmol/mg of protein) are incubated in DMEM, 5 mM theophylline, 10 mM HEPES (4-[2-hydroxyethyl]-l-piperazineethanesulfonic acid) and 10 D Dpargyline for 20 minutes at 37°C, 5% CO2. Drug concentration-effect curves are then conducted by adding 6 different final concentrations of drug, followed immediately by the addition of forskolin (10 D D Subsequently, the cells are incubated for an additional 10 minutes at 37°C, 5% CO2- The medium is aspirated and the reaction is stopped by the addition of 100 mM HC1. To demonstrate competitive antagonism, a concentration-response curve for 5-HT is measured in parallel, using a fixed dose of methio^'thepin (0. D D D D The plates are stored at 4°C for 15 minutes and then centrifuged for 5 minutes at 500 x g to pellet cellular debris, and the supernatant is aliquoted and stored at -20°C before assessment of cAMP formation by radioimmunoassay (cAMP radioimmunoassay kit; Advanced Magnetics, Cambridge, MA). Radioactivity is quantified using a Packard COBRA Auto Gamma counter, equipped with data reduction software. Compounds useful in the methods of the present invention are found to be agonists at the 5-HTι receptor in the cAMP assay.

B. iGluR5 Receptor Binding

The binding affinity of the selective iGluR5 antagonist compounds of the present invention, to the iGluR5 receptor, is first measured using standard methods.

For example, the activity of compounds acting at the iGluR5 receptor can be determined by radiolabelled ligand binding studies at the cloned and expressed human iGluR5 receptor (Korczak et al., 1994, Recept. Channels 3; 41-49), and by whole cell voltage clamp electrophysiological recordings of currents in acutely isolated rat dorsal root ganglion neurons (Bleakman et al., 1996, Mol. Pharmacol. 49; 581-585). The selectivity of compounds acting at the iGluR5 receptor subtype can then be determined by comparing antagonist activity at the iGluR5 receptor with antagonist activity at other AMPA and kainate receptors. Methods useful for such comparison studies include: receptor-ligand binding studies and whole-cell voltage clamp electrophysiological recordings of functional activity at human GluRj, GluR2,GluR3 and GIUR4 receptors (Fletcher et al., 1995, Recept. Channels 3; 21-31); receptor- ligand binding studies and whole-cell voltage clamp electrophysiological recordings of functional activity at human GluRg receptors (Hoo et al., Recept. Channels 2;327-

338); and whole-cell voltage clamp electrophysiological recordings of functional activity at AMPA receptors in acutely isolated cerebellar Purkmje neurons (Bleakman et al., 1996, Mol. Pharmacol. 49; 581-585) and other tissues expressing AMPA receptors (Fletcher and Lodge, 1996, Pharmacol. Ther. 70; 65-89).

iGluR5 antagonist binding affinity profiles

The iGluR5 antagonist binding profile for compounds of the present invention is determined essentially as described in WO98/45270. Cell lines (HEK293 cells) stably transfected with human iGluR receptors are employed. Displacement of 3[H] AMPA by increasing concentrations of antagonist is measured on iGluRj , iGluR2, iGluR3, and iGluR4 expressing cells, while displacement of 3[H] kainate (KA) is measured on iGluR5, iGluRβ, iGluR , and KA2-expressing cells. Estimated antagonist binding activity (Kj) in μM is determined for Compound I. As an indicia of selectivity, the ratio of binding affinity to the iGluR2 AMPA receptor subtype, versus the binding affinity to iGluR5 kainate receptor subtype, is also determined. Compounds useful in the methods of the present invention displayed a greater binding affinity for iGluR5 receptor subtype (lower Kj) versus that for iGluR2, preferably at least 10 fold greater for iGluR5 than that for iGluR2, and more preferably at least 100 fold.

Example III

The following animal model may be employed to determine the ability of the compounds of the present invention, to inhibit dural protein extravasation, a functional assay for the neuronal mechanism of migraine. The results of this assay, employing Compound I and Compound π, individually and in combination, are summarized in Figure 1 and Table 1 (infra).

Animal Model of Dural Protein Extravasation

Harlan Sprague-Dawley rats (225-325 g) or guinea pigs from Charles River Laboratories (225-325 g) are anesthetized with sodium pentobarbital intraperitoneally (65 mg/kg or 45 mg/kg respectively) and placed in a stereotaxic frame (David Kopf Instruments) with the incisor bar set at -3.5 mm for rats or -4.0 mm for guinea pigs. Following a midline sagital scalp incision, two pairs of bilateral holes are drilled through the skull (6 mm posterially, 2.0 and 4.0 mm laterally in rats; 4 mm posteriorly and 3.2 and 5.2 mm laterally in guinea pigs, all coordinates referenced to bregma). Pairs of stainless steel stimulating electrodes, insulated except at the tips (Rhodes Medical Systems, Inc.), are lowered through the holes in both hemispheres to a depth of 9 mm (rats) or 10.5 mm (guinea pigs) from dura.

The femoral vein is exposed and a dose of the test compound, or test compounds, is injected intravenously (i.v.) at a dosing volume of lml/Kg or, in the alternative, test compound may be administered orally (p.o) via gavage at a volume of 2.0ml/Kg . Approximately 7 minutes post i.v. injection, a 50 mg/Kg dose of Evans Blue, a fluorescent dye, is also injected intravenously. The Evans Blue complexes with proteins in the blood and functions as a marker for protein extravasation. Exactly 10 minutes post-injection of the test compound, the left trigeminal ganglion is stimulated for 3 minutes at a current intensity of 1.0 mA (5 Hz, 4 msec duration) with a Model 273 potentiostat/ galvanostat (EG&G Princeton Applied Research).

Fifteen minutes following stimulation, the animals are euthanized by exsanguination with 20 mL of saline. The top of the skull is removed to facilitate the collection of the dural membranes. The membrane samples are removed from both hemispheres, rinsed with water, and spread flat on microscopic slides. Once dried, the tissues are coverslipped with a 70% glycerol/water solution.

A fluorescence microscope (Zeiss) equipped with a grating monchromator and a spectrophotometer is used to quantify the amount of Evans Blue dye in each sample. An excitation wavelength of approximately 535 nm is utilized and the emission intensity at 600 nm is determined. The microscope is equipped with a motorized stage and also interfaced with a personal computer. This facilitates the computer- controlled movement of the stage with fluorescence measurements at 25 points (500 mm steps) on each dural sample. The mean and standard deviation of the measurements are determined by the computer.

The extravasation induced by the electrical stimulation of the trigeminal ganglion is an ipsilateral effect (i.e. occurs only on the side of the dura in which the trigeminal ganglion is stimulated). This allows the other (unstimulated) half of the dura to be used as a control. The ratio of the amount of extravasation in the dura from the stimulated side, over the amount of extravasation in the unstimulated side, is calculated ("extravasation ratio"). Control animals dosed with only with saline, yield an extravasation ratio of approximately 2.0 in rats and apprximately 1.8 in guinea pigs. In contrast, a compound which effectively completely prevents the extravasation in the dura from the stimulated side would yield an extravasation ratio of approximately 1.0.

A dose-response curve is generated for the 5HTlf agonist of Compound II and the dose that inhibits the protein extravasation ratio by 50% (ID50) is approximated.

The dose-response curve for Compound II is then repeated in the presence of the iGluR5 antagonist of Compound I which was administered at a dose that produced no change in extravasation ratio when administered alone. These dose response curves are depicted in Figure I (rats). Surprisingly, the administration of the selective iGluR5 antagonist, in combiniation with the 5HTlf agonist, shifted the dose response curve for the 5HTlf agonist to left, resulting in a 50 fold reduction in the resulting ED50 value. The respective ID50 values, for the individual and combinations of compounds employed in the methods of the present invention, are summarized in Table I below.

Table I

* This represents a 50 fold reduction in ID50 value compared with the value determined when Compound U was administered alone.

Claims

What is claimed is:

1. A method of treating a neurological disorder or neurodegenerative disease, comprising administering to a patient in need thereof, an effective amount of an excitatory amino acid receptor antagonist in combination with an effective amount of a 5HTi receptor agonist.

2. The method of Claim 1 wherein the neurological disorder is migraine.

3. The method of Claim 2 wherein the 5HTi receptor agonist is the compound of Compound U.

4. The method of Claim 2 wherein the excitatory amino acid receptor antagonist is a selective iGluR5 antagonist.

5. The method of Claim 4 wherein the selective iGluR5 antagonist is 3S, 4aR, 6S, 8aR-6-(((4-carboxy) phenyl) methyl) -1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a - decahydroisoquinoline-3-carboxylic acid.

6. The method according to Claim 3 wherein the excitatory amino acid receptor antagonist is a selective iGluR5 antagonist.

7. The method according to Claim 6 wherein the selective iGluR5 antagonist is 3S, 4aR, 6S, 8aR-6-(((4-carboxy) phenyl) methyl) -1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a - decahydroisoquinoline-3-carboxylic acid.

8. A pharmaceutical composition comprising an excitatory amino acid receptor antagonist and a 5HTif agonist in combination with with one or more pharmaceutically acceptable carriers, diluents, or excipients.

9. The composition according to Claim 8 wherein the 5HTif agonist is

Compound JJ.

10. The composition according to Claim 9 wherein the excitatory amino acid receptor antagonist is a selective iGluR5 antagonist.

11. The composition according to Claim 10 wherein the selective iGluR5 antagonist is 3S, 4aR, 6S, 8aR-6-(((4-carboxy) phenyl) methyl) -1, 2, 3, 4, 4a, 5, 6, 7,

8, 8a-decahydroisoquinoline-3-carboxylic acid.

12. The use of a selective iGluR5 antagonist in combination with a 5HTi agonist for the manufacture of a medicament for treating a neurological disorder.

13. The use of a selective iGluR5 antagonist in combination with a 5HTif agonist for the manufacture of a medicament for treating migraine.

14. A method of treating a neurological disorder comprising administering to a patient an effective amount of a compound which possesses the combined activities of an excitatory amino receptor antagonist and a 5HTif agonist.

15. A method of treating a neurological disorder comprising administering to a patient an effective amount of a compound which possesses the combined activities of a selective iGluR5 antagonist and a 5HTι f agonist.