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Arylalkylamine Drugs of Abuse: an Overview of Drug Discrimination Studies

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Arylalkylamine Drugs of Abuse: an Overview of Drug Discrimination Studies Pharmacology Biochemistry and Behavior, Vol. 64, No. 2, pp. 251–256, 1999 © 1999 Elsevier Science Inc. Printed in the USA. All rights reserved 0091-3057/99/$–see front matter PII S0091-3057(99)00045-3 Arylalkylamine Drugs of Abuse: An Overview of Drug Discrimination Studies RICHARD A. GLENNON Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298-0540 GLENNON, R. A. Arylalkylamine drugs of abuse: An overview of drug discrimination studies. PHARMACOL BIOCHEM BEHAV 64(2) 251–256, 1999.—Abused arylalkylamines fall into two major categories: the indolealkylamines, and the pheny- lalkylamines: These agents can be further subclassified on the basis of chemical structure. Examples of these agents possess hallucinogenic, stimulant, and other actions. Drug-discrimination techniques have been used to classify and investigate this large family of agents. Such studies have allowed the formulation of structure–activity relationships and investigations of mechanisms of action. Arylalkylamine designer drugs also possess the same or a combination of actions, and are being inves- tigated by the same methods. © 1999 Elsevier Science Inc. Hallucinogens Stimulants Empathogens DOM Amphetamine Designer drugs MDMA MDA PMMA a-ET SIMPLE arylalkylamines possess the common structural perception with little memory or intellectual impairment, and moiety Ar-C-C-N where Ar is typically an indole (i.e., the in- that produce little stupor, narcosis, or excessive stimulation, dolealkylamines) or phenyl group (i.e., the phenylalky- minimal autonomic side effects, and that are nonaddicting. As lamines). The arylalkylamine moiety is also found embedded restrictive as this classification might appear, Hollister was in a number of other structurally more complex agents (e.g. able to define a number of different classes of agents (Table opiates), but it is the more elaborate nature of these latter 1) that have since been shown to be behaviorally dissimilar in structures that accounts for their different pharmacological humans [see (7) for further discussion]. That is, hallucino- actions; the complex arylalkylamines will not be discussed genic agents are a pharmacologically diverse and heteroge- herein. Simple arylalkylamines are among a group of agents neous group of agents. Agents in the Hollister classification that has seen widespread abuse. Actions typically associated scheme include, for example, phencyclidine (PCP), canna- with these agents include (a) hallucinogenic activity, (b) cen- binoids (e.g., tetrahydrocannabinol or THC), and LSD-like tral stimulant activity, and (c) other activity. This last group agents. There now is evidence that these agents produce dis- encompasses, in particular, the so-called designer drugs that similar effects and likely work through distinct mechanisms. may display hallucinogenic, central stimulant or empatho- We have attempted to subcategorize some of these agents genic activity, or a combination of activities. and have identified what we term the “classical hallucino- gens.” The classical hallucinogens are agents that meet Hollis- CATEGORIZATION OF AGENTS ter’s original definition, but are also agents that: (a) bind at Arylalkylamines (AAAs) can be divided into the in- 5-HT2 serotonin receptors, and (b) are recognized by animals dolealkylamines (IAAS) and the phenylalkylamines (PAAs). trained to discriminate 1-(2,5-dimethoxy-4-methylphenyl)-2- These can be further subdivided into different subclasses. aminopropane (DOM) from vehicle (6). This will be further The indolealkylamines are divided into the N-substituted discussed below. tryptamines, a-alkyltryptamines, ergolines or lysergamides, and Some of our early studies were devoted to determining (tentatively) the b-carbolines (Fig. 1). The phenylalkylamines which arylalkylamines produce a common effect. To this ex- are subdivided into the phenylethylamines and the phenyl- tent we employed the drug discrimination paradigm, with ani- isopropylamines (Fig. 1). The actions of these agents can be mals trained to a suitable training drug, to determine which highly dependent upon the nature of various substituent agents produce stimulus effects similar to those of a known groups (i.e., in Fig. 1, R, R9, and R99). hallucinogen. However, the question immediately arises as to which hallucinogen should be used as the training drug? Ob- viously, the selection of training drug could influence any sub- HALLUCINOGENS sequent classification scheme. We investigated examples from Hollister (12) defined hallucinogens or psychotomimetic the different classes of arylalkylamines. For example, we ex- agents as those that produce changes in thought, mood, and plored the N-substituted tryptamine 5-methoxy-N,N-dimeth- 251 252 GLENNON FIG. 1. General structures of the two chemical classes of arylalkylamines: the indolealkyl- amines and the phenylalkylamines. yltryptamine (5-OMe DMT), the ergoline lysergic acid diethyl- the reported human hallucinogenic potencies of these same amide (LSD), the phenylethylamine mescaline, and the agents. During investigations of the mechanisms underlying phenylisopropylamines DOM, R(2)DOB or R(2)1-(4- the stimulus effects of DOM it was found that certain seroto- bromo-2,5-dimethoxyphenyl)-2-aminopropane, and DOI or nin (5-HT) antagonists were able to block the stimulus effects 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane. Eventually, of DOM. Later studies demonstrated that 5-HT2 antagonists, we settled on the use of DOM-trained animals to continue in particular, were especially effective. Thus, the idea was our studies. The DOM-stimulus generalized to 5-OMe DMT borne that hallucinogens might be producing their stimulus and other examples of N-substituted tryptamines; 5-methoxy- effects via a 5-HT2 agonist mechanism. If the classical halluci- a a -methyltryptamine, and other examples of -alkyl-tryptamines; nogens act as direct-acting 5-HT2 agonists, it might be possi- the ergoline LSD, the phenylethylamine mescaline, and other ble to demonstrate a relationship between their potencies and examples of phenylethylamines, and to DOB, DOI, and other their 5-HT2 receptor affinities. Indeed, we found that a signif- examples of phenylisopropylamines (5). The DOM-stimulus also generalized to several different examples of b-carbolines such as harmaline (5). As if to underscore the stimulus simi- larity among these agents, stimulus generalization occurred TABLE 1 among DOM, mescaline, LSD, and 5-OMe DMT, regardless HOLLISTER’S CLASSIFICATION OF of which was used as the training drug. Thus, using DOM- PSYCHOTOMIMETIC AGENTS (12) trained animals, it was possible to determine which of several hundred agents produced DOM-like stimulus effects in ani- Classes of mals. Figure 2 shows representative dose–response curves for Psychotomimetic Agents Examples DOM-stimulus generalization to examples of the different Lysergic acid derivatives Lysergic acid diethylamide (LSD) classes of arylalkylamines. Phenylethylamines Mescaline At this point it might be noted that no claim is made that Indolealkylamines N,N-Dimethyltryptamine (DMT) these agents all produce identical effects. Indeed, the effects Other indolic derivatives Harmala alkaloids, Ibogaine of some of these agents can be distinguished by humans. The Piperidyl benzilate esters JB-329 claim is made, however, that these agents produce a common Phenylcyclohexyl compounds Phencyclidine (PCP) DOM-like stimulus effect in rats [reviewed: (5,7)]. Miscellaneous agents Kawain, Dimethylacetamide, Subsequently, it was demonstrated that the stimulus po- Cannabinoids tencies of about two dozen agents were highly correlated with ARYLALKYLAMINE DRUGS OF ABUSE 253 ing, suggesting that similarities exist between the stimulus properties of the two agents. Most recently, however, we have replicated this latter study and have found that administration of DOM to harmaline-trained animals does indeed result in stimulus generalization (i.e., .80% harmaline-appropriate re- sponding) (Glennon and Young, unpublished findings). Be- cause the b-carbolines constitute a very large series of agents that has not been well investigated, it may be premature to decisively include them as members of the classical hallucino- gens. However, although additional investigations are obvi- ously required, there seems to be sufficient information to tentatively classify the b-carboline harmaline as a classical hallucinogen. CENTRAL STIMULANTS FIG. 2. Dose–response curves showing DOM-stimulus generaliza- The parent unsubstituted phenylisopropylamine is known tion to representative examples of the arylalkylamines: the ergoline as amphetamine and amphetamine is a central stimulant. Do lysergic acid diethylamide (LSD), the phenylisopropylamine DOM, the a-alkyltryptamine a-methyltryptamine (alpha-MeT), the N-sub- other examples of arylalkylamines possess this activity? Actu- stituted tryptamine N,N-dimethyltryptamine (DMT), the b-carboline ally, this has not been as well investigated as might have been harmaline, and the phenylethylamine mescaline. expected. An example of an indolealkylamine, the a-alkyl- tryptamine a-methyltryptamine (a-MeT) has been demon- strated to behave as a central stimulant in several species of animals (11). Other agents may also possess this action, but icant correlation exists between DOM-derived stimulus gen- their central stimulant actions may be overshadowed by their eralization potency, human hallucinogenic potency, and 5-HT 2 hallucinogenic nature; this remains to be investigated. receptor affinity for a large
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