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

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

doi:10.3390/biom11040570

Pramisha Adhikari, Amy H Newman + Show 6 more

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https://doi.org/10.3390/biom11040570

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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.

Highlights

Introduction published maps and institutional affilDopamine (DA) is a major neurotransmitter in the central nervous system responsible for various physiological functions such as motor control, cognition, reward, pain, and memory and learning [1]
Dopamine signaling is mediated by five G protein-coupled receptors (GPCRs) classified into two subgroups based on distinct sequence homologies and signal transduction activities [2]: D1 -like receptors that primarily couple to Gs protein and enhance the activity of adenylyl cyclase, leading to an increase in intracellular cAMP production, and D2 -like receptors that primarily couple to the Gi/Go class of G
The bitopic compounds characterized in this study all have the PF592,379 scaffold as the primary pharmacophore (PP)

Summary

Introduction

Dopamine (DA) is a major neurotransmitter in the central nervous system responsible for various physiological functions such as motor control, cognition, reward, pain, and memory and learning [1]. The dopamine D2 and D3 receptors (D2 R and D3 R), both belonging to the D2 -like receptor subfamily, represent the major targets for neuropsychiatric disorders such as schizophrenia, Parkinson’s disease (PD), and substance use disorders (SUDs) [3,4]. Between the two receptor subtypes, selective targeting of D3 R would have lower potential for side effects because of its relatively iations.

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