BU48: A novel buprenorphine analog that exhibits δ-opioid-Mediated convulsions but not δ-opioid-mediated antinociception in mice

N-Cyclopropylmethyl-[7α,8α,2',3']-cyclohexano-1 '[S]-hydroxy-6,14-endo-ethenotetrahydronororipavine (BU48) is a novel, ring-constrained analog of buprenorphine. In vivo, BU48 (0.1-10 mg/kg s.c.) produced brief, nonlethal convulsions in mice followed by brief Straub tail and a short period of catalepsy characteristic of BW373U86 and other nonpeptidic δ-receptor agonists. BU48-induced convulsions were sensitive to antagonism by naltrindole (10 mg/kg s.c.) and were also prevented by administration of the putative δ₁ antagonist 7-benzylidenenaltrexone and the putative δ₂ antagonist naltriben, with the latter being more potent. In the abdominal stretch assay in the mouse, only low-efficacy antinociceptive activity of BU48 (0.1-10 mg/kg) was seen. This was reversed by the κ-opioid antagonist norbinaltorphimine (32 mg/kg s.c.) but not by the δ-opioid antagonist naltrindole (10 mg/kg s.c.). BU48 (10 mg/kg s.c.) acted as a δ-antagonist in this assay. In mouse brain homogenates, BU48 had high (nanomolar) binding affinity for all three opioid receptors in the order μ <gt> δ = κ. In vitro, the compound acted as a potent (EC₅₀ = 1.4 nM) κ-opioid agonist in the guinea pig ileum and a potent (EC₅₀ = 0.2 nM) δ-opioid agonist in the mouse vas deferens but showed partial agonist activity at the rat cloned δ-opioid (40%) and human cloned κ-opioid (59%) receptors with very low efficacy at the rat cloned μ-opioid receptor (10%); findings consistent with its in vivo profile. BU48 is the first described compound that produces δ-opioid-mediated convulsions without any evidence of δ-opiold-mediated antinociception and will be a useful tool in investigations of the δ-opioid receptor.