Patent Highlights December 2018-January 2019

摘要

The nociceptin (previously, orphanin FQ) receptor is the fourth member of the opioid receptor superfamily. Nociceptin inhibits the expression of cocaine-induced conditioned place preference in the rat [i], but is without effect on place preference in cocaine-naive rats even at high intracerebroventricular doses. Griinenthal s cebranopadol (GRT-6005), an almost full high-affinity agonist at both nociceptin and (J.-opiod receptors [2], was equivalent to morphine in a Phase III clinical trial of patients with cancer-related pain. The discriminative stimulus exerted by its ^.-receptor agonism seems to be reduced by its nociceptin receptor agonism [3]. Considering all the above, nociceptin receptor agonists should be devoid of abuse liability not only as analgesics but also as therapeutics for stimulant addiction. Indeed, rat experiments showed that cebranopadol (25 or 50 M-g/kg p.o.) significantly reduced cocaine self-administration, without development of tolerance, under fixed and progressive ratio schedules of reinforcements indicating reduced motivation for cocaine following drug treatment. Neither the nociceptin receptor blocker SB-612111 nor naltrexone alone were able to antagonize cebranopadol-induced reduction of cocaine self-administration; however, they did so completely when coadministered. Cebranopadol also attenuated yohimbine- and cue-induced reinstatement of heroin seeking, a finding that has been, in part, addressed by GrunenthaTs WO/2016/116280. Note that similar effects have recently been reported for a pure nociception agonist, AT-312 (Astraea Therapeutics LLC) [4].