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BEHAVIORAL PHARMACOLOGY

SR 16435 [1-(1-(Bicyclo[3.3.1]nonan-9-yl)piperidin-4-yl)indolin-2-one], a Novel Mixed Nociceptin/Orphanin FQ/µ-Opioid Receptor Partial Agonist: Analgesic and Rewarding Properties in Mice

Center for Health Sciences (T.V.K.), Drug Discovery Program (N.T.Z., C.O., F.J.), and Neuropharmacology Program (W.E.P., J.O., L.T.), SRI International, Menlo Park, California

We identified a novel nociceptin/orphanin FQ (NOP)/µ-opioid receptor agonist, SR 16435 [1-(1-(bicyclo[3.3.1]nonan-9-yl)piperidin-4-yl)indolin-2-one], with high binding affinity and partial agonist activity at both receptors. It was hypothesized that SR 16435 would produce antinociception and yet, unlike morphine, would have diminished rewarding properties and tolerance development. Antinociception was assessed in mice using the tail-flick assay, whereas behavioral and rewarding effects were assessed using the place conditioning (PC) paradigm. PC was established by pairing drug injections with a distinct compartment. Behavioral effects were measured after acute and repeated drug administration, and the test for PC was carried out 24 h after four drug- and vehicle-pairing sessions. SR 16435 produced an increase in tail-flick latency, but SR 16435-induced antinociception was lower than that observed with morphine. Given that naloxone blocked SR 16435-induced antinociception, it is highly likely that this effect was mediated by µ-opioid receptors. Compared with morphine, chronic SR 16435 treatment resulted in reduced development of tolerance to its antinociceptive effects. SR 16435-induced conditioned place preference (CPP) was evident, an effect that was probably mediated via µ-opioid receptors, as it was reversed by coadministration of naloxone. NOP agonist activity was also present, given that SR 16435 decreased global activity, and this effect was partially reversed with the selective NOP antagonist, SR 16430 [1-(cyclooctylmethyl)-4-(3-(trifluoromethyl)phenyl)piperidin-4-ol]. Naloxone, however, also reversed the SR 16435-induced decrease in activity, indicating that both opioid and NOP receptors mediate this behavior. In summary, the mixed NOP/µ-opioid partial agonist SR 16435 exhibited both NOP and µ-opioid receptor-mediated behaviors.

Address correspondence to. Dr. Taline Khroyan, Center for Health Sciences, BN144, SRI International, 333 Ravenswood Ave., Menlo Park, CA 94025. E-mail: taline.khroyan{at}sri.com