Analgesics. 1. Synthesis and analgesic properties of N-sec-alkyl and N-tert-alkylnormorphines

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Abstract
A series of N-sec- and N-tert-alkylnormorphines was synthesized and evaluated for analgesic potency, antagonist activity and opiate receptor binding in mice. Computer-assisted conformational analysis profiles were utilized to assist in the selection of compounds for synthesis and correlation of receptor events with in vivo observations. N-tert-alkylnormorphines were devoid of agonist activity; however, some sec-alkyl analogues showed interesting mixed agonist-antagonist actions. N-sec-butyl- and N-(.alpha.-methylallyl)normorphine were separated into R and S isomers, which exhibited quantitative pharmacological differences. The N-sec-butyl S isomer showed analgesia approximating morphine with nalorphine-like antagonist activity. Preliminary testing indicates only slight evidence for physical dependence with this compound.