Phenylisopropylamine (PIA) drugs of abuse can be divided into several broad categories: central stimulants (e.g. amphetamine or AMPH), hallucinogens (e.g. DOM, DOB and DOI), and designer drugs. Stimulants have previously received the most attention; somewhat less is known about the hallucinogens. On the basis of their discriminative stimulus (and other) properties, certain PIA designer drugs can now be classified as stimulants and others as hallucinogens; some, such as PMMA, fit neither category. The overall goal of our work is elucidation of the mechanisms of action of PIA drugs of abuse; inherent to this goal is a need to understand which PIAs belong to which group of agents. That is, exactly what structural features govern the categorization of these agents and how do they influence potency? To this extent, we propose to use the drug discrimination paradigm for purposes of categorization; tests of stimulus generalization and stimulus antagonism using this paradigm also provide information on mechanism of action. For example, using groups of rats trained to discriminate (+)AMPH and DOM from saline, separate and distinct structure-activity relationships have been formulated for these PIAs. The mechanisms of action of these agents appear to involve dopamine and serotonin (5-HT), respectively. We have previously proposed the 5-HT2 hypothesis to account for the actions of PIA hallucinogens, and have developed [3H]DOB and [125I]DOI as radioligands for labeling the high- affinity state of 5-HT2 receptors. The present proposal uses drug discrimination, radioligand binding, and other functional assays to address several important issues: (i) what is the exact role of 5-HT2 receptors in the action of PIA hallucinogens, (ii) how do these agents bind at 5-HT2 receptors and what physicochemical properties control this interaction, (iii) is partial agonism a key feature of hallucinogenic agents, (iv) do 5-HT1C receptors rather that 5-HT2 receptors account for the mechanism of action of hallucinogens, (v) is the new non-AMPH, non-DOM designer drug PMMA prototypical of a new class of PIA drugs of abuse? We also propose to explore an entirely new mechanistic concept for the modulation of the DOM stimulus that might be useful for understanding basic mechanism involved in drug abuse. New agents are proposed for synthesis that will aid in solving these problems.
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