Bioorganic & Medicinal Chemistry Letters
Structure–activity relationships of N-substituted
4-(trifluoromethoxy)benzamidines with affinity
for GluN2B-containing NMDA receptors
Corinne Beinat a, Samuel D. Banister a,b, Jane Hoban a, John Tsanaktsidis c, Athanasios Metaxas d,
Albert D. Windhorst d, Michael Kassiou a,b,e,
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a School of Chemistry, The University of Sydney, NSW 2006, Australia
b Brain and Mind Research Institute, Sydney, NSW 2050, Australia
c CSIRO Materials Science & Engineering, Ian Wark Laboratory, Bayview Avenue, Clayton, Victoria 3168, Australia
d Department of Radiology & Nuclear Medicine, VU University Medical Centre, Amsterdam 1081HV, The Netherlands
e Discipline of Medical Radiation Sciences, University of Sydney, NSW 2006, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
GluN2B subtype-selective NMDA antagonists represent promising therapeutic targets for the symptom-
atic treatment of multiple CNS pathologies. A series of N-benzyl substituted benzamidines were synthes-
ised 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.
Received 26 November 2013
Revised 18 December 2013
Accepted 19 December 2013
Available online 28 December 2013
Keywords:
GluN2B
Ó 2013 Elsevier Ltd. All rights reserved.
NMDA
Amidine
CNS
Structure–activity relationships
N-Methyl-
D
-aspartate receptors (NMDARs) are hetero-
the hippocampus, olfactory bulb, and the cerebral cortex, with
minimal expression in the cerebellum.3 This differential anatomi-
cal distribution of GluN2A and GluN2B-comprised NMDARs allows
GluN2B-selective antagonists to exhibit the full therapeutic effects
of traditional non-selective NMDAR antagonists but with reduced
side-effect profiles, particularly undesirable locomotor effects,
due to reduced expression in the cerebellum.4
Early, non-selective GluN2B antagonists such as ifenprodil (1),
eliprodil (2), and haloperidol (3) (Fig. 1), were used to study
GluN2B-comprised NMDAR activity and were defined as first gen-
eration GluN2B antagonists. However, the off-target activity and
pharmacokinetic properties of these compounds limited their
therapeutic application. Researchers at Merck have since identified
(E)-N1-(benzyl)cinnamamidine (4, Ki = 9 nM vs [3H]1) to have
considerable affinity for GluN2B-containing NMDARs.5 As styryl
amidine 4 can potentially act as a Michael acceptor, a series of
non-styryl compounds were explored as a novel class of GluN2B
oligomeric ligand-gated cation channels widely distributed in the
CNS and activated by the major excitatory neurotransmitter,
L
-glutamate, in the presence of co-agonist glycine.1 NMDARs exist
as tetrameric or pentameric complexes of a glycine-binding GluN1
subunit with one or more glutamate-binding GluN2 (A, B, C, D)
subunits. NMDARs are essential to learning, memory, and informa-
tion processing within the human brain, and defects of NMDAR
function are implicated in multiple central nervous system (CNS)
disorders, including Parkinson’s disease, neuropathic pain, stroke
and major depressive disorder (MDD).1 Many historical NMDAR
antagonists were developed before the degree of receptor hetero-
geneity was known and have demonstrated therapeutic efficacy
against the aforementioned pathologies. However, the clinical
application of these drugs is restricted by side-effect profiles attrib-
utable to general NMDAR blockade, including hallucinations,
hypertension, dysphoria, and loss of co-ordination.2 Messenger
RNA (mRNA) mapping studies have since revealed a ubiquitous
distribution of the GluN2A subunit throughout the brain, whereas
the GluN2B subunit is confined to regions of the forebrain, such as
selective antagonists. Although benzamidine
5
displayed
weak affinity for the GluN2B subtype (Ki = 10,000 nM) against
[3H]ifenprodil, exploration of ring-substitution patterns identified
potent and selective GluN2B antagonists. The need for novel
therapeutic agents targeting GluN2B-containing NMDARs with
desirable pharmacokinetic and physiochemical properties
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Corresponding author.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.