Novel N¹‐(Benzyl)cinnamamidine Derived NR2B Subtype‐Selective NMDA Receptor Antagonists.

Abstract

Amidines Amidines Q 0500Novel N 1 -(Benzyl)cinnamamidine Derived NR2B Subtype-Selective NMDA Receptor Antagonists. -The synthesis of title compounds such as (V) and (X) by reaction of cinnamimidate (III) with the appropriate amine or via Horner-Wadsworth-Emmons reaction of an amidine phosphonate and their evaluation as NR2B subtype NMDA receptor ligands are described. Compound (Vb) showed excellent selectivity over NR2A (no yields given). -(CURTIS*, N. R.; DIGGLE, H. J.; KULAGOWSKI, J. J.; LONDON, C.; GRIMWOOD, S.; HUTSON, P. H.; MURRAY, F.; RICHARDS, P.; MACAULAY, A.; WAFFORD KEITH A.; Bioorg. Med. Chem. Lett. 13 (2003) 4, 693-696; Merck Sharp Dohme Res. Lab., Dep. Med. Chem., Neurosci. Res. Cent., Harlow, Essex CM20 2QR, UK; Eng.) -M. Schroeter 25-110

Synthesis and characterization of 11C‐labeled benzyl amidine derivatives as PET radioligands for GluN2B subunit of the NMDA receptors

“…These results were consistent with the results obtained using rat brain homogenate, as reported by Curtis (K i values of CBA and NBA for [ 3 H] ifenprodil binding are 0.7 and 1.3 nM, respectively). 13 Unfortunately, the IC 50 values of the newly developed quinoline derivative QBA was 52 nM, which was much higher than that of the naphthyl derivative NBA, suggesting that the replacement of the naphthyl functional group by quinoline significantly attenuated affinity for the GluN2B subunit. It is unclear why QBA has comparatively lower affinity for GluN2B than other derivatives, despite its high-specific binding to GluN2B-rich regions.…”

“…The amidines CBA, NBA, and 3a were synthesized according to the methods described in previous studies. 13,18 QBA was synthesized by treating 3quinolinecarbonitrile with a methylchloroaluminium amide (2) derived from 2-methoxybenzylamine hydrochloride and trimethylaluminium 19 (Scheme 1). CBA, NBA, and QBA were desmethylated by boron tribromide in dry-dichloromethane provided the radiosynthetic precursors 3a-c.…”

“…12 In addition, Curtis et al have reported that cinnamyl and 2-naphthyl analogs of benzyl amidine (CBA and NBA) have high-GluN2B selectivity, extremely high-binding affinity (the K i values of CBA, and NBA for [ 3 H] ifenprodil binding are 0.7 nM and 1.3 nM, respectively), and methoxy groups, which can be labeled with carbon-11. 13 Arstad evaluated several 11 C-labeled benzyl amidines ([ 11 C] CBA, [ 11 C] NBA, and [ 11 C]1) that showed excellent specific binding and a similar localization to that of GluN2B. However, these 11 C ligands are unsuitable imaging agents because of its metabolic instability.…”

Molecular Modeling of a Phenyl‐Amidine Class of NMDA Receptor Antagonists and the Rational Design of New Triazolyl‐Amidine Derivatives

“…Currently, the use of NMDA receptor antagonists for acute and chronic neuronal diseases therapy still present undesirable side‐effects, such as motor deficit and sedation that limit their use (9–11). Importantly, the absence of GLUN2B message in the cerebellum suggests that a GLUN2B selective antagonist might not adversely affect the locomotor function (4,12–14).…”

“…However, it still presents some side‐effects similar to other NMDA receptor antagonists (e.g., Co101676, PD174494, and Cl1041) (4,6) (Figure 1). Currently, many efforts are in progress to develop less toxic compounds for several neuropathological conditions, such as those based on styrylamidines ( I ), arylamidines ( II ), and cyclic benzamidines ( III ), that were described as orally efficacious selective GLUN1/GLUN2B NMDA receptor antagonists (Figure 1) (4,9,13,15–20).…”