RT Journal Article
SR Electronic
T1 Pharmacological Characterization of the Nociceptin/Orphanin FQ Receptor Antagonist SB-612111 [(–)-<em>cis</em>-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5<em>H</em>-benzocyclohepten-5-ol]: In Vitro Studies
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 961
OP 967
DO 10.1124/jpet.106.116764
VO 321
IS 3
A1 Barbara Spagnolo
A1 Giacomo Carrà
A1 Martina Fantin
A1 Carmela Fischetti
A1 Chris Hebbes
A1 John McDonald
A1 Timothy A. Barnes
A1 Anna Rizzi
A1 Claudio Trapella
A1 Giulia Fanton
A1 Michele Morari
A1 Dave G. Lambert
A1 Domenico Regoli
A1 Girolamo Calò
YR 2007
UL http://jpet.aspetjournals.org/content/321/3/961.abstract
AB 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-[35S]thio)triphosphate (GTPγ[35S]) 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 [3H]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 [3H]N/OFQ binding to CHOhNOP 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 GTPγ[35S] binding in CHOhNOP cell membranes (pKB, 9.70 and 8.71, respectively) and on cAMP accumulation in CHOhNOP cells (pKB, 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 [3H]5-HT, SB-612111 competitively antagonized the inhibitory effects of N/OFQ, with pA2 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 μM 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. The American Society for Pharmacology and Experimental Therapeutics