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Brief Report

Chirality of Novel Bitopic Agonists Determines Unique Pharmacology at the Dopamine D3 Receptor

1
Computational Chemistry and Molecular Biophysics Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse—Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA
2
Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, MA 02115, USA
3
Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse—Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA
*
Authors to whom correspondence should be addressed.
Academic Editor: Philippe De Deurwaerdere
Biomolecules 2021, 11(4), 570; https://doi.org/10.3390/biom11040570
Received: 15 March 2021 / Revised: 6 April 2021 / Accepted: 9 April 2021 / Published: 13 April 2021
The dopamine D2/D3 receptor (D2R/D3R) agonists are used as therapeutics for Parkinson’s disease (PD) and other motor disorders. Selective targeting of D3R over D2R is attractive because of D3R’s restricted tissue distribution with potentially fewer side-effects and its putative neuroprotective effect. However, the high sequence homology between the D2R and D3R poses a challenge in the development of D3R selective agonists. To address the ligand selectivity, bitopic ligands were designed and synthesized previously based on a potent D3R-preferential agonist PF592,379 as the primary pharmacophore (PP). This PP was attached to various secondary pharmacophores (SPs) using chemically different linkers. Here, we characterize some of these novel bitopic ligands at both D3R and D2R using BRET-based functional assays. The bitopic ligands showed varying differences in potencies and efficacies. In addition, the chirality of the PP was key to conferring improved D3R potency, selectivity, and G protein signaling bias. In particular, compound AB04-88 exhibited significant D3R over D2R selectivity, and G protein bias at D3R. This bias was consistently observed at various time-points ranging from 8 to 46 min. Together, the structure-activity relationships derived from these functional studies reveal unique pharmacology at D3R and support further evaluation of functionally biased D3R agonists for their therapeutic potential. View Full-Text
Keywords: dopamine D3 receptor; dopamine D2 receptor; bitopic ligand; biased agonism; functional selectivity; subtype selectivity; subtype affinity; chirality dopamine D3 receptor; dopamine D2 receptor; bitopic ligand; biased agonism; functional selectivity; subtype selectivity; subtype affinity; chirality
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MDPI and ACS Style

Adhikari, P.; Xie, B.; Semeano, A.; Bonifazi, A.; Battiti, F.O.; Newman, A.H.; Yano, H.; Shi, L. Chirality of Novel Bitopic Agonists Determines Unique Pharmacology at the Dopamine D3 Receptor. Biomolecules 2021, 11, 570. https://doi.org/10.3390/biom11040570

AMA Style

Adhikari P, Xie B, Semeano A, Bonifazi A, Battiti FO, Newman AH, Yano H, Shi L. Chirality of Novel Bitopic Agonists Determines Unique Pharmacology at the Dopamine D3 Receptor. Biomolecules. 2021; 11(4):570. https://doi.org/10.3390/biom11040570

Chicago/Turabian Style

Adhikari, Pramisha, Bing Xie, Ana Semeano, Alessandro Bonifazi, Francisco O. Battiti, Amy H. Newman, Hideaki Yano, and Lei Shi. 2021. "Chirality of Novel Bitopic Agonists Determines Unique Pharmacology at the Dopamine D3 Receptor" Biomolecules 11, no. 4: 570. https://doi.org/10.3390/biom11040570

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