以NMDAR为靶点的药物研究进展
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摘要
N-甲基-D-天冬氨酸受体(NMDAR)属于离子型谷氨酸能受体,是由NR1、NR2和NR3三种亚基构成。近年来NMDAR已经逐渐成为中枢系统疾病(如抑郁症、神经痛、精神分裂症和阿尔兹海默症等)治疗的重要靶点,目前已有多个治疗药物处于临床试验阶段。本文主要综述NMDAR拮抗剂、激动剂及其调节剂的药物研究进展。
NMDAR belongs to ionotropic glutamate receptor and consists of three kinds of subunits, including NR1,NR2 and NR3. In recent years,NMDAR has become an important target for CNS disorders such as depression,neuropathic pain,schizophrenia and Alzheimer' s disease. So far,several drugs have been in clinical trials. This article mainly reviews the research progresses for NMDAR antagonists,agonists and other modulators.
NMDAR belongs to ionotropic glutamate receptor and consists of three kinds of subunits, including NR1,NR2 and NR3. In recent years,NMDAR has become an important target for CNS disorders such as depression,neuropathic pain,schizophrenia and Alzheimer' s disease. So far,several drugs have been in clinical trials. This article mainly reviews the research progresses for NMDAR antagonists,agonists and other modulators.
引文
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[3]LEE C H,LU W,MICHEL J C,et al.NMDA receptor structures reveal subunit arrangement and pore architecture[J].Nature,2014,511(7508):191-198.
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[5]ITOA K,TATEBEB T,SUZUKIB K,et al.Memantine reduces the production of amyloid-beta peptides through modulation of amyloid precursor protein trafficking[J].Eur J Pharmacol,2017,798:16-25.
[6]ZOLADZ P R,CAMPBELL A M,PARK C R,et al.Enhancement of long-term spatial memory in adult rats by the noncompetitive NMDA receptor antagonists,memantine and neramexane[J].Pharmacol Biochem Behav,2006,85(2):298-306.
[7]PAUL R,SCHAAFF N,PADBERG F,et al.Comparison of racemic ketamine and S-ketamine in treatmentresistant major depression:report of two cases[J].World J Biol Psychiatry,2009,10(3):241-244.
[8]SINGH J B,FEDGCHIN M,DALY E,et al.Intravenous esketamine in adult treatment-resistant depression:a double-blind,double-randomization,placebocontrolled study[J].Biol Psychiatry,2016,80(6):424-431.
[9]MURROUGH J W.Ketamine for depression:an update[J].Biol Psychiatry,2016,80(6):416-418.
[10]SANACORA G,SMITH M,PATHAK S,et al.Lanicemine:a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects[J].Mol Psychiatry,2014,19(9):978-985.
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[13]SPIEKER S,BREIT S,KLOCKGETHER T,et al.Tremorlytic activity of budipine in Parkinson's disease[J].Clin Neuropharmacol,1999,22(2):115-119.
[14]GORDON R K,NIGAM S V,WEITZ J A,et al.The NMDA receptor ion channel:a site for binding of huperzine A[J].J Appl Toxicol,2001,21(Suppl.1):S47-S51.
[15]DAMAR U,GERSNER R,JOHNSTON J T,et al.Huperzine A:a promising anticonvulsant,disease modifying,and memory enhancing treatment option in Alzheimer's disease[J].Med Hypotheses,2017,99:57-62.
[16]PADMANABHAN S,PERLMAN M E,ZHANG L,et al.Identification and characterization of a potential ischemiaselective N-methyl-D-aspartate(NMDA)receptor ion-channel blocker,CNS 5788[J].Bioorg Med Chem Lett,2001,11(4):501-504.
[17]WALTERS M R,BRADFORD A P J,FISCHER J,et al.Early clinical experience with the novel NMDA antagonist CNS 5161[J].Br J Pharmacol,2002,53(3):305-311.
[18]KULAGOWSKI J J,LEESON P D.Review central&peripheral nervous systems:glycine-site NMDA receptor antagonists[J].Exp Opin Ther Parents,2008,5(10):1061-1075.
[19]HUETTNER J E.Indole-2-carboxylic acid:a competitive antagonist of potentiation by glycine at the NMDA receptor[J].Science,1989,243(4898):1611-1613.
[20]LEES K R,ASPLUND K,CAROLEI A,et al.Glycine antagonist(gavestinel)in neuroprotection(GAIN international)in patients with acute stroke:a randomised controlled trial[J].The Lancet,2000,355(9219):1949-1954.
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[22]BRENNAN T J,ZAHN P K.Effect of intrathecal ACEA-1021 in a rat model for postoperative pain[J].J Pain,2000,1(4):279-284.
[23]WEBSTER R,COLE S,GEDGE J,et al.Pharmacokinetics and disposition of a novel NMDA glycine site antagonist(UK-240,455)in rats,dogs and man[J].Xenobiotica,2003,33(5):541-560.
[24]DEUR C,AGRAWAL A K,BAUM H,et al.N-(6,7-Dichloro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-N-alkylsulfonamides as peripherally restricted NmethylD-aspartate receptor antagonists for the treatment of pain[J].Bioorg Med Chem Lett,2007,17(16):4599-4603.
[25]CARLING R W,LEESON P D,MOORE K W,et al.3-Nitro-3,4-dihydro-2(1H)-quinolones.Excitatory amino acid antagonists acting at glycine-site NMDA and(RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors[J].J Med Chem,1993,36(22):3397-3408.
[26]KOTLINSKA J,LILJEQUIST S.A characterization of anxiolytic-like actions induced by the novel NMDA/glycine site antagonist,L-701324[J].Psychopharmacology,1998,135(2):175-181.
[27]POTSCHKA H,L SCHER W,WLAZ'P,et al.LU73068,a new non-NMDA and glycine/NMDA receptor antagonist:pharmacological characterization and comparison with NBQX and L-701324 in the kindling model of epilepsy[J].British J Pharmacol,1998,125(6):1258-1266.
[28]PARSONS C G,DANYSZ W,QUACK G N,et al.Novel systemically active antagonists of the glycine site of the N-methyl-D-aspartate receptor:electrophysiological,biochemical and behavioral characteri-zation[J].J Pharmacol Exp Ther,1997,283(3):1264-1275.
[29]OHTANIA K-I,TANAKAA H,YASUDAA H,et al.Blocking the glycine site of NMDA receptors prevents the progression of ischemic pathology induced by bilateral carotid artery occlusion in rats[J].Brain Res,2000,871(2):311-318.
[30]CHAPMAN A G,DIIRMIILLER N,HARRISON B L,et al.Anticonvulsant activity of a novel NMDA/glycine site antagonist,MDL 104653,against kindled and sound-induced seizures[J].Eur J Pharmacol,1995,274:83-88.
[31]JIMONET P,RIBEILL Y,BOHME G A.Indeno[1,2-b]pyrazin-2,3-diones:a new class of antagonists at the glycine site of the NMDA receptor with potent in vivo activity[J].J Med Chem,2000,43(12):2371-2381.
[32]ZANOS P,PIANTADOSI S C,WU H-Q,et al.The prodrug 4-chlorokynurenine causes ketamine-like antidepressant effects,but not side effects,by NMDA/glycine B-site inhibition[J].J Pharmacol Exp Ther,2015,355(1):76-85.
[33]JANSEN M,DANNHARDT G.Antagonists and agonists at the glycine site of the NMDA receptor for therapeutic interventions[J].Eur J Med Chem,2003,38(7/8):661-670.
[34]FABIO R D,CONTI N,MAGISTRIS E D,et al.Substituted analogues of GV150526 as potent glycine binding site antagonists in animal models of cerebral ischemia[J].J Med Chem,1999,42(18):3486-3493.
[35]TEWES B,FREHLAND B,SCHEPMANN D,et al.Design,synthesis,and biological evaluation of 3-benzazepin-1-ols as NR2B-selective NMDA receptor antagonists[J].ChemMedChem,2010,5(5):687-695.
[36]TEWESA B,FREHLAND B,SCHEPMANNA D,et al.Conformationally constrained NR2B selective NMDAreceptor antagonists derived from ifenprodil:synthesis and biological evaluation of tetrahydro-3-benzazepine-1,7-diols[J].Bioorg Med Chem,2010,18(22):8005-8015.
[37]McCAULEY J A.NR2B subtype-selective NMDA receptor antagonists:2001-2004[J].Expert Opin Ther Patents,2005,15(4):389-407.
[38]BEINAT C,BANISTER S,MOUSSA I,et al.Insights into structure-activity relationships and CNS therapeutic applications of NR2B selective antagonists[J].Curr Med Chem,2010,17(34):4166-4190.
[39]MONY L,KEW J N,GUNTHORPE M J,et al.Allosteric modulators of NR2B-containing NMDAreceptors:molecular mechanisms and therapeutic potential[J].Br J Pharmacol,2009,157(8):1301-1317.
[40]NIKAM S S,MELTZER L T.NR2B selective NMDAreceptor antagonists[J].Curr Pharm Design,2002,8(10):845-855.
[41]GARNER R,GOPALAKRISHNAN S,McCAULEY JA,et al.Preclinical pharmacology and pharmacokinetics of CERC-301,a GluN2B-selective N-methyl-D-aspartate receptor antagonist[J/OL].Pharmacol Res Per,2015,3(6):e00198.
[42]GAGE A.Methods for treating neuropathic pain:US,20100048629[P].2010-02-15.
[43]WRIGHT J L,KESTEN S R,UPASANI R B,et al.4-Benzyl piperidine alkylsulfoxide heterocycles and their use as subtype-selective NMDA receptor anta-gonists:US,6284774[P].2001-09-04.
[44]ERIK A,STEFAN P,ACHIM B,et al.Towards NR2Breceptor selective imaging agents for PET-synthesis and evaluation of N-[11 C]-(2-methoxy)benzyl(E)-styrene-,2-naphthyl-and 4-trifluoromethoxyphenylamidine[J].Bioorg Med Chem,2006,14(18):6307-6313.
[45]NGUYEN K T,CLAIBORNE C F,McCAULEY J A,et al.Cyclic benzamidines as orally efficacious NR2B-selective NMDA receptor antagonists[J].Bioorg Med Chem Lett,2007,17(14):3997-4000.
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