Opioid agonist and antagonist activities of monofunctional nitrogen mustard analogues of beta-chlornaltrexamine.

In an effort to compare the role of a monofunctional nitrogen mustard with that of its bifunctional counterpart (i.e., beta-CNA, 1b) in modulating nonequilibrium activity of opioid receptors, we have synthesized and tested N-(2-chloroethyl)-N-methylamino analogues 2a and 2b. Compound 2b and beta-CNA (1b) possessed qualitatively similar pharmacologic profiles on the guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations. Moreover, the corresponding epimer 2a behaved somewhat like that reported for alpha-CNA (1a) in that it possessed irreversible agonist activity in the GPI. The similar pharmacologic profiles of the monofunctional and bifunctional nitrogen mustards suggest that possible cross-linking of receptor nucleophiles by the latter is not critical for activity. In addition, the results are consistent with the idea that the rank-order nonequilibrium activity of 2b at different opioid receptor types is related to its relative affinity at those sites rather than to the alkylation step.