Extensive rigid analogue design maps the binding conformation of potent N-benzylphenethylamine 5-HT2A serotonin receptor agonist ligands.
ACS Chemical Neuroscience January 16, 2013 Jose I Juncosa, Martin Hansen, Lisa A Bonner et al.
By modifying the structure of a known superpotent 5-HT(2A) receptor agonist, researchers synthesized a set of constrained analogues to determine the best arrangement of the ligand's key chemical features. The compounds included substituted tetrahydroisoquinolines, piperidines, and a benzazepine. One compound, (S,S)-9b, had the highest binding affinity and a 124-fold selectivity for the 5-HT(2A) receptor over the 5-HT(2C) receptor, making it the most selective 5-HT(2A) receptor agonist ligand currently known. An optimal binding conformation is proposed based on this compound.