Structure-activity relationships of N-substituted 4-(trifluoromethoxy)benzamidines with affinity for GluN2B-containing NMDA receptors

Corinne Beinat; Samuel D Banister; Jane Hoban; John Tsanaktsidis; Athanasios Metaxas; Albert D Windhorst; Michael Kassiou

doi:10.1016/j.bmcl.2013.12.087

Structure-activity relationships of N-substituted 4-(trifluoromethoxy)benzamidines with affinity for GluN2B-containing NMDA receptors

Bioorg Med Chem Lett. 2014 Feb 1;24(3):828-30. doi: 10.1016/j.bmcl.2013.12.087. Epub 2013 Dec 28.

Authors

Corinne Beinat¹, Samuel D Banister², Jane Hoban¹, John Tsanaktsidis³, Athanasios Metaxas⁴, Albert D Windhorst⁴, Michael Kassiou⁵

Affiliations

¹ School of Chemistry, The University of Sydney, NSW 2006, Australia.
² School of Chemistry, The University of Sydney, NSW 2006, Australia; Brain and Mind Research Institute, Sydney, NSW 2050, Australia.
³ CSIRO Materials Science & Engineering, Ian Wark Laboratory, Bayview Avenue, Clayton, Victoria 3168, Australia.
⁴ Department of Radiology & Nuclear Medicine, VU University Medical Centre, Amsterdam 1081HV, The Netherlands.
⁵ School of Chemistry, The University of Sydney, NSW 2006, Australia; Brain and Mind Research Institute, Sydney, NSW 2050, Australia; Discipline of Medical Radiation Sciences, University of Sydney, NSW 2006, Australia. Electronic address: michael.kassiou@sydney.edu.au.

PMID: 24412068
DOI: 10.1016/j.bmcl.2013.12.087

Abstract

GluN2B subtype-selective NMDA antagonists represent promising therapeutic targets for the symptomatic treatment of multiple CNS pathologies. A series of N-benzyl substituted benzamidines were synthesised and the benzyl ring was further replaced with various polycyclic moieties. Compounds were evaluated for activity at GluN2B containing NMDA receptors where analogues 9, 12, 16 and 18 were the most potent of the series, replacement of the benzyl ring with polycycles resulted in a complete loss of activity.

Keywords: Amidine; CNS; GluN2B; NMDA; Structure–activity relationships.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Benzamidines / chemical synthesis
Benzamidines / chemistry*
Benzamidines / pharmacology*
Cyclization
Fluorine / chemistry*
Glutamates / chemistry*
Glutamates / metabolism
Polycyclic Compounds / chemical synthesis
Polycyclic Compounds / chemistry
Protein Binding / drug effects
Receptors, N-Methyl-D-Aspartate / chemistry*
Receptors, N-Methyl-D-Aspartate / metabolism
Structure-Activity Relationship

Substances

4-trifluoromethoxy-N-(2-trifluoromethylbenzyl)benzamidine
Benzamidines
Glutamates
Polycyclic Compounds
Receptors, N-Methyl-D-Aspartate
Fluorine