Extensive rigid analogue design maps the binding conformation of potent N-benzylphenethylamine 5-HT2A serotonin receptor agonist ligands. ACS Chem Neurosci 2013 Jan 16;4(1):96-109
Date
01/22/2013Pubmed ID
23336049Pubmed Central ID
PMC3547484DOI
10.1021/cn3000668Scopus ID
2-s2.0-84866414310 (requires institutional sign-in at Scopus site) 49 CitationsAbstract
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.
Author List
Juncosa JI Jr, Hansen M, Bonner LA, Cueva JP, Maglathlin R, McCorvy JD, Marona-Lewicka D, Lill MA, Nichols DEAuthor
John McCorvy PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Affinity LabelsBenzazepines
Hallucinogens
Humans
Ligands
Models, Molecular
Phenethylamines
Protein Conformation
Receptor, Serotonin, 5-HT2A
Serotonin 5-HT2 Receptor Agonists
