Ibogalogs Activate the 5-HT2A Receptor through a Mechanism Involving Outward and Inward Movements of the Respective Transmembrane Segment TM6 and TM7
摘要
The objective of this study is to determine the binding and functional activity of a variety of ibogalogs and their pyridoindole homologs at the serotonin subtype 2 A receptor (5-HT2AR) and compare the molecular mechanisms with that at the 5-HT2BR. The binding results showed that ibogalos and their pyridoindole homologs (2MePI, 8MeO-2MePI) have affinities in the nM concentration range. In contrast, ibogalogs and PNU-22,394, but not catharanthalog (CAG) or pyridoindole homologs, activated the 5-HT2AR with relatively high potency and high efficacy. Subsequently, we determined the inhibitory activity of the least potent partial agonists, CAG and pyridoindole homologs, via functional competition experiments. Functionally, 2MePI and 8MeO-2MePI, but not CAG, behaved as relatively more potent competitive antagonists than agonists. To assess the mechanistic differences between agonists (ibogalogs) and antagonits (pyridoindole homologs) at the 5-HT2AR as well as the differences with the 5-HT2BR, molecular docking and molecular dynamics simulations were performed. The results showed that ibogalogs induce coordinated conformational changes across multiple microswitch networks in the 5-HT2AR, stabilizing the active state characterized by an outward movement of TM6 and inward movement of TM7. In the 5-HT2BR, most ibogalogs (except DM506 and PNU-22394) behave as competitive antagonists by promoting the ionic lock, characterized by a reduced distance between TM3 and TM6.