Development of Novel Tavapadon Analogs as Dual-targeted Partial Agonists Based on the Dopamine D<sub>1</sub>/D<sub>5</sub> Receptors
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 nov...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Georg Thieme Verlag KG
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| Series: | Pharmaceutical Fronts |
| Subjects: | |
| Online Access: | http://www.thieme-connect.de/DOI/DOI?10.1055/a-2638-1667 |
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| Summary: | 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. |
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| ISSN: | 2628-5088 2628-5096 |