title: 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 (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.
authors.affiliation: Neuroscience Research, Novartis Institutes for Biomedical Research, WSJ 386-745, Novartis Pharma AG, CH 4002 Basel, Switzerland. daniell.hoyer@pharma.novartis.com
authors.forename: D
authors.initials: D
authors.lastname: Hoyer
authors.forename: C
authors.initials: C
authors.lastname: Nunn
authors.forename: J
authors.initials: J
authors.lastname: Hannon
authors.forename: P
authors.initials: P
authors.lastname: Schoeffter
authors.forename: D
authors.initials: D
authors.lastname: Feuerbach
authors.forename: E
authors.initials: E
authors.lastname: Schuepbach
authors.forename: D
authors.initials: D
authors.lastname: Langenegger
authors.forename: R
authors.initials: R
authors.lastname: Bouhelal
authors.forename: K
authors.initials: K
authors.lastname: Hurth
authors.forename: P
authors.initials: P
authors.lastname: Neumann
authors.forename: T
authors.initials: T
authors.lastname: Troxler
authors.forename: P
authors.initials: P
authors.lastname: Pfaeffli
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001681:Biological Assay; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013004:Somatostatin / Q000494:pharmacology
chemical_list: C488795:1,2,3,4,4a,5,10,10a-octahydro-6-methoxy-1-methylbenz(g)quinoline-3-carboxylic acid 4-(4-nitrophenyl)piperazine amide; D006576:Heterocyclic Compounds, 4 or More Rings; D010879:Piperazines; D011804:Quinolines; D017981:Receptors, Neurotransmitter; D017481:Receptors, Somatostatin; C101130:somatostatin receptor type 1; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013004:Somatostatin; D000242:Cyclic AMP