NR2B selective antagonists

Obviously most of the known NR2B-selective antagonists very closely resemble ifenprodil thus belonging to the same structural class. Well known examples of NR2B-selective antagonists are eliprodil which was the follow-up compound to ifenprodil synthesized by Synthelabo (Avenet et al., 1997), CP-101,606 and analogs... 

A recent report on a NR2B selective NMDA receptor antagonist (9) supports the findings of Kalvass and Maurer [56], Rapid equilibration between plasma and CNS coupled with the lack of Pgp substrate activity led the authors to assume that plasma-free and brain-free drug concentrations were equivalent. An ex vivo receptor binding assay showed 50% occupancy at a total plasma concentration of 230 nM. Given a rat-free fraction of 15.3%, the authors concluded that 50% brain occupancy occurred at 35 nM unbound brain concentration, which was in reasonable agreement with the measured Ki of 3.4 nM versus the human receptor. 

Stump, G.L., Lynch, J.J., Macaulay, A., Wafford, K.A., Koblan, K.S. and Liverton, N.J. (2004) NR2B-selective N-methyl-D-aspartate antagonists synthesis and evaluation of 5-substituted benzimidazoles. Journal of Medicinal Chemistry, 47, 2089-2096. 

Nikam SS, Meltzer LT (2002) NR2B selective NMDA receptor antagonists. Curr Pharm Des 8 845-855... 

Borza I. and Domany G. (2006). NR2B selective NMDA antagonists the evolution of the ifenpiodil-type pharmacophore. Curr. Top. Med. Chem. 6 687-695. 

Higgins GA, Ballard TM, Huwyler J, Kemp JA, Gill R. Evaluation of the NR2B-selective NMDA receptor antagonist Ro 63-1908 on rodent behaviour evidence for an involvement of NR2B NMDA receptors in response inhibition. Neuropharmacology 2003 44(3) 324-341. 

Medicinal chemistry efforts around the NR2B receptor have predominantly focused on the phenylethanolamine series of NR2B selective noncompetitive antagonists, and this series is represented by 1 (ifenprodil), 2 (eliprodil), 3 (traxoprodil or CP-101606), 4 (radiprodil or RGH-896), and 5 (besonprodil or CI-1041) (Fig. 1) [87, 88]. In preclinical studies, Cl-1041, when coadministered with... 

Donevan, S.D. and McCabe, R.T. (2000) Conantokin G is an NR2B-selective competitive antagonist of N-methyl-o-aspartate receptors. Mol. Pharmacol, 58, 614-623. 

Boyce, S., Wyatt, A., Webb, J. K., O Donell, R., Mason, G., Rigby, M., Sirinathsinghji, D., Hill, R. G., Rupniak, N. M. J. Selective NMDA NR2B antagonists induce antinociception without motor dysfunction correlation with restricted localisation ofNR2B in dorsal horn, Neuropharmacology 1999, 38, 611-623. 

White, W. F., Zhao, D. (3R,4S)-3-[4-(4-Fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-4,7-diol a conformationally restricted analoque of the NR2B subtype-selective NMD A antagonist (1S,2S)-1-(4-hydroxyphenol)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol, J. Med. Chem. 1998, 41, 1172-1184. 

Chenard, B. L. and Menniti, F. S. Antagonists selective for NMDA receptors containing the NR2B subunit, Curr. Pharm. Des. 1999, 5, 381-404. 

Fig. 7. The NR2B antagonist ifenprodil completely blocks DOI-enhanced late evEPSCs. (1) DOI-enhanced late evEPSCs following its application in the perfusate (3 pM 15 min). (2) Selective suppression of late evEPSC during application of ifenprodil (3 M). Traces are averages of 10 sweeps taken during each of the conditions.

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