title: Synthesis of a series of γ-amino alcohols comprising an N-methyl isoindoline moiety and their evaluation as NMDA receptor antagonists.
abstract: We report a series of new stereoisomeric γ-amino alcohols comprising an N-methyl isoindoline moiety as ligands for the ifenprodil binding site of the NMDA receptor. Among the four series of stereoisomers, 8a-c, 9a-c, 10a-c, and 11a-c, synthesised, the highest potencies and NMDA-NR2B subtype selectivity was found for the methyl derivative 11a and the chloro derivative 11c, both possessing the [1S,1'S] configuration. However, additional moderate potency of 11a and 11c at the hERG channel with values of 2.6 ± 2.4% and 1.6 ± 2.0%, respectively, rendered them unsuitable for medical use.
authors.affiliation: Department of Pharmacy, Ludwig-Maximilians-University Munich, Butenandtstr. 5-13, D-81377 Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Müller
authors.forename: Georg
authors.initials: G
authors.lastname: Höfner
authors.forename: Thejavathi
authors.initials: T
authors.lastname: Renukappa-Gutke
authors.forename: Chris G
authors.initials: CG
authors.lastname: Parsons
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Wanner
mesh_terms: D000605:Amino Alcohols / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D016291:Dizocilpine Maleate / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008024:Ligands; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D016202:N-Methylaspartate / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D000605:Amino Alcohols; D051638:Ether-A-Go-Go Potassium Channels; D018691:Excitatory Amino Acid Antagonists; C496884:KCNH1 protein, human; D008024:Ligands; D018696:Neuroprotective Agents; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; C010739:ifenprodil