XB-ART-38862
J Med Chem
2008 Sep 25;5118:5506-21. doi: 10.1021/jm8002153.
Show Gene links
Show Anatomy links
Enantiomeric propanolamines as selective N-methyl-D-aspartate 2B receptor antagonists.
Tahirovic YA
,
Geballe M
,
Gruszecka-Kowalik E
,
Myers SJ
,
Lyuboslavsky P
,
Le P
,
French A
,
Irier H
,
Choi WB
,
Easterling K
,
Yuan H
,
Wilson LJ
,
Kotloski R
,
McNamara JO
,
Dingledine R
,
Liotta DC
,
Traynelis SF
,
Snyder JP
.
???displayArticle.abstract???
Enantiomeric propanolamines have been identified as a new class of NR2B-selective NMDA receptor antagonists. The most effective agents are biaryl structures, synthesized in six steps with overall yields ranging from 11-64%. The compounds are potent and selective inhibitors of NR2B-containing recombinant NMDA receptors with IC 50 values between 30-100 nM. Potency is strongly controlled by substitution on both rings and the centrally located amine nitrogen. SAR analysis suggests that well-balanced polarity and chain-length factors provide the greatest inhibitory potency. Structural comparisons based on 3D shape analysis and electrostatic complementarity support this conclusion. The antagonists are neuroprotective in both in vitro and in vivo models of ischemic cell death. In addition, some compounds exhibit anticonvulsant properties. Unlike earlier generation NMDA receptor antagonists and some NR2B-selective antagonists, the present series of propanolamines does not cause increased locomotion in rodents. Thus, the NR2B-selective antagonists exhibit a range of therapeutically interesting properties.
???displayArticle.pubmedLink??? 18800760
???displayArticle.pmcLink??? PMC3142473
???displayArticle.link??? J Med Chem
???displayArticle.grants??? [+]
NS036604 NINDS NIH HHS , NS036654 NINDS NIH HHS , NS039419 NINDS NIH HHS , NS056217 NINDS NIH HHS , R01 NS036604-10 NINDS NIH HHS , R01 NS036604-11 NINDS NIH HHS , R01 NS036604 NINDS NIH HHS , R01 NS036604-02 NINDS NIH HHS , R01 NS056217 NINDS NIH HHS , R37 NS036654 NINDS NIH HHS , R01 NS036654 NINDS NIH HHS , R01 NS039419 NINDS NIH HHS
Species referenced: Xenopus
Genes referenced: grin2b
References [+] :
Andiné,
Characterization of MK-801-induced behavior as a putative rat model of psychosis.
1999, Pubmed
Andiné, Characterization of MK-801-induced behavior as a putative rat model of psychosis. 1999, Pubmed
Barta-Szalai, Oxamides as novel NR2B selective NMDA receptor antagonists. 2004, Pubmed
Borza, Indole-2-carboxamides as novel NR2B selective NMDA receptor antagonists. 2003, Pubmed
Boyce, Selective NMDA NR2B antagonists induce antinociception without motor dysfunction: correlation with restricted localisation of NR2B subunit in dorsal horn. 1999, Pubmed
Bradford, Glutamate, GABA and epilepsy. 1995, Pubmed
Bräuner-Osborne, Ligands for glutamate receptors: design and therapeutic prospects. 2000, Pubmed
Chazot, The NMDA receptor NR2B subunit: a valid therapeutic target for multiple CNS pathologies. 2004, Pubmed
Chenard, Antagonists selective for NMDA receptors containing the NR2B subunit. 1999, Pubmed
Chenard, (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol: a potent new neuroprotectant which blocks N-methyl-D-aspartate responses. 1995, Pubmed
Choi, Identification and mechanism of action of two histidine residues underlying high-affinity Zn2+ inhibition of the NMDA receptor. 1999, Pubmed , Xenbase
Choi, Glutamate neurotoxicity in cortical cell culture. 1987, Pubmed
Connors, Actions and mechanisms of action of novel analogues of sotalol on guinea-pig and rabbit ventricular cells. 1992, Pubmed
Curtis, Novel N1-(benzyl)cinnamamidine derived NR2B subtype-selective NMDA receptor antagonists. 2003, Pubmed
Dingledine, The glutamate receptor ion channels. 1999, Pubmed
Dirnagl, Pathobiology of ischaemic stroke: an integrated view. 1999, Pubmed
Doğan, Effects of ifenprodil, a polyamine site NMDA receptor antagonist, on reperfusion injury after transient focal cerebral ischemia. 1997, Pubmed
Ellison, The N-methyl-D-aspartate antagonists phencyclidine, ketamine and dizocilpine as both behavioral and anatomical models of the dementias. 1995, Pubmed
Erreger, Glutamate receptor gating. 2004, Pubmed
Finlayson, [3H]dofetilide binding to HERG transfected membranes: a potential high throughput preclinical screen. 2001, Pubmed
Fischer, Ro 25-6981, a highly potent and selective blocker of N-methyl-D-aspartate receptors containing the NR2B subunit. Characterization in vitro. 1997, Pubmed , Xenbase
Gallagher, Modulation of the N-methyl-D-aspartate receptor by haloperidol: NR2B-specific interactions. 1998, Pubmed
Gill, Pharmacological characterization of Ro 63-1908 (1-[2-(4-hydroxy-phenoxy)-ethyl]-4-(4-methyl-benzyl)-piperidin-4-ol), a novel subtype-selective N-methyl-D-aspartate antagonist. 2002, Pubmed , Xenbase
Greengrass, Binding characteristics of 3H-prazosin to rat brain alpha-adrenergic receptors. 1979, Pubmed
Hawkins, Comparison of shape-matching and docking as virtual screening tools. 2007, Pubmed
Hiramatsu, Comparison of the behavioral and biochemical effects of the NMDA receptor antagonists, MK-801 and phencyclidine. 1989, Pubmed
Ilyin, Subtype-selective inhibition of N-methyl-D-aspartate receptors by haloperidol. 1996, Pubmed , Xenbase
Jorgensen, The many roles of computation in drug discovery. 2004, Pubmed
Junge, The contribution of protease-activated receptor 1 to neuronal damage caused by transient focal cerebral ischemia. 2003, Pubmed
Kalinichev, Individual differences in locomotor reactivity to a novel environment and sensitivity to opioid drugs in the rat. I. Expression of morphine-induced locomotor sensitization. 2004, Pubmed
Kew, A novel mechanism of activity-dependent NMDA receptor antagonism describes the effect of ifenprodil in rat cultured cortical neurones. 1996, Pubmed
Kew, Ionotropic and metabotropic glutamate receptor structure and pharmacology. 2005, Pubmed
Kew, State-dependent NMDA receptor antagonism by Ro 8-4304, a novel NR2B selective, non-competitive, voltage-independent antagonist. 1998, Pubmed , Xenbase
Koh, Quantitative determination of glutamate mediated cortical neuronal injury in cell culture by lactate dehydrogenase efflux assay. 1987, Pubmed
Kohl, The NMDA receptor complex: a promising target for novel antiepileptic strategies. 2001, Pubmed
Layton, Recent advances in the development of NR2B subtype-selective NMDA receptor antagonists. 2006, Pubmed
Low, Molecular determinants of coordinated proton and zinc inhibition of N-methyl-D-aspartate NR1/NR2A receptors. 2000, Pubmed , Xenbase
Löschmann, Antiparkinsonian activity of Ro 25-6981, a NR2B subunit specific NMDA receptor antagonist, in animal models of Parkinson's disease. 2004, Pubmed
Masuko, A regulatory domain (R1-R2) in the amino terminus of the N-methyl-D-aspartate receptor: effects of spermine, protons, and ifenprodil, and structural similarity to bacterial leucine/isoleucine/valine binding protein. 1999, Pubmed , Xenbase
McCauley, NR2B-selective N-methyl-D-aspartate antagonists: synthesis and evaluation of 5-substituted benzimidazoles. 2004, Pubmed
Mesecar, A new model for protein stereospecificity. 2000, Pubmed
Mezzetti, Mirror-image packing in enantiomer discrimination molecular basis for the enantioselectivity of B.cepacia lipase toward 2-methyl-3-phenyl-1-propanol. 2005, Pubmed
Miyabe, Comparative analysis of brain protection by N-methyl-D-aspartate receptor antagonists after transient focal ischemia in cats. 1997, Pubmed
Monyer, Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. 1994, Pubmed
Monyer, Heteromeric NMDA receptors: molecular and functional distinction of subtypes. 1992, Pubmed
Moriyoshi, Molecular cloning and characterization of the rat NMDA receptor. 1991, Pubmed , Xenbase
Mott, Phenylethanolamines inhibit NMDA receptors by enhancing proton inhibition. 1998, Pubmed , Xenbase
Nicholls, Molecular shape and electrostatics in the encoding of relevant chemical information. 2005, Pubmed
Nicholls, Variable selection and model validation of 2D and 3D molecular descriptors. 2004, Pubmed
PFEIFFER, Optical isomerism and pharmacological action, a generalization. 1956, Pubmed
Paoletti, Molecular organization of a zinc binding n-terminal modulatory domain in a NMDA receptor subunit. 2000, Pubmed , Xenbase
Park, The glutamate antagonist MK-801 reduces focal ischemic brain damage in the rat. 1988, Pubmed
Perin-Dureau, Mapping the binding site of the neuroprotectant ifenprodil on NMDA receptors. 2002, Pubmed , Xenbase
Rachline, The micromolar zinc-binding domain on the NMDA receptor subunit NR2B. 2005, Pubmed , Xenbase
Sajiki, Highly chemoselective hydrogenation with retention of the epoxide function using a heterogeneous Pd/C-ethylenediamine catalyst and THF. 2000, Pubmed
Sugihara, Structures and properties of seven isoforms of the NMDA receptor generated by alternative splicing. 1992, Pubmed , Xenbase
Tamiz, Structure-activity relationship of N-(phenylalkyl)cinnamides as novel NR2B subtype-selective NMDA receptor antagonists. 1999, Pubmed , Xenbase
Thornberg, A review of NMDA receptors and the phencyclidine model of schizophrenia. 1996, Pubmed
Traynelis, Control of voltage-independent zinc inhibition of NMDA receptors by the NR1 subunit. 1998, Pubmed , Xenbase
Tricklebank, The behavioural effects of MK-801: a comparison with antagonists acting non-competitively and competitively at the NMDA receptor. 1989, Pubmed
Wang, NMDA/NR2B selective antagonists in the treatment of ischemic brain injury. 2005, Pubmed
Whetsell, Current concepts of excitotoxicity. 1996, Pubmed
Williams, Ifenprodil discriminates subtypes of the N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors. 1993, Pubmed , Xenbase
Wlaź, Anticonvulsant effects of eliprodil alone or combined with the glycineB receptor antagonist L-701,324 or the competitive NMDA antagonist CGP 40116 in the amygdala kindling model in rats. 1999, Pubmed
Wong, Expression and characterization of soluble amino-terminal domain of NR2B subunit of N-methyl-D-aspartate receptor. 2005, Pubmed