glennon.arylalkylamine.drugs.of.abuse, biotransformation
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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
(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.
64
© 1999 Elsevier Science Inc.
Hallucinogens
Stimulants
Empathogens
DOM
Amphetamine
Designer drugs
MDMA
MDA
a
PMMA
-ET
SIMPLE arylalkylamines possess the common structural
moiety
perception with little memory or intellectual impairment, and
that produce little stupor, narcosis, or excessive stimulation,
minimal autonomic side effects, and that are nonaddicting. As
restrictive as this classification might appear, Hollister was
able to define a number of different classes of agents (Table
1) that have since been shown to be behaviorally dissimilar in
humans [see (7) for further discussion]. That is, hallucino-
genic agents are a pharmacologically diverse and heteroge-
neous group of agents. Agents in the Hollister classification
scheme include, for example, phencyclidine (PCP), canna-
binoids (e.g., tetrahydrocannabinol or THC), and LSD-like
agents. There now is evidence that these agents produce dis-
similar effects and likely work through distinct mechanisms.
We have attempted to subcategorize some of these agents
and have identified what we term the “classical hallucino-
gens.” The classical hallucinogens are agents that meet Hollis-
ter’s original definition, but are also agents that: (a) bind at
5-HT
where Ar is typically an indole (i.e., the in-
dolealkylamines) or phenyl group (i.e., the phenylalky-
lamines). The arylalkylamine moiety is also found embedded
in a number of other structurally more complex agents (e.g.
opiates), but it is the more elaborate nature of these latter
structures that accounts for their different pharmacological
actions; the complex arylalkylamines will not be discussed
herein. Simple arylalkylamines are among a group of agents
that has seen widespread abuse. Actions typically associated
with these agents include (a) hallucinogenic activity, (b) cen-
tral stimulant activity, and (c) other activity. This last group
encompasses, in particular, the so-called designer drugs that
may display hallucinogenic, central stimulant or empatho-
genic activity, or a combination of activities.
Ar-C-C-N
CATEGORIZATION OF AGENTS
serotonin receptors, and (b) are recognized by animals
trained to discriminate 1-(2,5-dimethoxy-4-methylphenyl)-2-
aminopropane (DOM) from vehicle (6). This will be further
discussed below.
Some of our early studies were devoted to determining
which arylalkylamines produce a common effect. To this ex-
tent we employed the drug discrimination paradigm, with ani-
mals trained to a suitable training drug, to determine which
agents produce stimulus effects similar to those of a known
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-
sequent classification scheme. We investigated examples from
the different classes of arylalkylamines. For example, we ex-
plored the N-substituted tryptamine 5-methoxy-
Arylalkylamines (AAAs) can be divided into the in-
dolealkylamines (IAAS) and the phenylalkylamines (PAAs).
These can be further subdivided into different subclasses.
The indolealkylamines are divided into the N-substituted
tryptamines,
2
-alkyltryptamines, ergolines or lysergamides, and
(tentatively) the
a
-carbolines (Fig. 1). The phenylalkylamines
are subdivided into the phenylethylamines and the phenyl-
isopropylamines (Fig. 1). The actions of these agents can be
highly dependent upon the nature of various substituent
groups (i.e., in Fig. 1, R, R
b
9
, and R
99
).
HALLUCINOGENS
Hollister (12) defined hallucinogens or psychotomimetic
agents as those that produce changes in thought, mood, and
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-
amide (LSD), the phenylethylamine mescaline, and the
phenylisopropylamines DOM,
the reported human hallucinogenic potencies of these same
agents. During investigations of the mechanisms underlying
the stimulus effects of DOM it was found that certain seroto-
nin (5-HT) antagonists were able to block the stimulus effects
of DOM. Later studies demonstrated that 5-HT
)1-(4-
bromo-2,5-dimethoxyphenyl)-2-aminopropane, and DOI or
1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane. Eventually,
we settled on the use of DOM-trained animals to continue
our studies. The DOM-stimulus generalized to 5-OMe DMT
and other examples of N-substituted tryptamines; 5-methoxy-
R
(
2
)DOB or
R
(
2
antagonists,
in particular, were especially effective. Thus, the idea was
borne that hallucinogens might be producing their stimulus
effects via a 5-HT
2
agonist mechanism. If the classical halluci-
nogens act as direct-acting 5-HT
2
a
-alkyl-tryptamines;
the ergoline LSD, the phenylethylamine mescaline, and other
examples of phenylethylamines, and to DOB, DOI, and other
examples of phenylisopropylamines (5). The DOM-stimulus
also generalized to several different examples of
-methyltryptamine, and other examples of
a
agonists, it might be possi-
ble to demonstrate a relationship between their potencies and
their 5-HT
2
receptor affinities. Indeed, we found that a signif-
2
-carbolines
such as harmaline (5). As if to underscore the stimulus simi-
larity among these agents, stimulus generalization occurred
among DOM, mescaline, LSD, and 5-OMe DMT, regardless
of which was used as the training drug. Thus, using DOM-
trained animals, it was possible to determine which of several
hundred agents produced DOM-like stimulus effects in ani-
mals. Figure 2 shows representative dose–response curves for
DOM-stimulus generalization to examples of the different
classes of arylalkylamines.
At this point it might be noted that no claim is made that
these agents all produce identical effects. Indeed, the effects
of some of these agents can be distinguished by humans. The
claim is made, however, that these agents produce a common
DOM-like stimulus effect in rats [reviewed: (5,7)].
Subsequently, it was demonstrated that the stimulus po-
tencies of about two dozen agents were highly correlated with
b
TABLE 1
HOLLISTER’S CLASSIFICATION OF
PSYCHOTOMIMETIC AGENTS (12)
Classes of
Psychotomimetic Agents
Examples
Lysergic acid derivatives
Lysergic acid diethylamide (LSD)
Phenylethylamines
Mescaline
Indolealkylamines
N,N-Dimethyltryptamine (DMT)
Other indolic derivatives
Harmala alkaloids, Ibogaine
Piperidyl benzilate esters
JB-329
Phenylcyclohexyl compounds
Phencyclidine (PCP)
Miscellaneous agents
Kawain, Dimethylacetamide,
Cannabinoids
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
.
-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
b
-carboline harmaline as a classical
hallucinogen.
CENTRAL STIMULANTS
FIG. 2. Dose–response curves showing DOM-stimulus generaliza-
tion to representative examples of the arylalkylamines: the ergoline
lysergic acid diethylamide (LSD), the phenylisopropylamine DOM,
the
a
-alkyltryptamine
a
-methyltryptamine (alpha-MeT), the N-sub-
stituted tryptamine
N,N
-dimethyltryptamine (DMT), the
b
-carboline
harmaline, and the phenylethylamine mescaline.
The parent unsubstituted phenylisopropylamine is known
as amphetamine and amphetamine is a central stimulant. Do
other examples of arylalkylamines possess this activity? Actu-
ally, this has not been as well investigated as might have been
expected. An example of an indolealkylamine, the
a
-alkyl-
tryptamine
-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
their central stimulant actions may be overshadowed by their
hallucinogenic nature; this remains to be investigated.
Amphetamine probably represents the protoypical central
stimulant, and most related stimulants possess a phenylisopro-
pylamine moiety. Although both optical isomers of amphet-
amine have been employed as training drugs in drug discrimi-
nation studies, (
a
-methyltryptamine (
a
icant correlation exists between DOM-derived stimulus gen-
eralization potency, human hallucinogenic potency, and 5-HT
2
receptor affinity for a large series of agents (6). The phenyl-
alkylamines have not been shown to bind with high affinity at
any population of receptors other than 5-HT
serotonin re-
ceptors. In contrast, indolealkylamines can be quite nonselec-
tive. That is, many tryptamine derivatives bind at multiple
populations of 5-HT receptors, and the tryptamine-containing
ergoline LSD is particularly promiscuous in this regard. Nev-
ertheless, all the classical hallucinogens share common bind-
ing at 5-HT
2
)amphetamine is without question the more
prevalent, and the more potent, of the two [reviewed in (19)].
The phenylisopropylamine central stimulants likely produce
their central stimulant and stimulus properties primarily via
an indirect dopaminergic mechanism (9, 19). Limited struc-
ture–activity relationships have been reported for both activi-
1
receptors. This was termed the 5-HT
hypothesis
2
2
of hallucinogenic drug action [reviewed in (7)].
Since this hypothesis was first proposed, 5-HT
receptors
have been found to represent a family of three subpopula-
tions: 5-HT
2
receptors (also referred to
in some of the earlier literature as 5-HT
, 5-HT
, and 5-HT
2A
2B
2C
, 5-HT
, and 5-HT
2
2F
1C
receptors, respectively). The classical hallucinogens bind at
all three subpopulations (15). Recent work by Ismaiel et al.
(14) Schreiber at al. (17), and Fiorella et al. (3) indicate that
the stimulus effects of DOM-related agents involve a 5-HT
2A
rather than 5-HT
mechanism. Furthermore, agents such as
AMI-193 and ketanserin, 5-HT
2C
antagonists that display rela-
2
tively low affinity for 5-HT
receptors, potently antagonize
the DOM stimulus suggesting that it is unlikely that the DOM
stimulus is 5-HT
2B
-mediated (15).
As of this time, two properties that the classical hallucino-
gens have in common is that (a) they bind at 5-HT
2B
recep-
tors and (b) they are recognized by DOM-trained animals.
Hence, we have used these criteria to define the classical hal-
lucinogens (7). Using radioligand binding and drug discrimi-
nation, the structure–activity relationships of these agents have
been investigated; a detailed discussion of structure–activity
relationships has been recently reviewed (5).
The
2A
-carbolines represent an interesting group of agents.
Examples of
b
-carbolines, such as harmaline (Fig. 1), are
known to be hallucinogenic in humans [see (10) for discus-
sion]. We have demonstrated that DOM-stimulus generaliza-
tion occurs to harmaline (Fig. 2). Recently, we reported that
harmaline binds at 5-HT
b
1
6
FIG. 3. Chemical structures of
S
(
)amphetamine, (
)methamphet-
) receptors (10).
Furthermore, animals have been trained to discriminate har-
maline from saline vehicle and administration of DOM re-
sulted in a maximum of 76% harmaline-appropriate respond-
(and at 5-HT
b
2A
2C
amine, and the
-oxidized phenylisopropylamines ephedrine, nor-
ephedrine, cathinone, methcathinone, and phenmetrazine. See also
Fig. 4 for the stereochemistry associated with ephedrine and norephe-
drine.
254
GLENNON
ties (18,19), and there seems to be significant similarities be-
tween them.
In general, incorporation of substituents into the aromatic
ring dramatically reduces amphetaminergic potency or, as is
more often the case, abolishes amphetamine-like stimulus ac-
tion (19). The nonaromatic portions of the molecule can be
modified, however, with interesting consequences. Although
N-alkylation of amphetamine results in a progressive de-
crease in amphetaminergic character as the size of the alkyl
substituent is increased, N-monomethylation provides a curi-
ous exception; N-monomethylamphetamine or methamphet-
amine is at least as potent as amphetamine in (
)amphet-
amine-trained animals and, as with amphetamine itself, the
1
S
)-iso-
mer (see Fig. 3 for chemical structures) (19). Homologation
of the
(
1
)-isomer is several times more potent than the
R
(
2
-methyl group essentially abolishes amphetamine-like
stimulus properties whereas removal of this group (i.e., re-
placement by hydrogen to afford phenylethylamine) de-
creases potency; the latter effect is probably due to a decrease
in lipophilicity and a resulting decrease in the ability to pene-
trate the blood–brain barrier, as well as to a greater suscepti-
bility to metabolism.
A remaining position that has not yet been mentioned is
the benzylic or
a
FIG. 4. The phenylpropanolamines. The top row shows the struc-
tures and names of the four optical isomers of N-monomethyl phe-
nylpropanolamine, and the bottom row shows the corresponding
N-des
methyl analogs. (
1
)Norpseuroephedrine is also known as (
1
)nor-
C
-ephedrine or (
1
)cathine.
-position has
not yet been thoroughly investigated; however, several
b
-position. Substitution at the
b
-sub-
stituted compounds retain amphetamine-like activity. Most of
what is known about the
b
-oxidized ana-
logs of amphetamine (Fig. 3). Incorporation of a benzylic hy-
droxyl group results in a series of phenylpropanolamines (Fig.
4). The best investigated of these is ephedrine. In (
b
-position relates to
b
ity include cyclic analogs such as phenmetrazine (Fig 3) (19),
indicating that the carbonyl group found in cathinone and
methcathinone is not per se, a requirement for amphetamine-
like stimulus action. Recent results further suggest that the
structure–activity relationships of amphetamine analogs and
cathinone analogs are not necessarily identical (2).
Although amphetamine probably represents one of the
most widely used training drugs in drug discrimination studies
(19), there is considerable work that remains to be done on
amphetamine analogs and related agents.
)amphet-
amine-trained animals, racemic ephedrine has been reported
to result in stimulus generalization (13) or partial generaliza-
tion (4). Recently, it has been demonstrated that (
1
2
)ephedrine,
but not (
)amphetamine-like respond-
ing in rats (23). Norephedrine has been reported to result in
generalization [e.g., (1)] (
1
)ephedrine, elicits (
1
)ephedrine, and nor-
ephedrine have been used as training drugs [see (21,23) for
discussion]. None of these agents is as potent as (
6
)Ephedrine, (
2
)amphet-
amine in drug discrimination studies, and most of the other
phenylpropanolamines shown in Fig. 4 have not been exam-
ined. One reason why these substances are currently attract-
ing some attention is due to their occurrence in so-called
“herbal dietary supplements” such as Herbal Ecstacy
1
DESIGNER DRUGS
Designer drugs or controlled substance analogs are struc-
turally modified derivatives of known drugs of abuse. In some
instances, it is possible to predict the actions, and sometimes
even the potencies, of designer drugs on the basis of estab-
lished structure–activity relationships. For example,
®
and
Herbal XTC
. These herbal preparations are reportedly pre-
pared using natural ephedra, and ephedra is known to contain
a number of phenylpropanolamines, with (
®
)ephedrine being
a major constituent. Oxidation of norephedrine and ephedrine
result in cathinone and methcathinone, respectively. Cathi-
none is a naturally occurring substance found in the shrub
2
is
a designer drug that has made an appearance in the southeast-
ern United States.
Nexus
Nexus
is 2-(4-bromo-2,5-dimethoxyphenyl)-l-
Ca-
aminoethane or
a
-
des
methyl DOB (see Fig. 5 for structure of
tha edulis
(khat). Cathinone is at least as potent as amphet-
amine in drug discrimination studies, and cathinone has been
used as a training drug in animals [reviewed in (9)]. Meth-
cathinone is to cathinone what methamphetamine is to am-
phetamine; that is, methcathinone, known on the street as
“CAT,” is a potent central stimulant, and is more potent than
amphetamine in drug discrimination studies (22)].
DOB). That is,
is the phenylethylamine counterpart of
the phenylisopropylamine hallucinogen DOB. Because
Nexus
-deme-
thylation of phenylisopropylamine hallucinogens is known to
usually result in retention of activity but in a severalfold re-
duction in potency, it would be expected that
a
would be
a DOM-like agent with a potency less than that of DOB. As
shown in Fig. 6, this was found to be the case. Thus, certain
designer drugs may represent analogs of hallucinogens,
whereas other may represent analogs of amphetamine.
However, the actions of designer drugs are not always pre-
dictable. A prototypical example is MDMA (“Ecstasy”,
“XTC”, “Adam”). MDMA is the N-monomethyl derivative
of MDA or 1-(3,4-methylenedioxyphenyl)-2-aminopropane
(Fig. 5). MDA possesses both hallucinogenic and central stim-
ulant actions; the
Nexus
)Meth-
cathinone recently has been used as a training drug in rats
(22). The results of these investigations indicate that
S
(
1
-oxi-
dized derivatives of amphetamine can retain amphetamine-
like properties, and that some are actually more potent than
amphetamine itself. The hydroxylated analogs likely suffer
from problems of reduced lipohilicity and/or metabolism, and
are less potent than amphetamine. The carbonylated analogs
cathinone and methcathinone, in contrast, are quite potent.
Other
b
)-isomer seems primarily responsible
for the former action, whereas the
R
(
2
b
-oxidized analogs that retain amphetaminergic activ-
S
(
1
)-isomer seems prima-
ARYLALKYLAMINE DRUGS OF ABUSE
255
FIG. 5. Chemical structure DOM, DOB, MDA, MDMA, PMA, PMMA,
a
-MeT,
and
a
-ET.
rily responsible for the latter. On the basis of established
structure–activity relationships indicating that N-monometh-
ylation decreases (or abolishes) hallucinogenic activity, and
that this same structural modification enhances amphet-
amine-like actions, it might have been expected that MDMA
would lack significant hallucinogenic activity but retain cen-
tral stimulant activity. The results of drug discrimination stud-
ies are consistent with this prediction; that is, MDMA pro-
duces (
PMMA and PMMA was three times more potent than
MDMA. In animals trained to discriminate PMMA from ve-
hicle, the PMMA stimulus failed to generalize to either
(
)amphetamine or DOM; the PMMA stimulus, however,
generalized to MDMA, and again, PMMA was three times
more potent than MDMA (8). It would seem that MDMA
and PMMA may share a common stimulus component of ac-
tion, but that PMMA lacks the amphetamine-like stimulant
character of MDMA.
On the basis of the above and other investigations, we
have proposed that the phenylalkylamines produce at least
three types of stimulus effects in animals: hallucinogenic (H),
stimulant (S), and “other” (O) actions (8). These relation-
ships are shown in schematic fashion in Fig. 7. For the time
being, and for the purpose of characterization, we consider
DOM as the prototypic phenylalkylamine hallucinogen, (
1
)amphetamine-like, but lacks DOM-like, stimulus
effects, regardless of which of the three agents is used as the
training drug (5). However, Nichols and co-workers [reviewed
in (16)] have argued that MDMA produces, in addition to its
stimulant actions, an effect that is uniquely distinct from that
of hallucinogens and central stimulants. In humans, MDMA
reportedly produces an empathogenic effect (increased socia-
bility, heightened empathy) and has seen some application as
an adjunct to psychotherapy. The
1
)am-
phetamine as the prototypical stimulant, and PMMA as a pro-
totypical “other” agent. MDMA can be considered an S/O-
type (see Fig. 7) agent in that it produces both effects. In addi-
tion to its DOM-like and (
1
-ethyl homolog of MDMA,
MBDB, retains the latter action but lacks amphetaminergic
character (16).
Another agent with unpredicted action is
a
-methoxy-
methamphetamine or PMMA (Fig. 5). PMMA is a structural
hybrid of two phenylisopropylamine stimulants: methamphet-
amine and a weaker stimulant
para
)amphetamine-like effects, MDA
produces MDMA-like effects; that is, an MDMA-stimulus gen-
eralizes to both optical isomers of MDA. Thus,
1
R
(
2
)MDA
-methoxyamphetamine
(PMA). Surprisingly, PMMA lacks central stimulant actions
[eg., fails to result in (
para
may be considered an H/O-type agent,
S
(
1
)MDA and S/O-
type agent, and (
)MDA an S/H/O-type agent. Other agents
have been and are continuing to be characterized as to which
of these three types of stimulus actions they produce.
Thus far, we have focussed on the phenylalkylamines. In-
dolealkylamines, however, might also be classifiable in a similar
6
)amphetamine-stimulus generaliza-
tion, does not produce locomotor stimulation in mice].
PMMA also fails to produce DOM-like effects in DOM-
trained animals. However, an MDMA stimulus generalized to
1
FIG. 7. Proposed relationships between the stimulus effects pro-
duced by arylalkylamines. Arylalkylamines can produce effects that
can be classified as hallucinogen-like (H), stimulant-like (S), or other
(O); see text for further expanation. The classification scheme is
adopted from Glennon et al. (8).
FIG. 6. DOM-stimulus generalization to the phenylisopropylamine hal-
lucinogen 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane (DOB)
and the phenylethylamine designer drug
Nexus
[2-(4-bromo-2,5-
dimethoxyphenyl)-1-aminoethane].
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