Nalorphine, levallorphan and their quaternary analogs, N-(eq) allyl derivatives of the two diastereoisomers at the nitrogen atom (N-methyl nalorphine and N-methyl levallorphan) were tested for their peripheral selectivity. We compared their relative ability to prevent morphine-induced (5 mg/kg i.v.) antinociception (central antagonism) and constipation (peripheral antagonism) in the same rats. Nalorphine and levallorphan reduced morphine-induced antinociception to half maximal response at doses of 5.1 and 0.89 mg/kg s.c. and restored the intestinal transit to 50% of controls (AD50) respectively at doses of 0.25 and 0.12 mg/kg. N-methyl nalorphine up to 24 and N-methyl levallorphan up to 3 mg/kg given s.c. 10 min before morphine did not antagonize narcotic-induced antinociception, fully preventing constipation (AD50 0.65 and 0.32 mg/kg respectively), but when injected 50 min before morphine they partially lost their antagonist potency (AD50 2.3 and 2.6 mg/kg respectively) and peripheral selectivity. N-methyl nalorphine and N-methyl levallorphan thus seem more peripherally selective than their tertiary analogs and more potent than quaternary narcotic antagonists tested to date.
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