title: Targeting the dopamine D3 receptor: an overview of drug design strategies.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: a Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) , Spain.|b Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona (IBUB) , University of Barcelona , Barcelona , Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Cortés
authors.affiliation: a Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) , Spain.|b Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona (IBUB) , University of Barcelona , Barcelona , Spain.
authors.forename: Estefanía
authors.initials: E
authors.lastname: Moreno
authors.affiliation: a Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) , Spain.|b Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona (IBUB) , University of Barcelona , Barcelona , Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Rodríguez-Ruiz
authors.affiliation: a Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) , Spain.|b Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona (IBUB) , University of Barcelona , Barcelona , Spain.
authors.forename: Enric I
authors.initials: EI
authors.lastname: Canela
authors.affiliation: a Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) , Spain.|b Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona (IBUB) , University of Barcelona , Barcelona , Spain.
authors.forename: Vicent
authors.initials: V
authors.lastname: Casadó
mesh_terms: D000818:Animals; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D015195:Drug Design; D054333:Drug Partial Agonism; D006801:Humans; D007980:Levodopa / Q000009:adverse effects; D008024:Ligands; D058990:Molecular Targeted Therapy; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000503:physiopathology; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D008024:Ligands; D050637:Receptors, Dopamine D3; D007980:Levodopa; D004298:Dopamine
keywords: Allosteric modulation; GPCR; L-DOPA-induced dyskinesia; Parkinson’s disease; drug addiction; heteromer-selective drug; heteromerization; homomerization; restless legs syndrome; schizophrenia