Chapter Seven - Beyond Small-Molecule SAR: Using the Dopamine D3 Receptor Crystal Structure to Guide Drug Design
Introduction
The neurotransmitter dopamine (DA) exerts its effects via DA receptors with varied signaling transduction mechanisms and expression patterns in the brain. DA receptors belong to the G protein-coupled receptor (GPCR) superfamily and are divided into two subfamilies. The D1-like DA receptors (D1 and D5) couple to stimulatory Gs proteins and enhance adenylyl cyclase (AC) activity and increase cytosolic cyclic adenosine monophosphate (cAMP) levels. D2-like DA receptors (D2, D3, and D4) couple to inhibitory Gi/o proteins that suppress AC activity and decrease cAMP. Within the D2-like receptor subfamily, the D2 and D3 receptors are the most homologous pair, sharing extensive sequence identity in the transmembrane domain and the putative ligand binding site (Chien et al., 2010).
First cloned and characterized in 1990 (Sokoloff, Giros, Martres, Bouthenet, & Schwartz, 1990), DA D3 receptors are expressed as postsynaptic receptors as well as autoreceptors (Diaz et al., 2000), providing inhibitory control on neuronal firing rates. The D3 receptor has a higher affinity for DA than the other receptor subtypes and may therefore be sensitive to tonic stimulation (Levesque et al., 1992). However, since D3 receptor antagonists fail to increase locomotor activity or elevate extracellular levels of DA in the nucleus accumbens or striatum, it appears that D3 autoreceptors exert primarily phasic rather than tonic control of DA neurons (Millan et al., 2000, Sokoloff et al., 2006).
The expression of D3 receptors in the human brain is primarily limited to mesolimbic regions, including particularly the ventral striatum, pallidum, nucleus accumbens, islands of Calleja, olfactory tubercle, and lateral septum (Cho et al., 2010, Gurevich and Joyce, 1999, Searle et al., 2010). This relatively focal expression of D3 receptors in brain regions that govern motivational behaviors and the reward properties of addictive drugs make the D3 receptor an enticing target for addiction pharmacotherapies. D3 receptors localized in the basolateral nucleus of the amygdala appear to regulate stimulus–reward associations that mediate reinstatement of drug-seeking behavior (Di Ciano, 2008). In the hippocampus, a modest density of D3 receptors have been found that regulate CREB signaling and could produce long-lasting effects on cognition and relapse behavior (Basile et al., 2006). In contrast, D2 receptors feature a broader distribution at higher concentrations, particularly in the dorsal striatum (Gurevich & Joyce, 1999); alteration of D2 receptor signaling is more commonly associated with side effects that influence locomotor activity, motor coordination, prolactin secretion, and catalepsy (Cho et al., 2010, Millan et al., 1995). Hence, selective targeting of D3 receptor signaling has the potential to provide a more focused therapeutic effect while limiting potential side effects believed to be mediated primarily through D2 receptors.
D3 receptors have additionally been shown to form heteromers with D1 receptors in the striatum. In these D1–D3 interactions, D3 receptor stimulation potentiates the effects of D1 signaling on neuronal and behavioral processes, including AC activation and locomotor activity (Fiorentini et al., 2008, Marcellino et al., 2008). Additional evidence exists for the functional coupling of D2 and D3 receptors, which may alter the apparent potency of some D2-like agonists (reviewed in Maggio, Aloisi, Silvano, Rossi, & Millan, 2009). It is tempting to consider future directions for the development of pharmacotherapeutics targeting these heteromeric complexes. However, it is too soon to know whether these complexes can be accessed by heteromer-selective drugs, in vivo.
The DA D3 receptor has been investigated as a potential target for medication development to treat substance use disorders (SUDs) with a particular focus on cocaine and methamphetamine. In addition to the expression and signaling patterns described earlier, alterations in D3 receptor expression patterns following drug exposure suggest an important role for D3 signaling in the development of addiction. Enhanced expression of D3 receptors has been shown following acute or chronic exposure to drugs of abuse in human postmortem studies (Mash and Staley, 1999, Segal et al., 1997, Staley and Mash, 1996). Increased expression of D3 receptors in polydrug users is correlated with self-reported drug craving (Boileau et al., 2012). This upregulation of D3 receptors may therefore contribute to the reinforcing effects of drugs of abuse and drug dependence (Le Foll et al., 2003, Segal et al., 1997).
Currently, there are no approved medications to treat cocaine and methamphetamine addiction, and thus, developing pharmacotherapeutics to complement existing behavioral strategies is a fundamental goal. A commentary highlighting the D3 receptor as a viable target for the development of SUDs, with an emphasis on psychostimulants, has recently appeared (Newman, Blaylock, et al., 2012).
Section snippets
Brief review of the D3 receptor pharmacophore template and examples of promising D3-selective agents for preclinical evaluation
Several comprehensive reviews describing dozens of D3-selective agents and derived structure–activity relationships (SAR) have been published recently (Heidbreder and Newman, 2010, Micheli, 2011, Ye et al., 2013). Despite fertile ground for modification of the classic D3 pharmacophore template, several challenges remain in identifying D3-selective ligands with efficacies that can be translated into in vivo models and ultimately therapeutic agents to treat human addiction.
In general, chemical
Clinical Studies Targeting the D3 Receptor in the Treatment of Addiction
A critical consideration for clinical trial success is the demonstration that the new drug engages its biological target (e.g., central D3 receptors) at doses that are related to its pharmacological action (e.g., drug craving cessation). Hence, the discovery of a D3-preferential positron emission tomography (PET) ligand to monitor drug occupancy and selectivity at D3 receptors was essential. As described earlier, selective D3 receptor ligands that are active in vivo have remained a challenge.
The Structural Basis of D3 over D2 Receptor Selectivity and the Future of Rational Drug Design for D3 Receptor-Selective Ligands
Despite a number of preclinical candidates and a handful of D3-selective antagonists or partial agonists in clinical trials for smoking cessation, the need to identify novel templates and better drug molecules to target the D3 receptor still exists. It is important to note, for example, that in treating SUDs, toxicology and safety studies must be done with the new medication candidate and in the presence of the abused drug, for example, cocaine. Drug combinations can produce untoward side
Conclusion
The DA D3 receptor remains an enticing target for addiction pharmacotherapy. A panoply of D3-selective compounds have been tested in vivo, producing promising results in addiction models and supporting the hypothesis that D3 receptor signaling is an important component of the reinforcing aspects of addictive drugs. Promising recent clinical trial results suggest that the D3 receptor remains a viable clinical target, but data are still limited in this regard. Continued development of novel
Conflict of Interest
The authors have no conflicts of interest to declare.
Acknowledgements
This work was supported in part by the NIDA Intramural Research Program (A. H. N.) and DA023694 (L. S.). T. M. K. is supported by an NIH IRTA postdoctoral fellowship and C. B. is supported by an NIH postbaccalaureate fellowship. A. H. N. and L. S. would like to acknowledge the members of our labs, past and present, and our wonderful collaborators who have helped move our D3 receptor program forward.
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2020, Neuroscience and Biobehavioral ReviewsCitation Excerpt :In support of this notion are the findings that D3R antagonists or partial agonists can reduce motivation to psychostimulant seeking in multiple animal models of relapse (Chen et al., 2014; Galaj et al., 2014; Gilbert et al., 2005, 2005; Higley et al., 2011, 2011; Peng et al., 2009, 2009; Song et al., 2014; Xi et al., 2006, 2004). In addition, under a progressive ratio (PR) schedule of reinforcement, during which work demands for drug self-administration are progressively increased, treatment with D3R antagonists reduce break points (BPs) for cocaine self-administration (Heidbreder, 2005; Keck et al., 2015, 2014; Le Foll et al., 2014; Newman et al., 2012; Sokoloff and Le Foll, 2017), suggesting a reduction in motivation for drug or drug reward. These findings have been corroborated by reports that D3R antagonists can reduce cocaine- or methamphetamine-enhanced brain stimulation reward (Pak et al., 2006; Song et al., 2014; Vorel et al., 2002; Xi et al., 2006, 2005) and block cocaine- or methamphetamine-induced CPP (Aujla and Beninger, 2005; Galaj et al., 2014; Hachimine et al., 2014; Song et al., 2013; Vorel et al., 2002).
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2018, Cellular SignallingCitation Excerpt :As the D3R shows a distribution more restricted to the limbic system as compared to the D2R [6], D3R-selective antagonists/partial agonists could, in theory, attenuate psychotic symptoms and/or drug-seeking behavior and relapse without inducing the motor side effects frequently associated with currently available D2-like antagonists. There are several excellent reviews covering the recent development and characterization of D3R-selective antagonists [37–43]. Notably, while some of these D3R-selective compounds exhibit reasonably high selectivity towards the D3R (> 100-fold), their global selectivity towards other GPCRs is either poor or untested.
Review on allosteric modulators of dopamine receptors so far
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