title: Synthesis and preliminary screening of novel indole-3-methanamines as 5-HT4 receptor ligands.
abstract: Twenty-three indole-3-methanamines were designed, synthesized and evaluated as ligands for the 5-HT(4) receptor. Compounds I-d, I-j, I-o, I-q and I-u showed good affinity at 100 microM and I-o was found to be only 5-fold less potent than the agonists serotonin (1) and 5-methoxytryptamine (2). Substitution on the 3-methanamine nitrogen clearly influenced activity with docking experiments into a homology model of the 5-HT(4) receptor showing a range of interactions with these side chain substituents. This modelling work together with the SAR determined in this study has provided promising ideas for future synthetic work.
authors.affiliation: Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
authors.forename: Amir
authors.initials: A
authors.lastname: Hanna-Elias
authors.forename: David T
authors.initials: DT
authors.lastname: Manallack
authors.forename: Isabelle
authors.initials: I
authors.lastname: Berque-Bestel
authors.forename: Helen R
authors.initials: HR
authors.lastname: Irving
authors.forename: Ian M
authors.initials: IM
authors.lastname: Coupar
authors.forename: Magdy N
authors.initials: MN
authors.lastname: Iskander
mesh_terms: D000588:Amines / Q000737:chemistry; D001224:Aspartic Acid / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D044422:Receptors, Serotonin, 5-HT4 / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D000588:Amines; D007211:Indoles; D008024:Ligands; D044422:Receptors, Serotonin, 5-HT4; D001224:Aspartic Acid