Synthesis and LSD-like discriminative stimulus properties in a series of N(6)-alkyl norlysergic acid N,N-diethylamide derivatives
Journal of Medicinal Chemistry – September 01, 1985
Source: OpenAlex
Summary
N(6)-alkyl norlysergic acid N,N-diethylamide derivatives show remarkable potency, with the N(6)-ethyl and -allyl compounds being 2-3 times more effective than LSD in a rat drug discrimination assay. In a sample of rats trained to distinguish between LSD (185.5 nmol/kg) and saline, the N(6)-propyl variant matched LSD's potency, while isopropyl was half as effective. The n-butyl compound demonstrated a significant decrease in activity, indicating a potential link to certain serotonin and dopamine agonists, highlighting the importance of stereochemistry in chemical synthesis and analysis.
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.