title: Synthesis and structure-activity relationships of N-benzyl phenethylamines as 5-HT2A/2C agonists.
abstract: N-Benzyl substitution of 5-HT2A receptor agonists of the phenethylamine structural class of psychedelics (such as 4-bromo-2,5-dimethoxyphenethylamine, often referred to as 2C-B) confer a significant increase in binding affinity as well as functional activity of the receptor. We have prepared a series of 48 compounds with structural variations in both the phenethylamine and N-benzyl part of the molecule to determine the effects on receptor binding affinity and functional activity at 5-HT2A and 5-HT2C receptors. The compounds generally had high affinity for the 5-HT2A receptor with 8b having the highest affinity at 0.29 nM but with several other compounds also exhibiting subnanomolar binding affinities. The functional activity of the compounds was distributed over a wider range with 1b being the most potent at 0.074 nM. Most of the compounds exhibited low to moderate selectivity (1- to 40-fold) for the 5-HT2A receptor in the binding assays, although one compound 6b showed an impressive 100-fold selectivity for the 5-HT2A receptor. In the functional assay, selectivity was generally higher with 1b being more than 400-fold selective for the 5-HT2A receptor.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, 2100 København Ø, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Hansen
authors.forename: Karina
authors.initials: K
authors.lastname: Phonekeo
authors.forename: James S
authors.initials: JS
authors.lastname: Paine
authors.forename: Sebastian
authors.initials: S
authors.lastname: Leth-Petersen
authors.forename: Mikael
authors.initials: M
authors.lastname: Begtrup
authors.forename: Hans
authors.initials: H
authors.lastname: Bräuner-Osborne
authors.forename: Jesper L
authors.initials: JL
authors.lastname: Kristensen
mesh_terms: D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D015394:Molecular Structure; D010627:Phenethylamines / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D011869:Radioligand Assay; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics*
chemical_list: D007295:Inositol Phosphates; D010627:Phenethylamines; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists