TY - JOUR
T1 - Pharmacological targeting of G protein-coupled receptor heteromers
AU - Moreno, Estefanía
AU - Casajuana-Martin, Nil
AU - Coyle, Michael
AU - Campos, Baruc Campos
AU - Galaj, Ewa
AU - del Torrent, Claudia Llinas
AU - Seyedian, Arta
AU - Rea, William
AU - Cai, Ning Sheng
AU - Bonifazi, Alessandro
AU - Florán, Benjamín
AU - Xi, Zheng Xiong
AU - Guitart, Xavier
AU - Casadó, Vicent
AU - Newman, Amy H.
AU - Bishop, Christopher
AU - Pardo, Leonardo
AU - Ferré, Sergi
N1 - Publisher Copyright:
© 2022
PY - 2022/11
Y1 - 2022/11
N2 - 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.
AB - 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.
KW - Dopamine D receptor
KW - Dopamine D receptor
KW - G protein-coupled receptor (GPCR) heteromers
KW - L-DOPA-induced dyskinesia
KW - Locomotor activation
KW - Mouse
KW - PG01037 (PubChem CID: 11477180)
KW - PG01042 (PubChem CID: 11443078)
KW - Pramipexole (PubChem CID: 119570)
KW - Rat
KW - SKF81297 (PubChem CID: 1218)
KW - VK4–116 (PubChem CID: 130431318)
UR - http://www.scopus.com/inward/record.url?scp=85139055726&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85139055726&partnerID=8YFLogxK
U2 - 10.1016/j.phrs.2022.106476
DO - 10.1016/j.phrs.2022.106476
M3 - Article
C2 - 36182040
AN - SCOPUS:85139055726
SN - 1043-6618
VL - 185
JO - Pharmacological Research
JF - Pharmacological Research
M1 - 106476
ER -