Synthesis and pharmacological evaluation of N-benzyl substituted 4-bromo-2,5-dimethoxyphenethylamines as 5-HT2A/2C partial agonists. Bioorg Med Chem 2015 Jul 15;23(14):3933-7
Date
01/15/2015Pubmed ID
25583099DOI
10.1016/j.bmc.2014.12.011Scopus ID
2-s2.0-84930872209 (requires institutional sign-in at Scopus site) 29 CitationsAbstract
N-Benzyl substitution of phenethylamine 5-HT2A receptor agonists has dramatic effects on binding affinity, receptor selectivity and agonist activity. In this paper we examine how affinity for the 5-HT2A/2C receptors are influenced by N-benzyl substitution of 4-bromo-2,5-dimethoxyphenethylamine derivatives. Special attention is given to the 2' and 3'-position of the N-benzyl as such compounds are known to be very potent. We found that substitutions in these positions are generally well tolerated. The 2'-position was further examined using a range of substituents to probe the hydrogen bonding requirements for optimal affinity and selectivity, and it was found that small changes in the ligands in this area had a profound effect on their affinities. Furthermore, two ligands that lack a 2'-benzyl substituent were also found to have high affinity contradicting previous held notions. Several high-affinity ligands were identified and assayed for functional activity at the 5-HT2A and 5-HT2C receptor, and they were generally found to be less efficacious agonists than previously reported N-benzyl phenethylamines.
Author List
Hansen M, Jacobsen SE, Plunkett S, Liebscher GE, McCorvy JD, Bräuner-Osborne H, Kristensen JLAuthor
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
Chemistry Techniques, SyntheticDimethoxyphenylethylamine
Drug Evaluation, Preclinical
Fluorescence Resonance Energy Transfer
HEK293 Cells
Humans
Receptor, Serotonin, 5-HT2B
Receptor, Serotonin, 5-HT2C
Serotonin 5-HT2 Receptor Agonists
Structure-Activity Relationship
