title: Extensive rigid analogue design maps the binding conformation of potent N-benzylphenethylamine 5-HT2A serotonin receptor agonist ligands.
abstract: Based on the structure of the superpotent 5-HT(2A) agonist 2-(4-bromo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine, which consists of a ring-substituted phenethylamine skeleton modified with an N-benzyl group, we designed and synthesized a small library of constrained analogues to identify the optimal arrangement of the pharmacophoric elements of the ligand. Structures consisted of diversely substituted tetrahydroisoquinolines, piperidines, and one benzazepine. Based on the structure of (S,S)-9b, which showed the highest affinity of the series, we propose an optimal binding conformation. (S,S)-9b also displayed 124-fold selectivity for the 5-HT(2A) over the 5-HT(2C) receptor, making it the most selective 5-HT(2A) receptor agonist ligand currently known.
authors: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States.
authors: Jose I
authors: JI
authors: Juncosa
authors: Martin
authors: M
authors: Hansen
authors: Lisa A
authors: LA
authors: Bonner
authors: Juan Pablo
authors: JP
authors: Cueva
authors: Rebecca
authors: R
authors: Maglathlin
authors: John D
authors: JD
authors: McCorvy
authors: Danuta
authors: D
authors: Marona-Lewicka
authors: Markus A
authors: MA
authors: Lill
authors: David E
authors: DE
authors: Nichols
mesh_terms: D000345:Affinity Labels / Q000378:metabolism; D001552:Benzazepines / Q000378:metabolism; D006213:Hallucinogens / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D010627:Phenethylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000378:metabolism*
chemical_list: D000345:Affinity Labels; D001552:Benzazepines; D006213:Hallucinogens; D008024:Ligands; D010627:Phenethylamines; D044402:Receptor, Serotonin, 5-HT2A; D058826:Serotonin 5-HT2 Receptor Agonists