title: 2,5-Disubstituted pyridines: the discovery of a novel series of 5-HT2A ligands.
abstract: This report describes the effect of replacing the central basic amine present in many known 5-HT(2A) ligands with an aromatic residue. We targeted the isomeric phenethylpyridines 2 and 3 and these compounds proved to be excellent leads, possessing good 5-HT(2A) receptor binding affinity and selectivity over the 5-HT(2C) subtype. Optimization of one isomer led to the identification of 25, a compound with sub-nanomolar 5-HT(2A) affinity and selectivity over 5-HT(2C) of greater than 4600-fold.
authors.affiliation: The Neuroscience Research Centre, Merck Sharp and Dohme, Terlings Park, Harlow, Essex CM20 2QR, UK. kevin_wilson2@merck.com
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Wilson
authors.forename: Monique B
authors.initials: MB
authors.lastname: van Niel
authors.forename: Laura
authors.initials: L
authors.lastname: Cooper
authors.forename: Dawn
authors.initials: D
authors.lastname: Bloomfield
authors.forename: Desmond
authors.initials: D
authors.lastname: O'Connor
authors.forename: L Rebecca
authors.initials: LR
authors.lastname: Fish
authors.forename: Angus M
authors.initials: AM
authors.lastname: MacLeod
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008956:Models, Chemical; D008968:Molecular Conformation; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry*; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D013450:Sulfones / Q000737:chemistry
chemical_list: D008024:Ligands; D011725:Pyridines; D044402:Receptor, Serotonin, 5-HT2A; D012702:Serotonin Antagonists; D013450:Sulfones