Product information and disease description Product description Product information Pharmacology

Mechanism of action

7 evidence topics · 4 sources

Mechanism of action in the prescribing information

“Tavapadon is a selective partial agonist at the dopamine D1 and D5 receptor subtypes (D1/D5).” (opens the prescribing information at this quote)

Receptor binding affinity and selectivity

“Tavapadon is a highly selective partial agonist at D1 and D5 dopamine receptors,” (opens the source at this quote in a new tab)
“with little to no functional activity at D2, D3, or D4 receptors in vitro (unpublished data).” (opens the source at this quote in a new tab)
“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human dopamine receptors have shown that tavapadon has a high affinity for both D1 (Ki = 9 nM) and D5 (Ki = 13 nM) (unpublished data).” (opens the source at this quote in a new tab)
“Conversely, tavapadon had a low affinity at D2 (Ki ≥ 6210 nM), D3 (Ki ≥ 6720 nM), and D4 (Ki ≥ 4870 nM) (unpublished data).” (opens the source at this quote in a new tab)

Intrinsic activity and potency at D1 and D5 receptors

“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inducing functional receptor activation, with half-maximal effective concentration (EC50) values of 19 nM and 17 nM (unpublished data).” (opens the source at this quote in a new tab)

Striatal direct pathway as the site of D1/D5 receptor action

“D1/D5 receptors coupled to stimulatory Gs/Golf are predominantly expressed on medium spiny neurons (MSNs) of the direct pathway, which projects to striatal nuclei that directly regulate motor output” (opens the source at this quote in a new tab)
“Conversely, the D2/D3 receptors coupled to inhibitory Gi/Go are expressed primarily on indirect pathway MSNs, which regulate motor output via multisynaptic connections to the basal ganglia” (opens the source at this quote in a new tab)

Non-catechol structure and reduced receptor desensitization

“Computational modeling of binding interactions between D1 dopamine receptors and a non-catechol-based D1/D5-selective agonist similar to tavapadon (PF-6142) showed no direct binding to transmembrane 3 amine and aspartate residues and reduced association with serine residues in transmembrane 5, instead binding to extracellular domains of the receptor” (opens the source at this quote in a new tab)
“Live-cell fluorescence imaging experiments demonstrated that PF-6142 was able to activate functional downstream signaling cascades with reduced recruitment of β-arrestin when compared to dopamine, largely preventing receptor desensitization” (opens the source at this quote in a new tab)

Receptor internalization and binding kinetics in vitro

“Tavapadon and apomorphine did not induce significant D1R internalization, whereas pronounced internalization was observed with A77636, dopamine, and dihydrexidine.” (opens the source at this quote in a new tab)
“GIRK response deactivation time courses upon agonist washout were longer for A77636 and tavapadon compared to dopamine, dihydrexidine, and apomorphine.” (opens the source at this quote in a new tab)
“Tavapadon and apomorphine were partial agonists in both assays, whereas A77636 and dihydrexidine showed efficacies similar to dopamine.” (opens the source at this quote in a new tab)

G protein subtype selectivity: Gαolf and Gαs

“In contrast, the non-catechol agonist tavapadon acted as a full agonist at Gαolf and a partial agonist at Gαs.” (opens the source at this quote in a new tab)
“In the brain, Gαolf is predominantly found in the striatum whereas Gαs is expressed elsewhere.” (opens the source at this quote in a new tab)