title: Metabolism studies of ifenprodil, a potent GluN2B receptor antagonist.
abstract: The NMDA receptor antagonist ifenprodil is an important lead structure for developing new GluN2B selective NMDA receptor antagonists. Ifenprodil itself has a high affinity to the GluN2B subunit but a poor selectivity for the NMDA receptor. This aspect and the fast biotransformation are the major drawbacks of ifenprodil. In order to optimize the development of new and more selective GluN2B (NMDA) receptor antagonists, the identification of the main metabolic pathways of ifenprodil is necessary. Herein the in vitro and in vivo phase I and phase II metabolites of ifenprodil were generated and analyzed via LC-MS(n) experiments. In vitro experiments were carried out with rat liver microsomes and various co-factors to generate phase I and phase II metabolites. The application of ifenprodil to a rat and the analysis of its urine led to the identification of diverse formed in vivo metabolites. The phenol represents the metabolically most labile structural element since glucuronide 7 and 8 appeared as main metabolites.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität, Münster, Germany.
authors.forename: Evamaria
authors.initials: E
authors.lastname: Falck
authors.forename: Frank
authors.initials: F
authors.lastname: Begrow
authors.forename: Eugen
authors.initials: E
authors.lastname: Verspohl
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
mesh_terms: D000818:Animals; D001665:Binding Sites; D001682:Biological Availability; D001711:Biotransformation; D002417:Cattle; D002853:Chromatography, Liquid; D005260:Female; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D019800:Phenol / Q000737:chemistry; D010880:Piperidines / Q000378:metabolism* / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012709:Serum Albumin / Q000737:chemistry
chemical_list: C121001:NR2B NMDA receptor; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D012709:Serum Albumin; D019800:Phenol; C010739:ifenprodil
keywords: BSA; CNS; COMT; EIC; GluN2B receptor antagonists; Ifenprodil; In vitro and in vivo metabolism; LC–MS; N-methyl-d-aspartate; NADPH; NMDA; NMDA receptor; PAPS; S-(5′-adenosyl)-l-methionine iodide; SAM; TIC; UDPGA; adenosine-3′-phosphate-5′-phosphosulfate lithium salt hydrate; bovine serum albumin; catechol-O-methyl transferase; central nervous system; extracted ion current; nicotinamide adenine dinucleotide phosphate; total ion current; uridine 5′-diphosphoglucuronic acid trisodium salt