A phenolic ether 2-methoxy-carvacrol isolated from Rhabdocaulon lavanduloides (Benth) Epling. (Lamiaceae): New crystal structure, Hirshfeld surface, quantum chemical calculation, anxiolytic and anticonvulsant potential in zebrafish, and molecular docking of GABAA receptor

Abstract

The drugs that treat anxiety disorder have variable efficacy and associated side effects. This study evaluated the anxiolytic and anticonvulsant potential of natural product 2-methoxy-carvacrol isolated from Rhabdocaulon lavanduloides, its respective mechanism of action in adult zebrafish (ZFa), in addition to an in silico. Each animal (n=6/group) was treated intraperitoneally (i.p.; 20 µL) with the natural product (4, 20 and 40 mg/Kg) and with the vehicle (DMSO 3 %; 20 µL), being submitted to the tests of locomotor activity and 96 h acute toxicity. The study showed that 2-methoxy-carvacrol was not toxic in the assessment of locomotion behavior of adult zebrafish at all doses evaluated. The two highest doses displayed anxiolytic effect, and when examining the mechanism of action, it was found that this effect is neuromodulated by the GABAergic pathway. Furthermore, the sample was able to reverse the convulsive behavior of the animals in the early stage of analysis (Stage I). Molecular docking simulations indicate that 2-methoxy-carvacrol has a distinct affinity from that of the co-crystallized inhibitor, suggesting allosteric activity. Furthermore, its interactions with the GABAAR receptor are like those of DZP, highlighting potential anxiolytic effects. The pharmacokinetic test showed that PAMPA suggests high cellular permeability for potential intestinal absorption.