1,049
Views
45
CrossRef citations to date
0
Altmetric
Review

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

, , , &
Pages 641-664 | Received 12 Feb 2016, Accepted 29 Apr 2016, Published online: 30 May 2016
 

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.

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 A2AR-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.

This box summarizes key points contained in the article.

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.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.