SNC-80, A SELECTIVE, NONPEPTIDIC AND SYSTEMICALLY ACTIVE OPIOID-DELTAAGONIST

The present study has investigated the pharmacology of SNC 80, a nonpe ptidic ligand proposed to be a selective delta agonist in vitro and in vivo. SNC 80 was potent in producing inhibition of electrically induc ed contractions of mouse vas deferens, but not in inhibiting contracti ons of the guinea pig isolated ileum (IC50 values of 2.73 nM and 5457 nM, respectively). The delta selective antagonist ICI 174,864 (1 mu M) and the mu selective antagonist CTAP (1 mu M) produced 236- and 1.9-f old increases, respectively, in the SNC 80 IC50 value in the mouse vas deferens. SNC 80 preferentially competed against sites labeled by [H- 3]naltrindole (delta receptors) rather than against those labeled by [ H-3]DAMGO (mu receptors) or [H-3]U69, 593 kappa receptors) in mouse wh ole-brain assays. The ratios of the calculated K-i values for SNC 80 a t mu/delta and kappa/delta sites were 495- and 248-fold, respectively, which indicates a significant degree of delta selectivity for this co mpound in radioligand binding assays. SNC 80 produced dose- and time-r elated antinociception in the mouse warm-water tail-flick test after i .c.v., i.th, and i.p. administration. The calculated A(50) values (and 95% C.I.) for SNC 80 administered i.c.v., i.th, and i.p. were 104.9 ( 63.7-172.7) nmol, 69 (51.8-92.1) nmol and 57 (44.5-73.1) mg/kg, respec tively. The i.c.v, administration of SNC 80 also produced dose- and ti me-related antinociception in the hot-plate test, with a calculated A( 50) value (and 95% C.I.) of 91.9 (60.3-140.0) nmol. Intraperitoneal SN C 80 antinociception was antagonized by pretreatment with i.c.v. nalox one (3 nmol), with i.c.v. or i.th. N,N-diallyl-Tyr-(Aib)(2)-Phe-Leu-OH (Aib = alpha-amino isobutyric acid) (4.4 nmol) or with i.p. naltrindol e (20 mg/kg), but not i.c.v. or i.th. beta-FNA (18.8 nmol at -24 hr). Furthermore, the antinociceptive effects of i.c.v. SNC 80 were antagon ized by i.c.v, pretreatment with either [D-Ala(2),Leu(5),Cys(6)]enkeph alin (a putative delta(1) antagonist) or [D-Ala(2), Cys(4)]deltorphin (a putative delta(2) antagonist), but not by beta-funaltrexamine (a mu antagonist). This suggests that the antinociceptive actions of SNC 80 are produced via both opioid delta(1) and delta(2), but not mu, recep tors. On the basis of its profile in vivo and in vitro, SNC 80 is perh aps the first highly selective, nonpeptidic and systemically active op ioid delta agonist. SNC 80 promises to be a useful compound for the ex ploration of opioid delta-receptor pharmacology and provides a basis f or the further identification of selective nonpeptidic delta ligands.