2. Academic Validation
  3. In vitro and in vivo biotransformation of WMS-1410, a potent GluN2B selective NMDA receptor antagonist

In vitro and in vivo biotransformation of WMS-1410, a potent GluN2B selective NMDA receptor antagonist

  • J Pharm Biomed Anal. 2014 Jun:94:36-44. doi: 10.1016/j.jpba.2014.01.017.
Evamaria Falck 1,  Frank Begrow 1,  Eugen J Verspohl 1,  Bernhard Wünsch 2
Affiliations

Affiliations

  • 1 Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität, Münster, Germany.
  • 2 Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität, Münster, Germany. Electronic address: [email protected].
PMID: 24534302 DOI: 10.1016/j.jpba.2014.01.017
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.

Keywords

GluN2B receptor antagonists; In vitro and in vivo biotransformation; LC–MS; NMDA receptor; Rate of degradation.

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