Activity of N-methyl-alpha- and -beta-funaltrexamine at opioid receptors

The N-methyl analogues (2a, 2b) of the nonequilibrium mu opioid receptor antagonist beta-funaltrexamine (1b) were synthesized and evaluated in the guinea pig ileum preparation (GPI). These analogues are highly potent, reversible opioid agonists and possess no nonequilibrium antagonist activity. The ineffectiveness of 2b in protecting against irreversible blockage of mu opioid receptors by 1b and the fivefold lower reactivity of 2b with cysteine suggest that N-methyl substitution adversely affects both the first and second recognition steps that are essential for effective covalent blockage of opioid receptors.