title: In vitro and in vivo biotransformation of WMS-1410, a potent GluN2B selective NMDA receptor antagonist.
abstract: Structural modification of the GluN2B selective NMDA receptor antagonist ifenprodil led to the 3-benzazepine WMS-1410 with similar GluN2B affinity but higher receptor selectivity. Herein the in vitro and in vivo biotransformation of WMS-1410 is reported. Incubation of WMS-1410 with rat liver microsomes and different cofactors resulted in four hydroxylated phase I metabolites, two phase II metabolites and five combined phase I/II metabolites. With exception of catechol 4, these metabolites were also identified in the urine of a rat treated with WMS-1410. However the metabolites 7, 8 and 12 clearly show that the catechol metabolite 4 was also formed in vivo. As shown for ifenprodil the phenol of WMS-1410 represents the metabolically most reactive structural element. The biotransformation of WMS-1410 is considerably slower than the biotransformation of ifenprodil indicating a higher metabolic stability. From the viewpoint of metabolic stability the bioisosteric replacement of the phenol of WMS-1410 by a metabolically more stable moiety should be favourable.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität, Münster, Germany.
authors.forename: Evamaria
authors.initials: E
authors.lastname: Falck
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität, Münster, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Begrow
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität, Münster, Germany.
authors.forename: Eugen J
authors.initials: EJ
authors.lastname: Verspohl
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität, Münster, Germany. Electronic address: wuensch@uni-muenster.de.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000378:metabolism*; D001711:Biotransformation / Q000502:physiology*; D002396:Catechols / Q000378:metabolism; D006900:Hydroxylation / Q000502:physiology; D050216:Metabolic Detoxication, Phase I / Q000502:physiology; D050217:Metabolic Detoxication, Phase II / Q000502:physiology; D008862:Microsomes, Liver / Q000378:metabolism; D019800:Phenol / Q000378:metabolism; D010880:Piperidines / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C556005:3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1,7-diol; D001552:Benzazepines; D002396:Catechols; C121001:NR2B NMDA receptor; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D019800:Phenol; C034221:catechol; C010739:ifenprodil
keywords: GluN2B receptor antagonists; In vitro and in vivo biotransformation; LC–MS; NMDA receptor; Rate of degradation