Quaternary derivatives of narcotic antagonists: stereochemical requirements at the chiral nitrogen for in vitro and in vivo activity.

We have studied three pairs of diastereoisomers of quaternary narcotic antagonists and their parent tertiary amines, levallorphan, nalorphine and naloxone, to see how configuration about the chiral nitrogen affects in vitro and in vivo activity. In each series only the diastereoisomer obtained by methylation of the N-allyl substituted tertiary amine (N-methyl diast.) was potent in displacing 3H-naltrexone from rat brain membranes (Ki 10(-8) - 10(-7)M) and as pure morphine antagonist in the guinea-pig ileum (Ki 10(-8)-10(-7)M). Conversely, diastereoisomers obtained by reacting N-methyl substituted tertiary amines with allyl halide (N-allyl diast.) did not displace 3H-naltrexone, up to 10(-6)M, and had negligible antagonist activity and slight agonist action in the guinea-pig ileum. In vivo findings (charcoal meal transit test in mice) were generally consistent with those in vitro. Thus only the N-methyl but not the N-allyl diast. inhibited morphine constipation and behaved as pure antagonists.