Exploring a Druggable Hydrophobic Tunnel in the 5-HT2A Receptor with Potent Phenethylamines

Abstract The serotonin 2A receptor is the most abundant excitatory serotonin receptor in the brain and the target for serotonergic psychedelics. Despite its importance, the mechanisms of action and structure−activity relationship of receptor agonists are not fully understood. Experimental 5-HT2AR structures have identified a hydrophobic tunnel lateral to the orthosteric site. Here, we have examined this tunnel and its implications for 5-HT2AR agonist pharmacology. The tunnel characteristics and the key role of Gly2385×43 were delineated by molecular modeling and by the design and synthesis, binding, and functional characterization of several phenethylamines. Our data demonstrate that the agonist potencies at the 5-HT2AR exhibited by analogs with substituents at C-4 of the phenyl ring, with at least four heavy atoms, are able to protrude into and form interactions within this tunnel. Thus, these findings provide new insights into the molecular basis for phenethylamine-induced 5-HT2AR activation and identify this tunnel as a druggable region.