The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Nov 1996
N-cyclobutylmethyl analog of normorphinone, N-CBM-TAMO: a short-term opioid agonist and long-term Mu-selective irreversible opioid antagonist.
The antinociceptive and opioid binding properties of the N-cyclobutylmethyl analog of normorphinone, 14 alpha, 14' beta-[dithiobis[(2-oxo-2, 1-ethanediyl)imino]]bis[7,8-dihydro-N-(cyclobutylmethyl)-normor phinone] (N-CBM-TAMO) were investigated. This compound is a dimer, containing a disulfide capable of binding to thiol groups on the opioid receptor. Competition radioligand binding assays with bovine striatal membranes demonstrated that N-CBM-TAMO displayed a higher affinity for mu opioid receptors than for kappa and delta receptors. ⋯ N-CBM-TAMO at doses of 3 nmol and higher, which produced supermaximal short-term antinociception in the writhing test, produced a time- and dose-dependent long-term antagonism of U50,488 (trans)-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methanesulfonate hydrate)-induced antinociception in a reversible manner, probably because of the development of tolerance. These in vivo data, together with the in vitro binding data, demonstrate that N-CBM-TAMO is a potent kappa agonist and at higher doses produces antinociception mediated by mu receptors. N-CBM-TAMO also produces long-term noncompetitive antagonism of antinociception mediated by mu opioid receptors.