Development of Novel Tavapadon Analogs as Dual-targeted Partial Agonists Based on the Dopamine D₁/D₅ Receptors

Abstract

Tavapadon is a potent, selective G protein-biased partial agonist for the dopamine D₁/D₅ receptors, with positive experimental results in phase 3 trials for the treatment of Parkinson's disease (PD). This study aims to study the structure–activity relationship (SAR) of tavapadon to discover novel compounds with improved binding activity to D₁/D₅ receptors. In this work, a series of tavapadon derivatives were designed and synthesized based on the pharmacophores of tavapadon. Their binding activity to D₁/D₅ receptors was evaluated by determining in vitro median effect concentration (EC₅₀). The binding mode was predicted by molecular docking. Our data showed that among those compounds, III-1 exhibited a similar binding pose to tavapadon at D₁ dopamine receptors and demonstrated nanomolar potency for both D₁ and D₅ receptors. Compound III-1 is a potent partial agonist for the D₁/D₅ receptors, and may be a potent alternative to tavapadon for the treatment of PD in further study.

Keywords

dopamine 1 receptor - dopamine 5 receptor - partial agonists - tavapadon - EC₅₀

^# These authors contributed equally to this work.

Publication History

Received: 24 February 2025

Accepted: 16 June 2025

Article published online:
28 July 2025

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