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In Vitro Pharmacology of Mitragynine at α-Adrenoceptors

Year: 2025

Type: article

Abstract: High Resolution Image Download MS PowerPoint Slide Mitragynine is a psychoactive alkaloid in Mitragyna speciosa with unique polypharmacology at G protein-coupled receptors. In addition to its well-known partial agonist activity at opioid receptors, mitragynine is an antagonist at human α 2A -adrenoceptors (α 2A Rs), as measured in an in vitro GTPγS G protein assay. Mitragynine’s in vitro α 2A R antagonist pharmacology contrasts with rat behavioral pharmacology studies that suggest mitragynine behaves as an in vivo agonist at rat α 2 Rs. This study investigates this apparent discrepancy using recombinant α-adrenoceptors and a range of orthogonal signal transducers. We evaluated whether mitragynine activates any of seven Gα i/o proteins coupled to α 2A, α 2B, and α 2C Rs, as well as Gα q and Gα 11 coupled to α 1A R. Additionally, we examined rat and human α 2A R-mediated cAMP inhibition, α 2A R-mediated β-arrestin2 recruitment, and tested α 2 R or α 1 R-mediated ERK phosphorylation in wild-type, β-arrestin 1/2 knockout, and Gα q/11 knockout cells. Finally, we report binding and enzyme-inhibition profiling results for mitragynine and its major metabolites, 7-Hydroxymitragynine and 9-Hydroxycorynantheidine, at 99 targets. The results did not support the hypothesis that mitragynine (or its primary metabolites) activates α 2 Rs, but, aligned with our previous GTPγS results, demonstrate that mitragynine is a low-potency, competitive α 2A R antagonist at Gα i1, cAMP, and β-arrestin2 transducers. However, we show that mitragynine is a low-potency (EC 50 ∼3 μM), partial agonist at α 1A R-Gα 11 and stimulates ERK phosphorylation via Gα q/11 -coupled α 1 Rs, supporting in vivo studies that suggest mitragynine is an α 1 R agonist. Nevertheless, the agonist effects of mitragynine at α 1A R-Gα 11 were modest compared to clonidine, a partial agonist control that also activated all α 2 R transducers. Mitragynine’s dual α 2A R antagonist/α 1 R partial agonist pharmacology might contribute to mitragynine’s psychostimulant-like properties.

Source: ACS Chemical Neuroscience

DOI: 10.1021/acschemneuro.5c00719