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

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 (p K d=7.8−8.6) and for human recombinant sst 1 receptors (p K d=8.0−8.1). SRA880 displayed significantly lower affinity for the other human recombinant somatostatin receptors (p K d≤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 p K 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.