Opioid Agonist and Antagonist Activities of Monofunctional Nitrogen Mustard Analogues of β-Chlornaltrexamine

Article abstract of DOI:10.1021/jm00388a033

In an effort to compare the role of a monofunctional nitrogen mustard with that of its bifunctional counterpart (i.e., β-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 β-CNA (1b) possessed qualitatively similar pharmacologic profiles on the quinea pig ileum (GPI) and mouse vas deferens (MVD) preparations.Moreover, the corresponding epimer 2a behaved somewhat like that reported for α-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 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.