Discovery of trans-3,4,4'-trihydroxystilbene as new lead vasorelaxant agent for antihypertensive drug development

The structure-vasorelaxant activity relationships (SARs) assessment in previous study has found that trans-3,4,4'-trihydroxystilbene (344OH) could potentially act as a vasorelaxing agent with demonstration of over 2-fold maximal relaxation (R_max) compared to its analogue, resveratrol. The present study focuses on the mechanism of actions and pathways employed by 344OH and compared to its analogue to further speculate the SAR of stilbenoids towards vasorelaxation.

The 344OH employed in present study was synthesized based on the protocol in previous study. The vascular responses towards the cumulative addition of 344OH were evaluated using in vitro rat aortic rings assays.

The pEC₅₀ and R_max values were found to be 4.33 ± 0.05 and 106 ± 3.99%, respectively. Results showed that the vasorelaxation of 344OH were predominated by G-protein-coupled muscarinic- (M₃) and β₂-adrenergic receptors, followed by PGI₂/AC/cAMP- and NO/sGC/cGMP-dependent pathways. It was also identified that 344OH employed voltage-activated- (K_v), calcium-activated- (K_ca) and inwardly-rectifying (K_ir) potassium channels and act as an antagonist for both VOCC and IP₃R while regulating the action potential in the vasculature.

The different position of hydroxyl substituent located in A-ring of the stilbenoid backbone in 344OH compared to resveratrol resulted in a significant difference in mechanistic actions that lead to 344OH's fast-acting and less time-dependent vasorelaxation behaviour. This has substantially increased the potential of 344OH to be developed as an effective antihypertensive drug in future. Present findings further strengthen our inferences where the SARs study approach should be carried out as the mainstream methodology in future drug development research.