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

Adhikari, Pramisha; Xie, Bing; Semeano, Ana; Bonifazi, Alessandro; Battiti, Francisco O.; Newman, Amy H.; Yano, Hideaki; Shi, Lei

doi:10.3390/biom11040570

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

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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

Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, MA 02115, USA

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

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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

(This article belongs to the Special Issue Dopamine D3 Receptor: Contemporary Views of Its Function and Pharmacology for Neuropsychiatric Diseases)

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Abstract

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

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

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