Alkylation of opioid receptor subtypes by alpha-chlornaltrexamine produces concurrent irreversible agonistic and irreversible antagonistic activities.

alpha-Chlornaltrexamine (1a, alpha-CNA), the C-6 epimer of the opioid receptor affinity label beta-CNA (1b), has been synthesized and tested in vitro and in vivo. In vitro, alpha-CNA appears to alkylate opioid receptor subtypes (mu, kappa, and delta) and is similar to beta-CNA in its ability to produce irreversible antagonism at all three subtypes. However, 1a differs from 1b in that it exhibits additionally an irreversible agonist activity in the guinea pig ileum preparation but not in the mouse vas deferens preparation. This latter activity is discussed in terms of an irreversible mixed agonism-antagonism at kappa receptors, or, alternatively, it may reflect differences between mu receptors in the two in vitro preparations.