SRA880, in vitro characterization of the first non-peptide somatostatin sst1 receptor antagonist*1

Abstract

This report describes the in vitro features of the first somatostatin sst1 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 sst1 receptors (pKd=7.8−8.6) and for human recombinant sst1 receptors (pKd=8.0−8.1). SRA880 displayed significantly lower affinity for the other human recombinant somatostatin receptors (pKd≤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-GTPγS binding, and SRIF stimulated luciferase gene expression; in all tests, SRA880 was devoid of intrinsic activity and acted as an apparently surmountable antagonist with pKB 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 sst1 receptor antagonist to be reported; SRA880 will be a useful tool for the characterization of somatostatin sst1 receptor-mediated effects both in vitro and in vivo.