Vol. 294, Issue 3, 1195-1200, September 2000

BU48: A Novel Buprenorphine Analog That Exhibits -Opioid-Mediated Convulsions but Not -Opioid-Mediated Antinociception in Mice¹

Daniel C. Broom, Li Guo, Andrew Coop² , Stephen M. Husbands, John W. Lewis, James H. Woods and John R. Traynor

Departments of Pharmacology (D.C.B., J.H.W., J.R.T.) and Psychology (J.H.W.), University of Michigan Medical School, Ann Arbor, Michigan; Department of Chemistry, University of Bristol, Bristol, United Kingdom (A.C., S.M.H., J.W.L.); and Department of Chemistry, Loughborough University, Loughborough, United Kingdom (L.G., J.R.T.)

N-Cyclopropylmethyl-[7,8,2',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 -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 ₁ antagonist 7-benzylidenenaltrexone and the putative ₂ 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 -opioid antagonist norbinaltorphimine (32 mg/kg s.c.) but not by the -opioid antagonist naltrindole (10 mg/kg s.c.). BU48 (10 mg/kg s.c.) acted as a -antagonist in this assay. In mouse brain homogenates, BU48 had high (nanomolar) binding affinity for all three opioid receptors in the order µ >  = . In vitro, the compound acted as a potent (EC₅₀ = 1.4 nM) -opioid agonist in the guinea pig ileum and a potent (EC₅₀ = 0.2 nM) -opioid agonist in the mouse vas deferens but showed partial agonist activity at the rat cloned -opioid (40%) and human cloned -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 -opioid-mediated convulsions without any evidence of -opioid-mediated antinociception and will be a useful tool in investigations of the -opioid receptor.