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

• Published in: Neuroscience letters Vol. 361; no. 1-3; pp. 132 - 135
• Main Authors: Hoyer, D, Nunn, C, Hannon, J, Schoeffter, P, Feuerbach, D, Schuepbach, E, Langenegger, D, Bouhelal, R, Hurth, K, Neumann, P, Troxler, T, Pfaeffli, P
• Format: Journal Article
• Language: English
• Published: Ireland 06.05.2004
• Subjects: Animals; Binding, Competitive - drug effects; Binding, Competitive - physiology; Biological Assay; Cells, Cultured; CHO Cells; Cricetinae; Cyclic AMP - metabolism; Fibroblasts - cytology; Fibroblasts - drug effects; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; Heterocyclic Compounds, 4 or More Rings - chemistry; Heterocyclic Compounds, 4 or More Rings - pharmacology; Humans; Mice; Molecular Structure; Piperazines - chemistry; Piperazines - pharmacology; Quinolines - chemistry; Quinolines - pharmacology; Radioligand Assay; Rats; Receptors, Neurotransmitter - drug effects; Receptors, Neurotransmitter - metabolism; Receptors, Somatostatin - antagonists & inhibitors; Receptors, Somatostatin - metabolism; Somatostatin - pharmacology
• ISSN: 0304-3940
• DOI: 10.1016/j.neulet.2004.02.017

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.