New structural concepts for narcotic antagonists defined in a 4-phenylpiperidine series.

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NARCOTIC antagonists are generally considered as N-methyl-cyclopropyl or N-allyl (for example, nalorphine) type derivatives of N-methyl (for example, morphine) agonists. This type of substitution has often been considered necessary for potent narcotic antagonist activity1,2. However, in the 4-phenylpiperidine series (as in meperidine) where a methyl substitution on the nitrogen has been associated with agonist activity, the substitution of an N-allyl derivative has not produced narcotic antagonists3–5. There are compounds, such as L-metazocine6,7 and profadol8, which contain a methyl-substituted basic nitrogen, and possess narcotic antagonist properties, but these are also agonists and their antagonist activity is relatively weak. During the pharmacological investigation of a new series of phenylpiperidines we discovered an N-methyl derivative that was a pure narcotic antagonist devoid of agonist effects. We also observed that nitrogen substituents that had increased agonist potency in the meperidine series9 when substituted in compounds of the present series surprisingly augmented antagonist potency to the level observed with naloxone4. Examination of the inhibition of specific 3H-naloxone binding of these derivatives in bovine striatal membranes demonstrated that their relative potency was due to differences in receptor interaction. We used the most potent member of the series to study its stereoselectivity. We report here the structure-activity relationships of some 1,3,4-trialkyl-4-phenylpiperidines that clearly demonstrate the importance of a 3-methyl substituent in contributing narcotic antagonist properties within the phenyl-piperidine series as a whole. These compounds may well represent the first new class of pure narcotic antagonists since the discovery of naloxone.