Add time:07/21/2019         Source:sciencedirect.com

This investigation is based on the premise that conformational restriction of abused phenylalkylamines in a tetrahydroisoquinoline conformation alters their pharmacology in such a manner that their original action is lost and that a new action emerges. TDIQ or 5,6,7,8-tetrahydro-1,3-dioxolo[4,5-g]isoquinoline, is a conformationally constrained phenylalkylamine that serves as a discriminative stimulus in animals. Although TDIQ bears structural resemblance to phenylalkylamine stimulants (e.g., amphetamine), hallucinogens (e.g., 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane [DOM]), and designer drugs (e.g., N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane [MDMA], N-methyl-1-(4-methoxyphenyl)-2-aminopropane [PMMA]), the TDIQ stimulus failed to generalize to (+)amphetamine or MDMA. In the present investigation, further evaluations were made of the stimulus nature of TDIQ. Specifically, the stimulus similarities of TDIQ, PMMA, and DOM were examined. In no case was stimulus generalization (substitution) observed. The results confirm that TDIQ produces stimulus effects distinct from those of the abovementioned phenylalkylamines. We also examined the structure–activity relationships of a series of TDIQ analogs, including several that might be viewed as conformationally restricted (CR) analogs of phenylalkylamine hallucinogens, stimulants, and designer drugs. These agents were examined in rats trained to discriminate either DOM (1.0 mg/kg), (+)amphetamine (1.0 mg/kg), MDMA (1.5 mg/kg), or TDIQ (5.0 mg/kg) from saline vehicle. Whereas we have demonstrated that none of these agents retains their respective phenylalkylamine stimulus actions, several of these agents were found to substitute for TDIQ. N-Methylation abolished TDIQ-stimulus action. These results, coupled with previous findings, imply that TDIQ derivatives represent a novel class of phenylalkylamines analogs with unique stimulus properties. Preliminary radioligand binding studies suggest that an α2-adrenergic mechanism might underlie the stimulus effects produced by TDIQ.

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