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 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Topics | Serotonin |
| Keywords | 5-ht2a agonists N-benzyl phenethylamines Selectivity Structure activity relations Serotonin-modulating compounds Receptors High affinity N-benzyl group 2'-benzyl substituent Chemical group Modifying Impacts Interaction New compounds Developing Pathways Molecules |
| Citations | 35 |
| Key findings | 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.
Comparable studies
Other experimental studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Healthy human volunteers | 1998 | Experimental study | |
| Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | 2000 | Experimental study | |
| Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity Rat brain | 1988 | Experimental study | |
| The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Human platelet plasma membrane vesicles and bovine adrenal chromaffin granule membrane... | 1992 | Laboratory study | |
| 5-HT2AReceptor-Mediated Regulation of Brain-Derived Neurotrophic Factor mRNA in the Hippocampus and the Neocortex Rat brain | 1997 | Experimental study |
Citations in the library
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- Discovery of β-Arrestin-Biased 25CN-NBOH-Derived 5-HT2A Receptor Agonists. Journal of Medicinal Chemistry September 22, 2022
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Cites 8
- Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Experimental Brain Research June 1, 2013
- Synthesis and structure-activity relationships of N-benzyl phenethylamines as 5-HT2A/2C agonists. ACS Chemical Neuroscience March 19, 2014
- The non-hallucinogen 2-bromo-lysergic acid diethylamide as preventative treatment for cluster headache: An open, non-randomized case series Cephalalgia March 26, 2010
- Radiosynthesis and Evaluation of 11C-CIMBI-5 as a 5-HT2A Receptor Agonist Radioligand for PET Journal of Nuclear Medicine October 18, 2010
- Hallucinogens. Pharmacology & Therapeutics February 1, 2004
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