Pharmacological targeting of G protein-coupled receptor heteromers

Estefanía Moreno; Nil Casajuana-Martin; Michael Coyle; Baruc Campos Campos; Ewa Galaj; Claudia Llinas Del Torrent; Arta Seyedian; William Rea; Ning-Sheng Cai; Alessandro Bonifazi; Benjamín Florán; Zheng-Xiong Xi; Xavier Guitart; Vicent Casadó; Amy H Newman; Christopher Bishop; Leonardo Pardo; Sergi Ferré

doi:10.1016/j.phrs.2022.106476

Pharmacological targeting of G protein-coupled receptor heteromers

Pharmacol Res. 2022 Nov:185:106476. doi: 10.1016/j.phrs.2022.106476. Epub 2022 Sep 28.

Authors

Estefanía Moreno¹, Nil Casajuana-Martin², Michael Coyle³, Baruc Campos Campos⁴, Ewa Galaj⁵, Claudia Llinas Del Torrent², Arta Seyedian⁶, William Rea⁶, Ning-Sheng Cai⁶, Alessandro Bonifazi⁷, Benjamín Florán⁸, Zheng-Xiong Xi⁵, Xavier Guitart⁶, Vicent Casadó¹, Amy H Newman⁷, Christopher Bishop⁹, Leonardo Pardo¹⁰, Sergi Ferré¹¹

Affiliations

¹ Laboratory of Molecular Neuropharmacology, Department of Biochemistry and Molecular Biomedicine, Faculty of Biology and Institute of Biomedicine, University of Barcelona, Barcelona, Spain.
² Laboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Autonomous University of Barcelona, Bellaterra, Spain.
³ Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY, USA.
⁴ Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA; Center for Research and Advanced Studies, Department of Physiology, Biophysics, and Neurosciences, Mexico City, Mexico.
⁵ Addiction Biology Unit, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
⁶ Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
⁷ Medicinal Chemistry Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
⁸ Center for Research and Advanced Studies, Department of Physiology, Biophysics, and Neurosciences, Mexico City, Mexico.
⁹ Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY, USA. Electronic address: cbishop@binghamton.edu.
¹⁰ Laboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Autonomous University of Barcelona, Bellaterra, Spain. Electronic address: leonardo.pardo@uab.cat.
¹¹ Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA. Electronic address: sferre@intra.nida.nih.gov.

Abstract

A main rationale for the role of G protein-coupled receptor (GPCR) heteromers as targets for drug development is the putative ability of selective ligands for specific GPCRs to change their pharmacological properties upon GPCR heteromerization. The present study provides a proof of concept for this rationale by demonstrating that heteromerization of dopamine D₁ and D₃ receptors (D₁R and D₃R) influences the pharmacological properties of three structurally similar selective dopamine D₃R ligands, the phenylpiperazine derivatives PG01042, PG01037 and VK4-116. By using D₁R-D₃R heteromer-disrupting peptides, it could be demonstrated that the three D₃R ligands display different D₁R-D₃R heteromer-dependent pharmacological properties: PG01042, acting as G protein-biased agonist, counteracted D₁R-mediated signaling in the D₁R-D₃R heteromer; PG01037, acting as a D₃R antagonist cross-antagonized D₁R-mediated signaling in the D₁R-D₃R heteromer; and VK4-116 specifically acted as a ß-arrestin-biased agonist in the D₁R-D₃R heteromer. Molecular dynamics simulations predicted potential molecular mechanisms mediating these qualitatively different pharmacological properties of the selective D₃R ligands that are dependent on D₁R-D₃R heteromerization. The results of in vitro experiments were paralleled by qualitatively different pharmacological properties of the D₃R ligands in vivo. The results supported the involvement of D₁R-D₃R heteromers in the locomotor activation by D₁R agonists in reserpinized mice and L-DOPA-induced dyskinesia in rats, highlighting the D₁R-D₃R heteromer as a main pharmacological target for L-DOPA-induced dyskinesia in Parkinson's disease. More generally, the present study implies that when suspecting its pathogenetic role, a GPCR heteromer, and not its individual GPCR units, should be considered as main target for drug development.

Keywords: Dopamine D(1) receptor; Dopamine D(3) receptor; G protein-coupled receptor (GPCR) heteromers; L-DOPA-induced dyskinesia; Locomotor activation; Mouse; PG01037 (PubChem CID: 11477180); PG01042 (PubChem CID: 11443078); Pramipexole (PubChem CID: 119570); Rat; SKF81297 (PubChem CID: 1218); VK4–116 (PubChem CID: 130431318).

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural

MeSH terms

Animals
Dopamine
Dyskinesias*
Levodopa*
Ligands
Mice
Rats
Receptors, Dopamine D1 / agonists
Receptors, Dopamine D3 / agonists
Receptors, G-Protein-Coupled

Substances

N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-4-(pyridin-3-yl)benzamide
Levodopa
N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)but-2-enyl)-4-pyridine-2-ylbenzamide
Receptors, Dopamine D3
Receptors, Dopamine D1
Dopamine
Receptors, G-Protein-Coupled
Ligands

Abstract

Publication types

MeSH terms

Substances

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