Tavapadon Explained

Tavapadon (developmental code names CVL-751, PF-06649751) is a dopamine receptor agonist which is under development for the treatment of Parkinson's disease.^{[1] [2] [3]} It is under development by Cerevel Therapeutics, which acquired tavapadon from Pfizer in 2018. It is taken by mouth.

Tavapadon acts as a highly selective partial agonist of the dopamine D₁ receptor (K_i = 9nM; = 65%) and the dopamine D₅ receptor (K_i = 13nM; = 81%).^[4] It has no significant affinity or functional activity at the D₂-like receptors (D₂, D₃, D₄) (K_i ≥ 4,870 to 6,720nM). Tavapadon also shows biased agonism for G_s-coupled signaling at the D₁-like receptors.

As of April 2024, tavapadon is in phase 3 clinical trials for Parkinson's disease.

See also

• Mevidalen (LY-3154207)
• Razpipadon (CVL-871)

Notes and References

1. Web site: Tavapadon - Cerevel Therapeutics . Adis Insight . Springer Nature Switzerland AG.
2. Cerri S, Blandini F . December 2020 . An update on the use of non-ergot dopamine agonists for the treatment of Parkinson's disease . Expert Opinion on Pharmacotherapy . 21 . 18 . 2279–2291 . 10.1080/14656566.2020.1805432 . 32804544. 221163451 .
3. Hall A, Provins L, Valade A . January 2019 . Novel Strategies To Activate the Dopamine D₁ Receptor: Recent Advances in Orthosteric Agonism and Positive Allosteric Modulation . Journal of Medicinal Chemistry . 62 . 1 . 128–140 . 10.1021/acs.jmedchem.8b01767 . 30525590. 54469910 .
4. Bezard E, Gray D, Kozak R, Leoni M, Combs C, Duvvuri S . Rationale and Development of Tavapadon, a D1/D5-Selective Partial Dopamine Agonist for the Treatment of Parkinson's Disease . CNS Neurol Disord Drug Targets . 23 . 4 . 476–487 . 2024 . 36999711 . 10909821 . 10.2174/1871527322666230331121028 . Tavapadon is a highly selective partial agonist at D1 and D5 dopamine receptors, [52] with little to no functional activity at D2, D3, or D4 receptors in vitro (unpublished data). Assays measuring the displacement of radioligand binding in cell lines expressing recombinant human dopamine receptors have shown that tavapadon has a high affinity for both D1 (Ki = 9 nM) and D5 (Ki = 13 nM) (unpublished data). Conversely, tavapadon had a low affinity at D2 (Ki ≥ 6210 nM), D3 (Ki ≥ 6720 nM), and D4 (Ki ≥ 4870 nM) (unpublished data). [...] In vitro assays of functional activity have confirmed that tavapadon acts as a partial agonist by binding at D1 and D5 receptors, corresponding to 65% and 81% of dopamine's intrinsic activity, respectively, and inducing functional receptor activation, with half-maximal effective concentration (EC50) values of 19 nM and 17 nM (unpublished data)..