We have shown that arylalkylamines of abuse can produce one or more of at least three distinct discriminative stimulus effects in rats: a 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane-like (D(c)M-like) effect typical of classical hallucinogens (H), a (+)amphetamine-like effect typical of stimulants (S), and a third type of effect that has not yet been well defined but is typified by the phenylalkylamine N-methyl-l-(4-methoxyphenyl)-2-aminopropane (PMMA) (P). The model implies three distinct effects, three distinct structure-activity relationships (SARs), and three distinct mechanisms of action. The actions, SARs, and mechanisms of action of phenylalkylamine hallucinogens and stimulants have been relatively well investigated. In contrast, almost nothing is known about the SAR and mechanism of action of PMMA-like agents. Furthermore, certain agents have been demonstrated to produce multiple effects and are best classified as, for example, H/P- or S/P- type agents; these agents likeiy act by composite mechanisms and likely possess composite SARs. The abused phenyiaikylamine MDMA (""""""""Ecstasy') is such an agent. We have classified this agent as belonging to the S/P-category, and what is known about its actions and SAR are consistent with the model. Types of questions now being addressed include: What structural traits did MDMA-iike agents inherit from (+)amphetamine and which were inherited from PMMA? We have been able to antagonize the stimulus effects of MDMA; are the effects of both MDMA isomers inhibited to the same degree or by the same mechanism? Can the PMMA-stimulus be antagonized in a similar manner? Using primarily a drug discrimination paradigm [with groups of animals trained to discriminate either DOM, (+)amphetamine, PMMA, MDMA, (-)MDMA, (+)MDMA from vehicle], we propose to investigate structure-activity relationships for PMMA-like activity, to study the stimulus mechanism of action of PMMA, and to classify various agents as to the type of effect(s) they produce. For example, the actions of numerous controlled (i.e., Schedule 1) substances are poorly understood; various novel street drugs (including their metabolites and synthetic by-products) are even less well understood. Investigation of such agents not only allows their classification, it also adds to the structure-activity data being collected that can ultimately be used to forecast the actions of newer agents. Compounds necessary for the studies are proposed for synthesis. Because stereochemistry plays a key role in the actions of many of the compounds (with enantiomers sometimes producing different effects), most will be examined as individual isomers. Where agents possess two chiral centers, all four isomers will be prepared and examined. Other studies relevant to the above model include examination of the stimulus effects of DOM and MDMA metabolites. The novel classification scheme provides a platform from which mechanism of action (and mixed mechanisms of action) can be investigated and unraveled. This will eventually lead to a better understanding of abuse prevention and treatment modalities.

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National Institute on Drug Abuse (NIDA)
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Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
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Rapaka, Rao
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Virginia Commonwealth University
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Glennon, Richard A (2014) Bath salts, mephedrone, and methylenedioxypyrovalerone as emerging illicit drugs that will need targeted therapeutic intervention. Adv Pharmacol 69:581-620
Khorana, Nantaka; Young, Richard; Glennon, Richard A (2009) Effect of 8-hydroxy-2-(N,N-di-n-propylamino)tetralin and MDMA on the discriminative stimulus effects of the classical hallucinogen DOM in rats. Pharmacol Biochem Behav 91:385-92
Young, Richard; Glennon, Richard A (2009) S(-)Propranolol as a discriminative stimulus and its comparison to the stimulus effects of cocaine in rats. Psychopharmacology (Berl) 203:369-82
Young, Richard; Glennon, Richard A (2008) MDMA (N-methyl-3,4-methylenedioxyamphetamine) and its stereoisomers: Similarities and differences in behavioral effects in an automated activity apparatus in mice. Pharmacol Biochem Behav 88:318-31
Glennon, Richard A; Young, Richard; Dukat, Malgorzata et al. (2007) N-Methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA) and N-Methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) produce non-identical discriminative stimuli in rats. Pharmacol Biochem Behav 86:477-84
Glennon, Richard A; Bondareva, Tatiana; Young, Richard (2006) alpha-Ethyltryptamine (alpha-ET) as a discriminative stimulus in rats. Pharmacol Biochem Behav 85:448-53
(1994) Hallucinogenic agents: drugs of abuse as neurochemical tools. NIDA Res Monogr 140:94-8
Glennon, R A (1994) Classical hallucinogens: an introductory overview. NIDA Res Monogr 146:4-32
Young, R; Glennon, R A (1993) Cocaine-stimulus generalization to two new designer drugs: methcathinone and 4-methylaminorex. Pharmacol Biochem Behav 45:229-31
Glennon, R A (1993) MDMA-like stimulus effects of alpha-ethyltryptamine and the alpha-ethyl homolog of DOM. Pharmacol Biochem Behav 46:459-62

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