Targeting the dopamine D3 receptor: an overview of drug design strategies

ABSTRACT

Introduction: Dopamine is a neurotransmitter widely distributed in both the periphery and the central nervous system (CNS). Its physiological effects are mediated by five closely related G protein-coupled receptors (GPCRs) that are divided into two major subclasses: the D₁-like (D₁, D₅) and the D₂-like (D₂, D₃, D₄) receptors. D3 receptors (D₃Rs) have the highest density in the limbic areas of the brain, which are associated with cognitive and emotional functions. These receptors are therefore attractive targets for therapeutic management.

Areas covered: This review summarizes the functional and pharmacological characteristics of D₃Rs, including the design and clinical relevance of full agonists, partial agonists and antagonists, as well as the capacity of these receptors to form active homodimers, heterodimers or higher order receptor complexes as pharmacological targets in several neurological and neurodegenerative disorders.

Expert opinion: The high sequence homology between D₃R and the D₂-type challenges the development of D₃R-selective compounds. The design of new D₃R-preferential ligands with improved physicochemical properties should provide a better pharmacokinetic/bioavailability profile and lesser toxicity than is found with existing D₃R ligands. It is also essential to optimize D₃R affinity and, especially, D₃R vs. D₂-type binding and functional selectivity ratios. Developing allosteric and bitopic ligands should help to improve the D₃R selectivity of these drugs. As most evidence points to the ability of GPCRs to form homomers and heteromers, the most promising therapeutic strategy in the future is likely to involve the application of heteromer-selective drugs. These selective ligands would display different affinities for a given receptor depending on the receptor partners within the heteromer. Therefore, designing novel compounds that specifically target and modulate D₁R–D₃R heteromers would be an interesting approach for the treatment of levodopa (L-DOPA)-induced dyskinesias.

KEYWORDS:

• Allosteric modulation
• drug addiction
• GPCR
• heteromerization
• heteromer-selective drug
• homomerization
• L-DOPA-induced dyskinesia
• Parkinson’s disease
• restless legs syndrome
• schizophrenia

Article highlights

• Limbic areas and, more specifically, the mesolimbic pathways, contain the highest density of D₃Rs in the brain. As these pathways are associated with cognitive and emotional functions, D₃Rs are a target of pharmacotherapeutic interest in a variety of neurological and neuropsychiatric disorders including PD, RLS, schizophrenia and drug addiction.

• D₃R and D₂R share 79% amino acid sequence homology in their transmembrane regions and near the identity of the residues inferred to form their binding site. Consequently, most D₃R ligands are also active in D₂R, making their use as chemical probes problematic.

• A number of promising D₃R-selective compounds, such as the antagonists GSK598809, YQA14 and SR21502, have recently been developed, and they show high affinity, selectivity and half-life, as well as improved oral bioavailability and pharmacodynamic properties.

• Many GPCRs can function as oligomers and are capable of forming heteromeric complexes with novel properties. Allosteric mechanisms are responsible for many of their exclusive properties.

• To date, four different D₃R oligomers have been reported: the D₃R-D₃R homomer, the A_2AR-D₃R heteromer, the D₂R-D₃R heteromer and the D₁R-D₃R heteromer, the latter being the most widely studied.

• The use of heteromer-selective drugs is likely to be the most promising therapeutic strategy in the future. These selective ligands would display different affinities for a given receptor depending on the receptor partners within the heteromer.

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Declaration of interests

This research was supported by grants from the Government of Catalonia [2014-SGR-1236], the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) [CB06/05/0064] and the Spanish Ministerio de Economía y Competitividad with European Regional Development Funds of the European Union [SAF2014-54840-R]. M Rodríguez-Ruiz is a scholarship from the University of Barcelona. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.