Synthesis and LSD-like discriminative stimulus properties in a series of N(6)-alkyl norlysergic acid N,N-diethylamide derivatives

A series of N(6)-alkyl norlysergic acid N,N-diethylamide derivatives was synthesized and tested in rats trained to discriminate LSD from saline. The N(6)-ethyl and -allyl derivatives were 2–3 times more potent than LSD itself, the N(6)-propyl was equally potent, the isopropyl derivative was half as active, and the n-butyl compound was 10 times less potent. No substitution occurred for norlysergic acid N,N-diethylamide or the N(6)-2-phenethyl derivative. These structure-activity relationships resemble those of certain serotonin and dopamine agonists.

Study at a glance

Abstract

A convenient method for the synthesis of N(6)-alkyl norlysergic acid N,N-diethylamide derivatives was developed. A series of these compounds was synthesized and tested for substitution in the two-lever drug discrimination assay, in rats trained to discriminate injections of d-LSD tartrate (185.5 nmol/kg, ip) from saline. A dose-response curve for each of the compounds in the series was generated. Structure-activity relationships were developed, based on comparison of the estimated ED50 values from these curves. Of the compounds that substituted for LSD, the N(6)-ethyl and -allyl were approximately 2-3 times more potent than LSD itself. The N(6)-propyl was equipotent to LSD, while the isopropyl derivative was half as active. The n-butyl compound was 1 order of magnitude less potent than LSD, suggesting a similarity to the SAR of certain serotonin and dopamine agonists. By contrast, no generalization occurred to norlysergic acid N,N-diethylamide and the N(6)-2-phenethyl derivative.