A NOVEL, POTENT AND SELECTIVE NONPEPTIDIC DELTA-OPIOID RECEPTOR AGONIST BW373U86

Four different opioid receptor binding assays and three different isol ated tissue studies were used to screen for de/ta receptor-selective n onpeptidic compounds. piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzami de (BW373U86) was a potent delta receptor-selective ligand in receptor binding assays. The K(i) values were 1.8 +/- 0.4, 15 +/- 3, 85 +/- 4 and 34 +/- 3 nM for delta, mu, epsilon and kappa receptor binding site s, respectively. BW373U86 inhibited electrically evoked muscle contrac tion of mouse vas deferens with an ED50 value of 0.2 +/- 0.06 nM. This inhibitory effect of BW373U86 was antagonized by the delta receptor-s elective antagonist naltrindole in a competitive manner: the Schild pl ot indicated a slope of 1 and a pA2 value of 9.43 (K(e) = 3.7 x 10(-10 ) M), which is consistent with the high affinity of naltrindole in del ta receptors. BW373U86 did not interact significantly with other recep tors. BW373U86 inhibited the acoustic startle reflex after subcutaneou s administration from 0.2- to 2-mg/kg doses in rats, and this inhibiti on was blocked by naltrindole. BW373U86 also induced a dose-dependent increase of locomotor activity in rats at similar doses. This effect w as inhibited by naltrindole. These data suggest that BW373U86 is a pot ent and selective nonpeptidic delta agonist, and it elicits distinct i n vivo pharmacological activities.