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Hoyer D, Nunn C, Hannon J, Schoeffter P, Feuerbach D, Schuepbach E, Langenegger D, Bouhelal R, Hurth K, Neumann P, Troxler T, Pfaeffli P: SRA880, in vitro characterization of the first non-peptide somatostatin sst (1) receptor antagonist. Neurosci Lett. 2004 May 6;361(1-3):132-5.
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. |
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