Synthesis and pharmacological evaluation of N-benzyl substituted 4-bromo-2,5-dimethoxyphenethylamines as 5-HT2A/2C partial agonists.
Martin Hansen, Stine Engesgaard Jacobsen, Shane Plunkett, Gudrun Eckhard Liebscher, John D McCorvy, Hans Bräuner-osborne, Jesper Langgaard Kristensen
Bioorganic & medicinal chemistry July 15, 2015 DOI: 10.1016/j.bmc.2014.12.011 via PubMed
Summary
AI-generated from the abstractN-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.
Study at a glance
| Characteristics | Experimental study Peer reviewed |
|---|---|
| Topics | Serotonin |
| Keywords | 5-ht2a agonists N-benzyl phenethylamines Selectivity Structure activity relations Serotonin-modulating compounds |
| Citations | 35 |
| Key finding | Small changes in the 2' position of the N-benzyl group profoundly affect binding affinity, and two ligands lacking a 2'-benzyl substituent exhibited high affinity, contradicting prior assumptions. |
Abstract
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.