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

A series of N-sec- and N-tert-alkylnormorphines was synthesized and evaluated for analgesic potency, antagonist activity, and opiate receptor binding. 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 5a-c were devoid of agonist activity; however, some sec-alkyl analogues showed interesting mixed agonist-antagnoist actions. N-sec-Butyl- and N-(alpha-methylally)normorphine were separated into R and S isomers, which exhibited quantitative pharmacological differences. The N-sec-butyl S isomer 10a showed analgesia approximating morphine with nalorphine-like antagonist activity. Preliminary testing indicates only slight evidence for physical dependence with this compound.