Stereoselective aspects of hallucinogenic drug action and drug discrimination studies of entactogens

Robert Arthur Oberlender, Purdue University

Abstract

Stereochemical aspects of the structure-activity relationships of hallucinogenic drugs were explored through the asymmetric syntheses and pharmacological evaluations of two sets of analogues. The two lever drug discrimination (DD) paradigm was utilized with LSD (0.08 mg/kg) as the training drug. Four stereoisomeric derivatives of LSD were prepared in which the diethyl amide moiety was replaced with a 2-chloro-1-methylpropyl amide group. All of these analogues completely substituted for LSD with a 22-fold potency range and one of these novel derivatives exhibited a potency greater than LSD itself. The results are discussed in terms of the role of the amide portion of hallucinogenic ergolines in the drug-receptor interaction. Steric effects on the behavioral activity of phenethylamine type hallucinogens were investigated by comparing the DOM analogues 1- (2,5-dimethoxy-4-(2-methylpropyl)phenyl) -2-aminopropane, and 1- (2,5-dimethoxy-4-(2-butyl)phenyl) -2-aminopropane. The effect of stereochemistry at the 4-position of these analogues was also studied. An asymmetric hydroboration procedure was employed in the preparation of the R and S 4-secbutyl analogues of DOM. The results suggest that steric bulk at the 4-position attenuates activity to a greater degree when it occurs close to the aromatic ring. A modest difference in the activities of the optically active derivatives was also observed and the results are discussed in terms of the possible role of charge-transfer complexation between hallucinogenic phenethylamines and the receptor. Finally, a series of drug discrimination experiments was performed in order to test the hypothesis that 3,4-methylenedioxymethamphetamine (MDMA)-like compounds, termed entactogens, exert a novel type of psychopharmacology. Thus, the racemic mixtures and optical isomers of MDMA, the primary amine derivative, MDA, as well as MBDB, the $\alpha$-ethyl homologue of MDMA, were synthesized and compared with respect to discriminative stimulus properties. Groups of rats were trained to discriminate saline from ($\pm$)-MDMA (1.75 mg/kg), (+)-MBDB (1.75 mg/kg), LSD (0.08 mg/kg), or (+)-amphetamine (1.0 mg/kg) and substitution tests, as well as a limited number of antagonist tests, were performed. The results clearly indicate that MDA, MDMA and MBDB share a common component of behavioral activity which is distinct from both hallucino-gen-like and stimulant-like effects. The structure-activity relationships of entactogens were also explored and found to be consistent with the concept that entactogens represent a novel class of drugs. In addition, since MBDB and the rigid analogue, 5,6-MDAI, lack the stimulant-like effects of MDMA, these drugs will be useful tools in future studies.

Degree

Ph.D.

Advisors

Nichols, Purdue University.

Subject Area

Pharmacology

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