Current perspectives on selective dopamine D(3) receptor antagonists as pharmacotherapeutics for addictions and related disorders

Abstract

Repeated exposure to drugs of abuse produces long-term molecular and neurochemical changes that may explain the core features of addiction, such as the compulsive seeking and taking of the drug, as well as the risk of relapse. A growing number of new molecular and cellular targets of addictive drugs have been identified, and rapid advances are being made in relating those targets to specific behavioral phenotypes in animal models of addiction. In this context, the pattern of expression of the dopamine (DA) D(3) receptor in the rodent and human brain and changes in this pattern in response to drugs of abuse have contributed primarily to direct research efforts toward the development of selective DA D(3) receptor antagonists. Growing preclinical evidence indicates that these compounds may actually regulate the motivation to self-administer drugs and disrupt drug-associated cue-induced craving. This report will be divided into three parts. First, preclinical evidence in support of the efficacy of selective DA D(3) receptor antagonists in animal models of drug addiction will be reviewed. The effects of mixed DA D(2)/D(3) receptor antagonists will not be discussed here because most of these compounds have low selectivity at the D(3) versus D(2) receptor, and their efficacy profile is related primarily to functional antagonism at D(2) receptors and possibly interactions with other neurotransmitter systems. Second, major advances in medicinal chemistry for the identification and optimization of selective DA D(3) receptor antagonists and partial agonists will be analyzed. Third, translational research from preclinical efficacy studies to so-called proof-of-concept studies for drug addiction indications will be discussed.

Figure 1

Three-dimensional reconstruction of the expression of the DA D₃ receptor in the mouse brain (strain, C57BL/6J; age, 56 days; sex, male; technique: in situ hybridization, riboprobe RP_060412_04_A01) using the Allen Brain Atlas (Brain Explorer Version 1.4.1. Build 32, © 2006–2007 Allen Institute for Brain Science) and the Anatomic Gene Expression Atlas. Highest expression/densities were observed in the ventral striatum, olfactory tubercle, lateral septum, medulla, pallidum, and thalamus. (In color in Annals online.)

Figure 2

Drug self-administration paradigm with its drug-taking and drug-seeking components. Selective DA D₃ receptor antagonists do not affect drug self-administration under low fixed-ratio schedules of reinforcement but rather regulate the motivation to self-administer drugs under schedules of reinforcement that require an increase in work demand. These selective antagonists also seem to be particularly effective in preventing drug-seeking behavior evoked by reexposure to either the drug itself (drug priming), environmental cues that had been previously associated with drug taking (cue presentation), or stressors (stress) after behavioral extinction. (In color in Annals online.)

Figure 3

Some key neurocircuits that might be modulated by selective blockade of the DA D₃ receptor. This scheme is based on recent information provided by local microinfusion of selective DA D₃ receptor antagonists into specific brain areas. NAc shell, shell subregion of the nucleus accumbens; BLA, basolateral amygdala; mPFC, medial prefrontal cortex. (In color in Annals online.)

Figure 4

Structure–activity relationship template for high-affinity and selective D₃ receptor antagonists. (In color in Annals online.)

Figure 5

Hybrid D₃ partial agonists.

Figure 6

Evolution of the D₃ receptor antagonists from GlaxoSmithKline.

Figure 7

Evolution of the D₃ receptor antagonists from Servier.

Figure 8

Evolution of RGH-237 from BP 897.

Figure 9

Evolution of D₃ receptor antagonists from NGB 2904.