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

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Abstract
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 posses 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.