Medicinal Chemistry Section,
Molecular Targets and Medications Discovery
Branch, National Institute on Drug
Abuse-Intramural Research Program, Baltimore,
USA.
1. Overview of the challenge in
medications development for substance use
disorders: focus on cocaine and
methamphetamine
Major challenges exist for developing
medications to treat substance use disorders
(SUDs) in general, and psychostimulant
addiction, in particular. Despite a considerable
global burden [1], the negative health
and societal consequences of cocaine and
methamphetamine abuse have continued unabated.
Based on decades of research, it is clear that
therapeutic strategies that include medications
are necessary to reduce, and ultimately,
eliminate illicit drug taking. Nevertheless,
translation from mechanistic target
identification to preclinical testing in animal
models of self-administration and relapse
through clinical evaluation of novel or
repurposed molecules has progressed at a snail's
pace. The reasons for failure to deliver
effective medications to treat psychostimulant
addictions have been described and debated
(e.g., [2]). The lack of consistent
efforts in drug development for this patient
population in the private sector has
historically been a barrier to success. Further,
the multi-billion dollar price tag [3]
coupled with the high risk of developing
psychiatric medications has contributed to the
recent exodus of big pharma from development of
drugs that act on the central nervous system
(CNS). This disengagement from psychiatric drug
development will undoubtedly further slow this
process because of downstream effects on smaller
pharmaceutical and biotech firms that have
traditionally relied on the resources of big
pharma in the latter stages of drug development
[4]. Translation from animal to clinical
studies, low medication compliance during the
conduct of clinical trials, placebo effects, and
the current FDA perspective to demonstrate
complete abstinence, as opposed to reduction in
drug use [5], all provide formidable
challenges to the successful development of
medications to treat SUDs [2,6].
Nevertheless, scientific advances have led
to the identification of ''druggable'' targets,
and medicinal chemistry efforts have, in turn,
resulted in the development of small molecules
that show promise in preclinical models of
addiction. In this commentary, we present the
dopamine D3 receptor (D3R) as a uniquely suited
target for drug development, with D3R
antagonists and partial agonists showing promise
in models of cocaine and methamphetamine abuse.
We briefly summarize recent advances in the
discovery of small molecules that bind with high
affinity and selectivity to D3R and have
properties in preclinical models that forecast
successful translation to the clinic. We
highlight selected novel agents and in addition,
present promising data on a repurposed molecule,
buspirone, as a candidate for clinical
trials.
2. Why the dopamine D3 receptor (D3R) may
be a uniquely suited target for psychostimulant
abuse and addiction
Although both cocaine and methamphetamine
are psychostimulants and bind to all three
monoamine transporters (norepinephrine,
dopamine, serotonin), their mechanisms of action
differ. Cocaine blocks neurotransmitter
transport into the cell, but cannot be
transported itself, whereas methamphetamine
serves as a substrate, competing for the
neurotransmitter both at the membrane and
vesicular transporters, ultimately facilitating
the release of neurotransmitter into the
synapse. Although all three transporters are
affected by chronic use of these drugs and the
neurotoxicity associated with methamphetamine is
certainly one consequence of this, it is the
dopamine transporter that appears to be most
closely linked to the psychomotor stimulant
Chronic exposure to cocaine and/or
methamphetamine causes long lasting molecular
and cellular neuroadaptations of the
mesencephalic dopaminergic system that may
ultimately contribute to the addict's inability
to stop taking drugs, despite serious negative
consequences [7&endash;10]. Indeed, an
increased extracellular concentration of
dopamine has been implicated as a critical
factor in morphological changes that can lead to
changes in neural plasticity and behavior.
These changes may contribute to excessive
activation of all dopamine receptor subtypes
[11]. Specifically, increased expression
and function of D3R upon exposure to
psychostimulant drugs has led to further
investigation into the role of D3R in cocaine
and methamphetamine addiction
[12&endash;14]. In addition, the
restricted high density localization of D3Rs in
neurocircuits that play a critical role in
emotional and cognitive functions as well as
increases in D3R in the ventral striatum of
human cocaine fatalities [15,16] has
further heightened interest in D3R. More
recently, PET studies using the D3R-preferential
ligand [11C]-(+)PHNO in methamphetamine
polydrug abusers showed upregulation of D3R but
not D2R in this subject population [17].
These studies, coupled with preclinical studies
that will be briefly summarized below suggest
that normalization of D3R function may reduce
vulnerability to relapse in psychostimulant
3. D3R selective antagonists and partial
agonists
A seminal report describing the
D3R-selective partial agonist/ antagonist BP 897
(Fig. 1) (hD3R and hD2R Ki = 0.92 and 61 nM,
respectively) showed inhibition of conditioned
cue-controlled cocaine-seeking behavior in rats
without producing rewarding effects of its own
[18]. Many subsequent studies
[19] expanded these results in other
models of cocaine and methamphetamine abuse and
laid the groundwork for establishing a role of
D3R in psychomotor stimulant associated cues and
drug seeking.
The similarly potent and D3R selective
antagonists SB277011A and NGB 2904 also
demonstrated efficacy in these animal models
[14,20], and have provided both critical
tools for further characterization of D3R in
addiction and pharmacophoric templates for the
evolution of subsequent generations of D3R
selective agents [14,21].
Structure&endash;activity relationships have
been derived through extensive medicinal
chemistry efforts, resulting in highly potent
and D3R selective agents with varying intrinsic
activities (for review see
[22,23]).
Recently, the human D3R was crystallized in
complex with the antagonist eticlopride
[24], which has further illuminated
structural components of the receptor-binding
domain, and will undoubtedly provide the basis
for novel ligand discovery [25,26].
However, discovering small molecules that bind
with high affinity and selectivity to the D3R is
only the initial hurdle in drug development. The
successful molecule must also possess
appropriate biopharmaceutical properties (ADME)
that provide adequate levels of an efficacious
medication for treating addicted patients and
preventing relapse. Although numerous animal
models developed to mirror human addiction
predict that these agents will be effective,
clinical trials testing the efficacy of D3R
selective antagonists and partial agonists in
SUDs are still on the horizon.
4. Utilization of preclinical nonhuman
primate models in addiction research
Effective preclinical models are essential
toward identifying the in vivo profile of novel
D3R partial agonists and antagonists as well as
enhancing the field's understanding of the role
of D3Rs in psychostimulant addiction. Since the
cloning of D3Rs in 1990 [27], animal
studies have been crucial to elucidating how
these receptors function in situ. Over the past
15 years, a number of factors influencing the in
vivo selectivity and efficacy of D3R selective
compounds have been elucidated through employing
various behavioral pharmacology assays in both
rodents and nonhuman primates. While rodents
offer beneficial characteristics such as the
ability to make genetic modifications (e.g.,
knock-out mice) important to investigating
specific roles of D3Rs in the behavioral effects
of drugs of abuse [28,29], ongoing
research strongly supports the use of nonhuman
primates in this field of research. When
considering translational research, nonhuman
primates are an advantageous preclinical model
due to phylogenetic similarities and 95% overall
shared gene homology to humans [30].
Furthermore, the ability to conduct
within-subject longitudinal assessments in
monkeys with an extensive history of
self-administration is an essential attribute to
modeling the human condition, as addicts have
typically abused cocaine for many years. With
respect to dopamine D2-like receptors, nonhuman
primate imaging studies show similar
neurobiological changes in response to long-term
drug self-administration to that of humans
[31&endash;33]. Moreover, recent reports
using the D3Rpreferring ligand
[11C]-PHNO [34] have shown that
rhesus macaques demonstrate comparable regional
binding to humans [35,36] suggesting
similarities in D3R distribution and
availability. In addition, monkeys can
self-administer cocaine for years, which
provides a truly chronic model of addiction. All
of these factors lend advantages toward
employing nonhuman primates in preclinical
behavioral pharmacology studies aimed toward
evaluating potential compounds for treating drug
addiction. The focus of this commentary is on
the evaluation of D3R-selective agents, first
with unconditioned behaviors, and then in drug
self-administration and relapse models in
nonhuman primates as a means to further progress
candidate compounds to the clinic.
5. Unconditioned behaviors for
understanding in vivo profiles of novel D3R
compounds
Although in vitro assays aid in identifying
receptor-selectivity and efficacy to guide
medicinal chemistry efforts to obtain highly
selective and potent drug-like molecules, in
vivo assessments are necessary to corroborate in
vitro findings in order to validate
structure&endash;activity relationships. Seminal
reports by Collins et al. [37,38]
demonstrated, in rodents, that a dopamine
D2R/D3R agonist will produce an inverted-U
function on drug-elicited behavior in which
low-doses would elicit yawning and higher
doses would produce less yawning and
concomitantly induce hypothermia. Through a
series of elegant antagonist studies, it was
shown that D3Rs mediate the ascending limb of
the drug-elicited yawning curve whereas
D2Rs were implicated in the actions described on
the descending limb in which yawning was
lower and hypothermia was observed. While many
neurotransmitter systems contribute to
yawning (for review see [39]),
this simple behavioral assay has been shown to
be pharmacologically sensitive to D3R-selective
compounds, thus making it a suitable framework
for determining the selectivity and efficacy of
novel compounds in vivo [37,38]. D3R-
and D2R-elicited yawning and hypothermia,
respectively, have recently been validated in
nonhuman primates (Fig. 2) and employed to
understand how a pharmacological history can
functionally alter D3Rs (for methods see
[40]).
Differential effects of the profile of D3R
partial agonists in drug-naġ¨ve rhesus
monkeys compared to monkeys with an extensive
history of cocaine selfadministration were
recently reported [40]. For these
studies, monkeys were placed in primate chairs
in a quiet room with a video camera. Quinpirole,
PG 619 (both 0.03&endash;1.0 mg/kg) or saline
(1.0 ml) was administered intravenously and
yawning measured for 30 mins beginning
immediately after the injection. Scoring of
yawns was done by researchers blind to the drug
condition. While the D3R-preferrential agonist
quinpirole dose-dependently elicits
yawning in a similar fashion in all
age-matched monkeys irrespective of drug
history, the partial agonist PG 619 (hD3R and
hD2R Ki = 2.8 and 284 nM, respectively)
[41] (Fig. 1) elicited yawning
comparable to that of the D2R/D3R receptor
agonist quinpirole only in cocaine-history
monkeys [40,42] (Fig. 2A and B)
suggesting functional sensitivity following
cocaine self-administration. We also extended
this finding to the partial agonist CJB 090
(hD3R and hD2R Ki = 0.5 and 25 nM, respectively;
Fig. 1), showing that it would elicit yawns only
in monkeys with an extensive cocaine history
[43,44]. These findings suggest that in
individuals currently abusing cocaine, a partial
agonist may function as a full agonist in vivo.
Interestingly, such consequences appear to be
long lasting, as rhesus monkeys exposed to
cocaine in utero show enhancements in
quinpirole-elicited yawning some 13 years
later, in adulthood [45]. An even more
promising outcome was that in the same monkeys
in which the D3R-partial agonist PG 619 (0.1
mg/kg) elicited yawning, it did not
induce reinstatement of cocaine seeking (Fig.
2C, open triangle). When given in combination
with cocaine, a range of PG 619 doses attenuated
cocaine-induced reinstatement (Fig. 2C, filled
triangles). There is still much research to be
conducted to understand the functional role of
D3R in reinstatement. All doses of PG 619 were
equally effective in decreasing cocaine-elicited
reinstatement to approximately 50% (Fig. 2C),
while CJB 090, a drug that also elicited
yawning in these monkeys, did not affect
cocaine-induced reinstatement [46].
Factors such as those presented above, which
more closely resemble the treatment population,
are critical to comprehensively identify
pharmacological mechanisms of D3R partial
agonists and antagonists to facilitate a faster
progression from bench to bedside. One
advantageous use of a model involving
unconditioned behaviors is to initially identify
mechanisms of action of compounds and to
determine appropriate dose ranges for
selfadministration studies. For example,
quinpirole robustly elicits yawning in
monkeys and the shape of the quinpirole
dose&endash; response curve is characterized as
an inverted-U shaped function (Fig. 2A)
[40]. Just as has been reported in
rodents [38], the descending limb of the
quinpirole dose&endash;response curve is
associated with hypothermia in monkeys (see Fig.
3). Administration of the D3R-selective partial
agonist PG 619 attenuated quinpirole-elicited
yawning but did not affect
quinpirole-induced hypothermia, suggesting a
primarily D3R mediated effect.
