B CARBOLINE HALLUCINOGENS

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The beta-carboline hallucinogens remain as the last category of classical hallucinogenic agents that has not been studied in a systematic and comprehensive manner. These agents, which have been termed fantasy- enhancing agents, are receiving increased attention in the media. Due to their relative ease of synthesis, and because of a resurgent interest in hallucinogenic agents, the beta-carboline hallucinogens may either prove to be future drugs of abuse in this country or may serve as templates for the development of new designer drugs. Little is known about their structure-activity relationships (SAR) and essentially nothing is known regarding their mechanism of action. The beta-carboline hallucinogens, because they possess an indolealkylamine nucleus, have been categorized as classical hallucinogens (i.e. members of a hallucinogen family to which the indolealkylamine LSD, and the phenalkylamine 1-(2,5-dimethoxy-4- methylphenyl)-2-aminopropane or DOM, belong). Because significant progress has been made in recent years with respect to understanding the SAR and mechanism of action of classical hallucinogens, it may be extra olate or apply this information to the beta-carboline hallucinogens if, indeed, they can be demonstrated to be members of the same hallucinogen family. Preliminary data suggest that some beta-carbolines do behave like classical hallucinogens whereas other data indicate that differences may exist. That is, what little SAR results are available are inconsistent with what is known about other classical hallucinogens; and yet, two examples of beta-carboline hallucinogens (i.e. harmaline and 6- methoxyharmalan), like (+ )LSD, produce stimulus effects similar to those produced by DOM. The overall goals of this study are to systematically examine beta-carboline hallucinogens and to identify their SAR and to determine if they act via a mechanism common to other classical hallucinogens or via a unique mechanism of action. To this extent, drug discrimination studies employing rats as subjects, and radioligand binding to determine receptor affinity, will be undertaken. Specifically, tests of stimulus generalization and stimulus antagonism will be conducted with animals trained to discriminate harmaline from vehicle in order to identify stimulus mechanisms of action, tests of stimulus generalization will be conducted with animals trained to discriminate either DOM or harmaline from vehicle to determine similarity of stimulus effects, and radioligand binding studies will be performed, and correlations attempted with stimulus potency, to see if relationships exist as they do with other classical hallucinogens. Compounds required to test specific hypotheses are planned for synthesis. Pharmacological and SAR comparisons will be made with other classical hallucinogens and with non-hallucinogenic beta- carbolines. Because preliminary data suggest that certain of these agents bind at serotonin and tryptamine receptors, the project will initially focus on these two neurotransmitter mechanisms.