Pharmacological studies with a nonpeptidic, delta-opioid (−)-(1R,5R,9R)-5,9-dimethyl-2′-hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride ((−)-NIH 11082)

Abstract

In the search for a selective delta-opioid receptor agonist, (-)-(1R,5R,9R)-5,9-dimethyl-2'-hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride ((-)-NIH 11082) and the (+)-enantiomer were synthesized and tested. (-)-NIH 11082 displayed antinociceptive activity in the paraphenylquinone test (PPQ test) in male ICR mice [ED 50 = 1.9 (0.7 -5.3) mg/kg, s.c.] and showed little, if any, activity in the tail-flick and hot-plate assays. The (+)-enantiomer was essentially inactive indicating stereoselectivity. Opioid receptor subtype characterization studies indicated that naltrindole, a delta-opioid receptor antagonist, was potent versus the ED 80 of (-)-NIH 11082 in the PPQ test [AD 50 = 0.75 (0.26 -2.20) mg/kg, s.c]. beta-Funaltrexamine and norbinaltorphimine, selective mu-and kappa-receptor antagonists, respectively, were inactive versus the ED 80 of (-)-NIH 11082. In rats with inflammation-induced pain, (-)-NIH 11082 produced antihyperalgesic effects that were attenuated by naltrindole. In morphine-dependent rhesus monkeys of both sexes, (-)-NIH 11082 neither substituted for morphine nor exacerbated withdrawal signs in the dose range of 4.0 to 32.0 mg/kg, s.c. Neither convulsions nor other overt behavioral signs were observed in any of the species tested. The results indicate that (-)-NIH 11082 has delta-opioid receptor properties.

The delta opioid receptor: an evolving target for the treatment of brain disorders

“…More recently, the identification of several novel systemically active delta opioid agonists has confirmed the potential of delta opioid receptors as a useful target for chronic pain (see [4,22,25,26,54-59] and Table 1) and some of these drugs are under clinical trials (http://clinicaltrials.gov/ct2/results?term=“delta+opioid”). …”

Delta opioid agonists: a concise update on potential therapeutic applications

“…163 ii JOM-13 was designed to decrease the residual flexibility in the backbone of DPDPE 164 and was found to be antidepressant in an animal model, but at doses that induced seizures. 113 iii (-)-NIH-11082 is a non-peptide DOR agonist with antinociceptive 165 and antidepressant activity 107 without seizures. iv Rubiscolin, a bioactive hexapeptide derived from spinach rubisco (ribulose-1,5-bisphosphate carboxylase/oxygenase), 166 improves learning (specifically memory consolidation) at doses less than antinociceptive doses 126 and has been reported to be anxiolytic 167 and orexigenic.…”

NIH 11082 produces anti-depressant-like activity in the mouse tail-suspension test through a delta-opioid receptor mechanism of action

“…The selective delta-opioid receptor agonist Tyr-D-Ser-(O-C(CH3)3)-Gly-PheLeu-Thr-(O-C(CH3)3 (BUBU) produced significant effects in the learned helplessness model of depression (TejedorReal et al, 1998). Similarly, increasing levels of endogenous delta-opioid peptides with enkephalinase inhibitors such as RB101 revealed antidepressant-like effects in both mice and rats (Baamonde et al, 1992;Tejedor-Real et al, 1998). In addition, the nonpeptidic delta-opioid receptor agonists SNC80 ( (+)-4-(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1piperazinyl)-3-methoxybenzyl)N,N-diethylbenzamide) and (+)BW373U86 ((+)-4-[(alpha-R*)-alpha-[(2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl]-3-hydroxybenzyl]-N,Ndiethylbenzamide) to rats elicited naltrindole-sensitive antidepressant-like properties, as assessed in the forced swim test (Broom et al, 2002a;Jutkiewicz et al, 2004;Jutkiewicz et al, 2005).…”