Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1993-10-05
1999-03-16
Ulm, John
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
435 71, 435 72, 435 691, 4352523, 4353201, 526 235, 530350, C07K 14705, C12N 1512
Patent
active
058828559
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Throughout this application various publications are referenced by full citations within parentheses. The disclosures of these publications in their entireties are hereby incorporated by reference in this application in order to more fully describe the state of the art to which this invention pertains.
Pharmacological studies, and more recently gene cloning, have established that multiple receptor subtypes exist for most, if not all, neurotransmitters. The existence of multiple receptor subtypes provides one mechanism by which a single neurotransmitter can elicit distinct cellular responses. The variation in cellular response can be achieved by the association of individual receptor subtypes with different G proteins and different signalling systems. Further flexibility is provided by the ability of distinct receptors for the same ligand to activate or inhibit the same second messenger system.
Individual receptor subtypes reveal characteristic differences in their abilities to bind a number of ligands, but the structural basis for the distinct ligand-binding properties is not known. Physiologists and pharmacologists have attempted to specify particular biological functions or anatomical locations for some receptor subtypes, but this has met with limited success. Similarly, the biochemical mechanisms by which these receptors transduce signals across the cell surface have been difficult to ascertain without having well-defined cell populations which express exclusively one receptor subtype.
Dopamine receptors have been classified into two subtypes, D.sub.1 and D.sub.2, based on their differential affinities for dopamine agonists and antagonists, and their stimulation or inhibition of adenylate cyclase (for reviews, see Kebabian, J. W. and Calne, D. B. (1979), Nature 277, 93-96; Creese, I., Sibley, D. R., Hamblin, M. W., Leff, S. E. (1983), Ann. Rev. Neurosci. 6, 43-71; Niznik, H. B. and Jarvie, K. R. (1989), Dopamine receptors. in "Receptor Pharmacology and Function", eds. Williams, M., Glennon, R., and Timmermans, P., Marcel Dekker Inc., New York, pp. 717-768). The D.sub.1 receptor of the central nervous system is defined as an adenylate cyclase stimulatory receptor. The location of the prototypic D.sub.1 receptor is the bovine parathyroid gland, where dopamine agonists stimulate cAMP synthesis via adenylate cyclase, accompanied by parathyroid hormone release. Dopamine-stimulated adenylate cyclase activity and parathyroid hormone release are sensitive to both GTP and cholera toxin. This suggests that the D.sub.1 receptor is associated with a G.sub.S guanine nucleotide binding protein. The D.sub.2 receptor, in contrast, inhibits adenylate cyclase activity, and appears to be the primary target of most neuroleptic drugs (Niznik, H. B. and Jarvie, K. R. (1989). Dopamine receptors, in "Receptor Pharmacology and Function", eds. Williams, M., Glennon, R., and Timmermans, P., Marcel Dekker Inc., New York, pp. 717-768). The prototypic D.sub.2 receptor has been characterized in the anterior pituitary where it is associated with the inhibition of release of prolactin and alpha-melanocyte stimulating hormones. Recent work has shown that several different D.sub.1 and D.sub.2 receptor subtypes may be present in the mammalian nervous system (Andersen, P. H., Gingrich, J. A., Bates, M. D., Dearry, A., Falardeau, P., Senogles, S. E., and Caron, M. G. Trends in Pharmacolog. Sci. 11: 231 (1990)), which would suggest that a family of different proteins with pharmacological properties similar to the classically defined D.sub.1 and D.sub.2 receptors may exist.
Neuroleptics, in addition to their use as drugs to treat severe psychiatric illnesses, are high affinity ligands for dopamine receptors. Butyrophenones such as haloperidol and spiperone are antagonists specific for the D.sub.2 receptor, while the recently developed benzazepines such as SCH-23390 and SKF-38393 are selective for the D.sub.1 receptor (Niznik, H. B. and Jarvie, K. R. (1989), Dopamine receptors, in "Receptor Pharmacology and Functio
REFERENCES:
Sunahara, R.K., et al. Cloning of the gene for a human dopamine D5 receptor with higher affinity for dopamine than D.sub.1. Nature 1991; 350:614-619 (Exhibit I).
Dearry et al., Nature 347:72-76, Sep. 6, 1990.
Hartig Paul R.
Weinshank Richard L.
Synaptic Pharmaceutical Corporation
Ulm John
White John P.
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