Synthesis and pharmacological evaluation of N(6)-alkyl norlysergic acid N,N-diethylamide derivatives

Andrew Joseph Hoffman, Purdue University

Abstract

A convenient method for the synthesis of N(6)-alkyl norlysergic acid diethylamide (norLSD) derivatives was developed in our laboratory and 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 nM/kg, i.p.) from saline. Dose-response curves for each of the compounds in the series were generated, and structure-activity relationships were developed based on comparison of the estimated ED$\sb{50}$ values from these curves. Of the compounds which substituted for LSD, the N(6)-ethyl and allyl were approximately 2 to 3 times more potent than LSD itself. The N(6)-1-propyl and cyclopropylmethyl analogues were equipotent to LSD, while the 2-propyl derivatives was one-half as active. The 1-butyl and propargyl compounds were an order to magnitude less potent than LSD. By contrast, only partial generalization occurred to norLSD and the N(6)-2-phenethyl derivative at the doses tested. Receptor binding affinity measurements utilizing rat frontal cortex homogenates were performed to examine binding affinities of the N(6)-alkylergolines at 5-HT$\sb1$ and 5-HT$\sb2$ receptor subtypes. $\sp3$H-5-HT (2 nM) and $\sp3$H-ketanserin (0.75 nM) were used to label the 5-HT$\sb1$ and 5-HT$\sb2$ sites, respectively. Saturation experiments defined K$\sb{\rm d}$ = 2.03 nM ($\pm$0.04, mean $\pm$SEM) and B$\sb{\rm max}$ = 200 fmol/mg protein for $\sp3$H-5-HT binding, likewise for $\sp3$H-ketanserin, K$\sb{\rm d}$ = 2.22 nM ($\pm$0.26) and B$\sb{\rm max}$ = 340 fmol/mg protein. Normal, short side-chain derivatives had the highest affinities at the 5-HT$\sb1$ subtype, while a chain four carbons in length had an order of magnitude lower affinity, thus demonstrating an apparent receptor steric boundary. This steric constraint was not evident in 5-HT$\sb2$ binding, as even a four carbon alkyl showed nanomolar affinity. Multiple linear regression analysis was employed to develop models which explain the behavioral potency of the derivatives measured in the drug discrimination assay with LSD vs. saline-trained rats. Using a parabolic relationship of Log P (partition coefficient) to pED$\sb{50}$ explains about 90% of the variation in potency seen in the behavioral assay. Adding a linear dependence on pK$\sb{\rm a}$ and a linear dependence on pK$\sb{\rm i}$ measured at 5-HT$\sb2$ sites results in a model which explains 98% of the variation.

Degree

Ph.D.

Advisors

Nichols, Purdue University.

Subject Area

Pharmacology

COinS