Chapter Seven - Beyond Small-Molecule SAR: Using the Dopamine D3 Receptor Crystal Structure to Guide Drug Design

https://doi.org/10.1016/B978-0-12-420118-7.00007-XGet rights and content

Abstract

The dopamine D3 receptor is a target of pharmacotherapeutic interest in a variety of neurological disorders including schizophrenia, restless leg syndrome, and drug addiction. The high protein sequence homology between the D3 and D2 receptors has posed a challenge to developing D3 receptor-selective ligands whose behavioral actions can be attributed to D3 receptor engagement, in vivo. However, through primarily small-molecule structure–activity relationship (SAR) studies, a variety of chemical scaffolds have been discovered over the past two decades that have resulted in several D3 receptor-selective ligands with high affinity and in vivo activity. Nevertheless, viable clinical candidates remain limited. The recent determination of the high-resolution crystal structure of the D3 receptor has invigorated structure-based drug design, providing refinements to the molecular dynamic models and testable predictions about receptor–ligand interactions. This chapter will highlight recent preclinical and clinical studies demonstrating potential utility of D3 receptor-selective ligands in the treatment of addiction. In addition, new structure-based rational drug design strategies for D3 receptor-selective ligands that complement traditional small-molecule SAR to improve the selectivity and directed efficacy profiles are examined.

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.

References (131)

  • J.N. Joyce et al.

    Dopamine D3 receptor antagonists as therapeutic agents

    Drug Discovery Today

    (2005)
  • I. Kufareva et al.

    Status of GPCR modeling and docking as reflected by community-wide GPCR Dock 2010 assessment

    Structure

    (2011)
  • B. Le Foll et al.

    The dopamine D3 receptor and drug dependence: Effects on reward or beyond?

    Neuropharmacology

    (2005)
  • J. Liang et al.

    Roles of BDNF, dopamine D(3) receptors, and their interactions in the expression of morphine-induced context-specific locomotor sensitization

    European Neuropsychopharmacology

    (2011)
  • C.A. Lipinski

    Drug-like properties and the causes of poor solubility and poor permeability

    Journal of Pharmacological and Toxicological Methods

    (2000)
  • C.A. Lipinski et al.

    Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings

    Advanced Drug Delivery Reviews

    (1997)
  • R. Maggio et al.

    Heterodimerization of dopamine receptors: New insights into functional and therapeutic significance

    Parkinsonism & Related Disorders

    (2009)
  • D. Marcellino et al.

    Identification of dopamine D1-D3 receptor heteromers. Indications for a role of synergistic D1-D3 receptor interactions in the striatum

    Journal of Biological Chemistry

    (2008)
  • A.H. Newman et al.

    Medication discovery for addiction: Translating the dopamine D3 receptor hypothesis

    Biochemical Pharmacology

    (2012)
  • A.H. Newman et al.

    N-(4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl, butenyl and butynyl)arylcarboxamides as novel dopamine D(3) receptor antagonists

    Bioorganic and Medicinal Chemistry Letters

    (2003)
  • C.P. O'Brien et al.

    Critical assessment of how to study addiction and its treatment: Human and non-human animal models

    Pharmacology & Therapeutics

    (2005)
  • X.Q. Peng et al.

    The preferential dopamine D3 receptor antagonist S33138 inhibits cocaine reward and cocaine-triggered relapse to drug-seeking behavior in rats

    Neuropharmacology

    (2009)
  • C. Achat-Mendes et al.

    Dopamine D3 and D2 receptor mechanisms in the abuse-related behavioral effects of cocaine: Studies with preferential antagonists in squirrel monkeys

    Journal of Pharmacology and Experimental Therapeutics

    (2010)
  • C. Achat-Mendes et al.

    The dopamine D3 receptor partial agonist CJB 090 inhibits the discriminative stimulus but not the reinforcing or priming effects of cocaine in squirrel monkeys

    Psychopharmacology

    (2009)
  • N.E. Austin et al.

    Pharmacokinetics of the novel, high-affinity and selective dopamine D3 receptor antagonist SB-277011 in rat, dog and monkey: In vitro/in vivo correlation and the role of aldehyde oxidase

    Xenobiotica

    (2001)
  • J.A. Ballesteros et al.

    Structural mimicry in G protein-coupled receptors: Implications of the high-resolution structure of rhodopsin for structure-function analysis of rhodopsin-like receptors

    Molecular Pharmacology

    (2001)
  • A.K. Banala et al.

    N-(3-fluoro-4-(4-(2-methoxy or 2,3-dichlorophenyl)piperazine-1-yl)butyl)arylcarboxamides as selective dopamine D3 receptor ligands: Critical role of the carboxamide linker for D3 receptor selectivity

    Journal of Medicinal Chemistry

    (2011)
  • R.J. Beninger et al.

    Dopaminergic mechanism of reward-related incentive learning: Focus on the dopamine D(3) receptor

    Neurotoxicity Research

    (2008)
  • J. Bergman et al.

    Modification of cocaine self-administration by buspirone (buspar®): Potential involvement of D3 and D4 dopamine receptors

    International Journal of Neuropsychopharmacology

    (2013)
  • B.L. Blaylock et al.

    Influence of cocaine history on the behavioral effects of dopamine D(3) receptor-selective compounds in monkeys

    Neuropsychopharmacology

    (2011)
  • F. Boeckler et al.

    CoMFA and CoMSIA investigations revealing novel insights into the binding modes of dopamine D3 receptor agonists

    Journal of Medicinal Chemistry

    (2005)
  • I. Boileau et al.

    Higher binding of the dopamine D3 receptor-preferring ligand [11C]-(+)-propyl-hexahydro-naphtho-oxazin in methamphetamine polydrug users: A positron emission tomography study

    Journal of Neuroscience

    (2012)
  • G. Bonanomi et al.

    Triazolyl azabicyclo[3.1.0]hexanes: A class of potent and selective dopamine D(3) receptor antagonists

    ChemMedChem

    (2010)
  • S. Butini et al.

    Discovery of bishomo(hetero)arylpiperazines as novel multifunctional ligands targeting dopamine D(3) and serotonin 5-HT(1A) and 5-HT(2A) receptors

    Journal of Medicinal Chemistry

    (2010)
  • S.B. Caine et al.

    Cocaine self-administration in dopamine D(3) receptor knockout mice

    Experimental and Clinical Psychopharmacology

    (2012)
  • J. Carlsson et al.

    Ligand discovery from a dopamine D3 receptor homology model and crystal structure

    Nature Chemical Biology

    (2011)
  • V. Cherezov et al.

    High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor

    Science

    (2007)
  • E.Y. Chien et al.

    Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist

    Science

    (2010)
  • D.I. Cho et al.

    Current perspectives on the selective regulation of dopamine D(2) and D(3) receptors

    Archives of Pharmacal Research

    (2010)
  • L. Citrome

    Cariprazine: Chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability

    Expert Opinion on Drug Metabolism & Toxicology

    (2013)
  • M. Congreve et al.

    Progress in structure based drug design for G protein-coupled receptors

    Journal of Medicinal Chemistry

    (2011)
  • M.D.C. de Oliveira Citó et al.

    Reversal of cocaine withdrawal-induced anxiety by ondansetron, buspirone and propranolol

    Behavioural Brain Research

    (2012)
  • J. Diaz et al.

    Dopamine D3 receptors expressed by all mesencephalic dopamine neurons

    Journal of Neuroscience

    (2000)
  • P. Di Ciano

    Drug seeking under a second-order schedule of reinforcement depends on dopamine D3 receptors in the basolateral amygdala

    Behavioral Neuroscience

    (2008)
  • K. Ehrlich et al.

    Dopamine D2, D3, and D4 selective phenylpiperazines as molecular probes to explore the origins of subtype specific receptor binding

    Journal of Medicinal Chemistry

    (2009)
  • C. Fiorentini et al.

    Reciprocal regulation of dopamine D1 and D3 receptor function and trafficking by heterodimerization

    Molecular Pharmacology

    (2008)
  • F.J. Garcia-Ladona et al.

    BP 897, a selective dopamine D3 receptor ligand with therapeutic potential for the treatment of cocaine-addiction

    CNS Drug Reviews

    (2003)
  • N. Ginovart et al.

    Positron emission tomography quantification of [11C]-(+)-PHNO binding in the human brain

    Journal of Cerebral Blood Flow and Metabolism

    (2007)
  • M.P. Gleeson

    Generation of a set of simple, interpretable ADMET rules of thumb

    Journal of Medicinal Chemistry

    (2008)
  • A. Graff-Guerrero et al.

    The effect of antipsychotics on the high-affinity state of D2 and D3 receptors: A positron emission tomography study with [11C]-(+)-PHNO

    Archives of General Psychiatry

    (2009)
  • Cited by (42)

    • Dopamine D3 receptor-based medication development for the treatment of opioid use disorder: Rationale, progress, and challenges

      2020, Neuroscience and Biobehavioral Reviews
      Citation 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).

    • Advances and challenges in the search for D<inf>2</inf> and D<inf>3</inf> dopamine receptor-selective compounds

      2018, Cellular Signalling
      Citation 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.

    View all citing articles on Scopus
    View full text