Synthesis and pharmacological evaluation of N-benzyl substituted 4-bromo-2,5-dimethoxyphenethylamines as 5-HT2A/2C partial agonists.
Bioorganic & medicinal chemistry July 15, 2015 Martin Hansen, Stine Engesgaard Jacobsen, Shane Plunkett et al. 35 citations
N-Benzyl substitution dramatically alters how phenethylamine 5-HT2A receptor agonists bind to and activate serotonin receptors. This work examined how adding an N-benzyl group to 4-bromo-2,5-dimethoxyphenethylamine derivatives affects affinity for 5-HT2A and 5-HT2C receptors, focusing on the 2' and 3' positions of the benzyl ring. Substitutions at these positions were generally well tolerated. Probing the 2' position with various substituents revealed that small changes profoundly affected affinity, and two ligands lacking a 2'-benzyl substituent unexpectedly showed high affinity, contradicting earlier assumptions. Several high-affinity ligands were tested for functional activity and were less efficacious agonists than previously reported N-benzyl phenethylamines.