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SRA880, in vitro characterization of the first non-peptide somatostatin sst(1) receptor antagonist.

Hoyer, Daniel and Nunn, Caroline and Hannon, Jason and Schoeffter, Philippe and Feuerbach, Dominik and Schuepbach, Edi and Langenegger, Daniel and Bouhelal, Rochdi and Hurth, Konstanze and Neumann, Peter and Troxler, Thomas J. and Pfaeffli, Paul (2004) SRA880, in vitro characterization of the first non-peptide somatostatin sst(1) receptor antagonist. Neuroscience Letters, 361 (1-3). pp. 132-135. ISSN 0304-3940

Abstract

This report describes the in vitro features of the first somatostatin sst(1) receptor selective non-peptide antagonist, SRA880 ([3R,4aR,10aR]-1,2,3,4,4a,5,10,10a-Octahydro-6-methoxy-1-methyl-benz[g] quinoline-3-carboxylic-acid-4-(4-nitro-phenyl)-piperazine-amide, hydrogen malonate). SRA was evaluated in a number of in vitro systems of various species, both at native and recombinant receptors, using radioligand binding and second messenger/transduction studies. SRA880 has high affinity for native rat, mouse, monkey and human cerebral cortex somatostatin sst(1) receptors (pK(d) = 7.8-8.6) and for human recombinant sst(1) receptors (pK(d) = 8.0-8.1). SRA880 displayed significantly lower affinity for the other human recombinant somatostatin receptors ( pK(d) < or = 6.0) or a wide range of neurotransmitter receptors, except for the human dopamine D4 receptors. SRA880 was characterized in various transduction assays: somatotropin release inhibiting factor (SRIF) induced inhibition of forskolin-stimulated cAMP accumulation, SRIF stimulated-GTPgammaS binding, and SRIF stimulated luciferase gene expression; in all tests, SRA880 was devoid of intrinsic activity and acted as an apparently surmountable antagonist with pK(B) values of 7.5-7.7. Combined with the data from binding studies, these results suggest that SRA880 acts as a competitive antagonist. Thus, SRA880 is the first non-peptide somatostatin sst(1) receptor antagonist to be reported; SRA880 will be a useful tool for the characterization of somatostatin sst(1) receptor-mediated effects both in vitro and in vivo.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: Somatostatin receptors; Radioligand binding; Second messengers; Recombinant cells; Neuropeptides
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Date Deposited: 14 Dec 2009 13:55
Last Modified: 31 Jan 2013 01:07
URI: https://oak.novartis.com/id/eprint/757

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