Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1999-03-03
2001-06-12
Jarvis, William R. A. (Department: 1614)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C436S092000, C514S380000
Reexamination Certificate
active
06245521
ABSTRACT:
This invention relates to a method of treating psychiatric disorders including cognitive disorders and assays for compounds having such activity.
BACKGROUND OF THE INVENTION
It is well known that excitatory neurotransmission in the mammalian central nervous system is primarily mediated by the amino acid, L-glutamate, acting on ionotropic and metabotropic receptors. Glutamate can act at three types of ionotropic glutamate receptors, (R,S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propanoate (AMPA), kainate (KA) and N-methyl-D-aspartate (NMDA) receptors (Hollman and Heinemann, 1994,
Annu. Rev. Neurosci.
17; 31-108). Molecular biological studies have established that AMPA receptors are composed of subunits (GluR 1-4) that can assemble to form functional channels. Five kainate receptors, classified as either high affinity (KA1 and KA2) or low affinity (Glur5, GluR6, and GluR7) kainate receptors have been identified (Bleakman et al., 1996,
Mol. Pharmacol.
49, No. 4; 581-585).
It is well established that the hippocampus is important in learning and memory (Squire, 1992,
Psychol. Rev.
99; 195-231) and it is considered that such cognitive functions are mediated by plastic changes in glutamatergic transmission within the hippocampus involving AMPA, NMDA and metabotropic receptor activation (Bliss and Collingridge, 1993,
Nature,
361, 31-39). An example of such a plastic change is long term potentiation which can be demonstrated using standard electrophysiological methods in vivo, and in vitro, in hippocampal slices. Recently, it has been reported that kainate modulates neurotransmitter release in the hippocampus (Chittajullu et al., 1995,
Nature
379, 78-81), but it remains unclear which receptors underlie this modulating effect of kainate.
We have presently discovered that compounds having activity at one of the kainate receptor subtypes, namely GluR5, modulate synaptic transmission within the hippocampus. Such compounds thus have potential for altering cognitive functions and are therefore indicated for the treatment of cognitive disorders.
One such compound having activity at the GluR5 receptor is ATPA (2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid). ATPA is a known compound (Lauridsen et al., 1985;
J. Med. Chem.
28: 668-672) and was hitherto regarded as a selective AMPA receptor agonist (Krogsgaard-Larsen et al.,1996,
Eur.J. Med. Chem.
31: 515-537). We have discovered that ATPA is a potent GluR5 ligand with nanomolar activity on human GluR5 in binding studies, and is more than 1000-fold less potent on other human AMPA and kainate receptors. Furthermore, in electrophysiological studies we have discovered that ATPA is a potent GluR5 agonist with micromolar activity on human GluR5 and rat DRG neurons and is 100-fold less potent on other human AMPA and kainate receptors.
It i s also well known that the hippocampus is involved in many other physiological and pathological functions (Kato, N. (ed) 1996,
The Hippocampus: Functions and Clinical Relevance.
Elsevier, Amsterdam). Importantly the hippocampus is involved in convulsive disorders (Dingledine et al., 1990
TIPS
11, 334-338) and is subject to neurodegeneration as a result of ischaemic, hypoxic, and hypoglycemic episodes (Meldrum and Garthwaite, 1990
TIPS
11; 379-387). It is also well known that GluR5 receptors are distributed in other parts of the brain (Bettler et al., 1990,
Neuron
5; 583-595).
It is further known that kainate receptors are located on dorsal root fibers and dorsal root ganglion neurons. ATPA is a potent agonist on these neurons which conduct nociceptive information into the spinal cord.
Thus, the present invention relates to methods of treating psychiatric and neurological disorders by administration of a compound that modulates the GluR5 receptor. Further, the present invention relates to assays for the identification of compounds that modulate the GluR5 receptor.
The treatment of mammalian psychiatric and neurological disorders is hereby furthered.
SUMMARY OF THE INVENTION
The present invention provides a method of treating a cognitive disorder which comprises administering to a patient in need thereof, a compound that modulates the GluR5 receptor in the hippocampus. Further, the present invention provides a method of treating a cognitive disorder which comprises administering to a patient in need thereof, a compound that shows selectivity for the GluR5 receptor, preferably ATPA, or a pharmaceutically acceptable salt thereof.
The present invention also provides a method of evaluating the binding activity of a test compound to recombinant or native GluR5 receptors, which method comprises; treating a sample containing recombinant or native GluR5 receptors with a measured quantity of the test compound; adding a measured quantity of labeled ATPA, or a salt thereof; and assaying the binding activity by measurement of the amount of labeled ATPA bound and test compound displaced.
Also provided in the present invention is a method of evaluating the effectiveness of a test compound for use in treating cognitive, psychiatric, or neurological disorders, which method comprises; measuring the binding affinity of the test compound to GluR5 receptors in the hippocampus or other tissue; and selecting the test compound according to its binding affinity to GluR5, relative to ATPA.
Additional methods provided in the present invention include a method of treating pain, or a neurological or psychiatric disorder, which method comprises administering to a patient in need thereof, a compound that modulates the GluR5 receptor in the hippocampus. Further, the present invention provides a method of treating pain, or a neurological or psychiatric disorder which comprises administering to a patient in need thereof, a compound that shows selectivity for the GluR5 receptor, preferably ATPA, or a pharmaceutically acceptable salt thereof.
REFERENCES:
patent: 5565580 (1996-10-01), Wätjen
patent: 5721234 (1998-02-01), Bigge et al.
patent: 5731348 (1998-03-01), Gu
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Wahl, et al., Pharmacology and Toxicology of ATOA an AMPA receptor antagonist and a partial agonist at GluR5 receptors, neuropharmacology, Sep. 1998. vol. 37, pp. 1205-1210.
Proctor, Actions of Kainate and AMPA Selective Glutamate Receptor Ligands on Nociceptive Processing in the Spinal Cord, Neuropharmacology, Sep. 1998, vol. 37, pp. 1287-1297.
Vignes, et al., The GluR5 subtype of kainate receptor regulates excitatory synaptic transmission in areas CA1 and CA3 of the rat hippocampus,Neuropharmacology, (1998) vol. 37, pp. 1269-1277.
Stensbøl, et al., Resolution, absolute Stereochemistry and molecular pharmacology of the enantiomers of ATPA,European Journal of Pharmacology, (1999), vol. 380, pp. 153-162.
Clarke, et al., A hippocampal GluR5 kainate receptor regulating inhibitory synaptic transmission,Nature, vol. 389, Oct. 9, 1997, pp. 599-603.
Carroll, et al., Regional distribution of low affinity kainate receptors in brain of Macaca fascicularis determined by autoradiography using [3H](2S,4R)-4-methylglutamate,Neuroscience Letters, vol. 255, (1998), pp. 71-74.
Thomas, et al., Pharmacological differentiation of kainate receptors on neonatal rat spinal motoneurones and forsal roots,Neuropharmacology, vol. 37, (1998), pp. 1223-1237.
Johansen, et al., Synthesis of Deuterium and Tritium labelled (RS)-2-Amino-3-(5-tert-butyl-3-hydroxy-4-isoxazolyl)-propionic Acid (ATPA), a selective Kainic Acid Receptor Agonist,Journal of Labelled Compounds and Radiopharmaceuticals, vol. 42, (1999), pp. 937-947.
Bleakman★and Hoo†, A high radioligand selective for the GluR5 kainate receptor , Life Science News 3, 1999 Amersham Pharmacia Biotech, pp. 10,★Eli Lilly and Company, Indianapolis, IN;†Allelix Biopharmaceuticals, Mississauga, Ontario Canada.
Bleakman David
Lodge David
Eli Lilly and Company
Jarvis William R. A.
Wilson Alexander
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