title: Synthesis and pharmacological evaluation of N-benzyl substituted 4-bromo-2,5-dimethoxyphenethylamines as 5-HT2A/2C partial agonists.
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.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 København Ø, Denmark; Center for Integrated Molecular Brain Imaging (CIMBI), Rigshospitalet and University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Hansen
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: Stine Engesgaard
authors.initials: SE
authors.lastname: Jacobsen
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: Shane
authors.initials: S
authors.lastname: Plunkett
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: Gudrun Eckhard
authors.initials: GE
authors.lastname: Liebscher
authors.affiliation: Pharmacology Department, School of Medicine, University of North Carolina at Chapel Hill, 120 Mason Farm Road, 4009 Genetic Medicine Bldg, Campus Box 7365, Chapel Hill, NC 27599-7365, United States.
authors.forename: John D
authors.initials: JD
authors.lastname: McCorvy
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: Hans
authors.initials: H
authors.lastname: Bräuner-Osborne
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 København Ø, Denmark; Center for Integrated Molecular Brain Imaging (CIMBI), Rigshospitalet and University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark. Electronic address: jesper.kristensen@sund.ku.dk.
authors.forename: Jesper Langgaard
authors.initials: JL
authors.lastname: Kristensen
mesh_terms: D060326:Chemistry Techniques, Synthetic; D004118:Dimethoxyphenylethylamine / Q000031:analogs & derivatives* / Q000737:chemistry; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D031541:Fluorescence Resonance Energy Transfer; D057809:HEK293 Cells / Q000187:drug effects; D006801:Humans; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism; D058826:Serotonin 5-HT2 Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004118:Dimethoxyphenylethylamine; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; C079321:2-(4-bromo-2,5-dimethoxyphenyl)ethylamine
keywords: 5-HT(2A) agonists; N-Benzyl phenethylamines; Selectivity; Serotonin; Structure activity relations