SNC 80, a selective, nonpeptidic and systemically active opioid delta agonist

The present study has investigated the pharmacology of SNC 80, a nonpeptidic ligand proposed to be a selective δ agonist in vitro and in vivo. SNC 80 was potent in producing inhibition of electrically induced contractions of mouse vas deferens, but not in inhibiting contractions of the guinea pig isolated ileum (IC₅₀ values of 2.73 nM and 5457 nM, respectively). The δ selective antagonist ICI 174,864 (1 μM) and the μ selective antagonist CTAP (1 μM) produced 236- and 1.9-fold increases, respectively, in the SNC 80 IC₅₀ value in the mouse vas deferens. SNC 80 preferentially competed against sites labeled by [³H]naltrindole (δ receptors) rather than against those labeled by [³H]DAMGO (μ receptors) or [³H]U69, 593 κ receptors) in mouse whole-brain assays. The ratios of the calculated K(i) values for SNC 80 at μ/δ and κ/δ sites were 495- and 248- fold, respectively, which indicates a significant degree of δ selectivity for this compound in radioligand binding assays. SNC 80 produced dose- and time-related antinociception in the mouse warm-water tail-flick test after i.c.v., i.th. and i.p. administration. The calculated A₅₀ 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, respectively. The i.c.v. administration of SNC 80 also produced dose- and time-related antinociception in the hot-plate test, with a calculated A₅₀ value (and 95% C.I.) of 91.9 (60.3-140.0) nmol. Intraperitoneal SNC 80 antinociception was antagonized by pretreatment with i.c.v. naloxone (3 nmol), with i.c.v. or i.th. N,N-diallyl- Tyr-(Aib)²-Phe-Leu-OH(Aib=α-amino isobutyric acid) (4.4 nmol) or with i.p. naltrindole (20 mg/kg), but not i.c.v. or i.th. β-FNA (18.8 nmol at -24 hr). Furthermore, the antinociceptive effects of i.c.v. SNC 80 were antagonized by i.c.v. pretreatment with either [D-Ala²,Leu⁵,Cys⁶]enkephalin (a putative δ₁ antagonist) or [D-Ala², Cys⁴]deltorphin (a putative δ₂ antagonist), but not by β-funaltrexamine (a μ antagonist). This suggests that the antinociceptive actions of SNC 80 are produced via both opioid δ₁ and δ₂, but not μ, receptors. On the basis of its profile in vivo and in vitro, SNC 80 is perhaps the first highly selective, nonpeptidic and systemically active opioid δ agonist. SNC 80 promises to be a useful compound for the exploration of opioid δ-receptor pharmacology and provides a basis for the further identification of selective nonpeptidic δ ligands.