Polypeptides having a dopaminergic receptor activity, nucleic ac

Details Polypeptides having a dopaminergic receptor activity, nucleic ac Polypeptides having a dopaminergic receptor activity, nucleic ac

1991-12-31

1995-04-18

Hill, Jr., Robert J.

Chemistry: molecular biology and microbiology

Micro-organism, per se ; compositions thereof; proces of...

Bacteria or actinomycetales; media therefor

4353201, 530350, 536 235, C07K 1300, C12N 1512

Patent

active

054078237

DESCRIPTION:

BRIEF SUMMARY
The object of the invention is polypeptides having a dopaminergic receptor activity and the genes coding for these polypeptides.
The invention also relates to receptor activity, possible to evaluate the activity of agonist or antagonist agents towards the said receptors, above-mentioned polypeptides, probes which should be susceptible of being used for the in vitro diagnosis of diseases, in particular neurological, psychiatric, cardio-vascular or neuroendocrine diseases, polypeptides and which can be used both to purify the said polypeptides and analytically for in vitro diagnosis or therapeutically, in particular in the treatment of diseases involving the dopaminergic systems, above-mentioned polypeptides, neurological, cardio-vascular or neuroendocrine diseases and containing substances which are active towards the above-mentioned polypeptides having a dopaminergic receptor activity, or containing substances active on cells transfected by the genes or gene fragments coding for the said polypeptides with dopaminergic receptor activity, certain of whose side-effects, attributable to their interaction with the said polypeptides, it would be desirable to diminish.
It has been accepted hitherto that the various effects of dopamine are the result of its interaction with two types of receptors commonly designated by the names of D-1 and D-2 receptors (Kekabian J. W. and Calne D. B., "Multiple receptors for dopamine". Nature, 1979, 277: 93-96). Of the latter, only the sequence of the D-2 receptor was known (Bunzow J. R., Van Tol H. H. M., Grandy D. K., Albert P., Salon J., Christie Mc D., Machida C. A., Neve K. A. and Civelli O. "Cloning and expression of a D-2 dopamine receptor cDNA". Nature, 1988, 336: 783-787) and two isoforms of the D-2 receptor (sometimes designated D-2A and D-2B or also D-2(415) and D-2(444) resulting from the alternative splicing of the messenger RNA of the gene for the said receptor had been described (Giros B., Sokoloff P., Martres M. P., Riou J. F., Emorine L. J. and Schwartz J. C. "Alternative splicing directs the expression of two D-2 dopamine receptor isoforms". Nature, 1989, 342:923-926; Dal Toso R., Sommer B., Ewert M., Herb A., Pritchett D. B., Bach A., Shivers B. D. and Seeburg P. H. "The dopamine D-2 receptor: two molecular forms generated by alternative splicing". The EMBO Journal, 1989, 8:4025-4034).
The D-2 receptor belongs to the family of the receptors containing seven transmembrane domains, coupled to a G protein and exhibiting a certain degree of homology with the receptors of the family of the rhodopsins which are expressed by the photoreceptors of the retina.
The existence of distinct dopaminergic receptors corresponding to the D-1 and D-2 receptors had been suspected by various authors on the basis of indirect observations (see in particular Schwartz J. C., Delandre M., Martres M. P., Sokoloff P., Protais P., Vasse M., Costentin J., Laibe P., Wermuth C. G., Gulat C. and Lafitte A. "Biochemical and behavioral identification of discriminant benzamide derivatives: new tools to differentiate subclasses of dopamine receptors". Catecholamines: neuropharmacology and central nervous system. Theoretical aspects. Alan R. Liss, Inc. N.Y. 1984, pp. 59-72) but had never been proved because the said receptors had never been isolated, nor identified as regards their structure, nor completely defined with respect to their pharmacological properties. In particular, the existence of autoreceptors regulating the synthesis and/or the release of dopamine and/or also the activity of the dopaminergic neurones had been demonstrated but it was commonly accepted that they were identical with the D-2 receptors as far as their pharmacology was concerned.
The object of the invention is to make available novel polypeptides having a dopaminergic receptor activity unrelated to either that of the D-1 dopaminergic receptors or that of the D-2 dopaminergic receptors.
The object of the invention is also screening procedures for novel medicines which act on the novel polypeptides having a dopaminergic re

REFERENCES:
patent: 4675285 (1987-06-01), Clark et al.
Biochem. Pharmacol. 31; 1183-1187, 1982, Davis et al. Solubilized Receptors for [.sup.3 H] dopamine (D.sub.3 Binding Sites) From Canine Brain.
Nature 329; 836-838, 29 Oct. 1987, Masu et al. cDNA cloning of bovine substance-K receptor through oocyte expression system.
Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, publisher; Cold Spring Harbor, N.Y.; Contents pp. iii-ix (1988).
Martes et al., "Widespread Distribution of Brain Dopamine Receptors Evidenced with [.sup.125 I]Iodosulpride, a Highly Selective Ligand", Science, 228:752-755 (1985).
Sokoloff et al., "Three classes of Dopamine Receptor (D-2, D-3, D-4) Identified by Binding Studies with .sup.3 H-Apomorphine and .sup.3 H-Doperidone", Naunyn-Smiedebergs Arch. Pharmacol., 315:89-102 (1980).

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