title: Pharmacological characterization of the nociceptin/orphanin FQ receptor antagonist SB-612111 [(-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol]: in vitro studies.
abstract: The compound SB-612111 [(-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol] was recently identified as a selective antagonist for the nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP). In the present study, the in vitro pharmacological profile of SB-612111 at human recombinant NOP receptors expressed in Chinese hamster ovary (CHO) cells [receptor binding, guanosine 5'-O-(3-[(35)S]thio)triphosphate (GTPgamma[(35)S]) binding, and cAMP level experiments] as well as at native NOP receptors expressed in peripheral (mouse and rat vas deferens, guinea pig ileum) and central (mouse cerebral cortex synaptosomes releasing [(3)H]5-HT) preparations was evaluated and compared with that of the standard nonpeptide antagonist (+/-)J-113397 [(+/-)-trans-1-[1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one]. SB-612111 produced a concentration-dependent displacement of [(3)H]N/OFQ binding to CHO(hNOP) cell membranes, showing higher affinity and NOP selectivity over classical opioid receptors than (+/-)J-113397. SB-612111 and (+/-)J-113397 competitively antagonized the effects of N/OFQ on GTPgamma[(35)S] binding in CHO(hNOP) cell membranes (pK(B), 9.70 and 8.71, respectively) and on cAMP accumulation in CHO(hNOP) cells (pK(B), 8.63 and 7.95, respectively), being per se inactive. In isolated peripheral tissues of mice, rats, and guinea pigs and in mouse cerebral cortex synaptosomes preloaded with [(3)H]5-HT, SB-612111 competitively antagonized the inhibitory effects of N/OFQ, with pA(2) values in the range of 8.20 to 8.50. In parallel experiments, (+/-)J-113397 was found to be 2- to 9-fold less potent than SB-612111. In the electrically stimulated tissues, 1 microM SB-612111 did not modify the effects of classical opioid receptor agonists. In conclusion, the results of the present study demonstrated that SB-612111 is among the most potent and NOP-selective nonpeptide antagonists identified to date.
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, Ferrara, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Spagnolo
authors.forename: Giacomo
authors.initials: G
authors.lastname: Carrà
authors.forename: Martina
authors.initials: M
authors.lastname: Fantin
authors.forename: Carmela
authors.initials: C
authors.lastname: Fischetti
authors.forename: Chris
authors.initials: C
authors.lastname: Hebbes
authors.forename: John
authors.initials: J
authors.lastname: McDonald
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Barnes
authors.forename: Anna
authors.initials: A
authors.lastname: Rizzi
authors.forename: Claudio
authors.initials: C
authors.lastname: Trapella
authors.forename: Giulia
authors.initials: G
authors.lastname: Fanton
authors.forename: Michele
authors.initials: M
authors.lastname: Morari
authors.forename: Dave G
authors.initials: DG
authors.lastname: Lambert
authors.forename: Domenico
authors.initials: D
authors.lastname: Regoli
authors.forename: Girolamo
authors.initials: G
authors.lastname: Calò
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D003508:Cycloheptanes / Q000378:metabolism / Q000494:pharmacology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009292:Narcotic Antagonists / Q000378:metabolism / Q000494:pharmacology; D018847:Opioid Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000235:genetics / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014162:Transfection; D014649:Vas Deferens / Q000187:drug effects / Q000378:metabolism; D000094942:Nociceptin Receptor
chemical_list: D001562:Benzimidazoles; D003508:Cycloheptanes; C402921:J 113397; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D010446:Peptide Fragments; D010880:Piperidines; D011957:Receptors, Opioid; C482404:cis-1-methyl-7-((4-(2,6-dichlorophenyl)piperidin-1-yl)methyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol; C466980:nociceptin orphanin FQ(1-17)OH; D005576:Colforsin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000242:Cyclic AMP; D000094942:Nociceptin Receptor