Hoyer, Daniel, Nunn, Caroline, Hannon, Jason, Schoeffter, Philippe, Feuerbach, Dominik, Schuepbach, Edi, Langenegger, Daniel, Bouhelal, Rochdi, Hurth, Konstanze, Neumann, Peter, 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
Related URLs:	http://www.ncbi.nlm.nih.gov/sites/entrez... doi:10.1016/j.neulet.2004.02.017
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
Related URLs:	http://www.ncbi.nlm.nih.gov/sites/entrez... doi:10.1016/j.neulet.2004.02.017
Date Deposited:	14 Dec 2009 13:55
Last Modified:	31 Jan 2013 01:07
URI:	https://oak.novartis.com/id/eprint/757