新型Sigma-1 受体变构调节剂的发现和潜在应用

doi:10.3969/j.issn.2095-1396.2018.01.005

摘要/Abstract

摘要： Sigma-1 受体是许多神经精神疾病治疗中的重要靶点。除了正位调节，变构调节也是调节该受体功能重要途径。由于变构调节的优越性，变构调节剂也成为靶向 sigma-1 受体药物发现的新策略。该文在总结sigma-1 受体生物学功能和相关配基的基础上，重点介绍新型变构调节剂的发现与潜在应用，旨在为以 sigma-1受体为靶点的药物研发提供新的思路。

关键词: sigma-1 受体, 变构调节剂, 神经精神疾病

Abstract: Sigma-1 receptors are involved in the pathophysiological process of several neuropsychiatric diseases. Allosteric modulation of receptor represents an important mechanism for receptor functional regulation. Compared to orthodox ligands of sigma-1 receptor，allosteric modulator has tremendous advantages in selectivity and safety. Thus，development of allosteric modulation toward sigma-1 receptors has become a new approach for treatment of neuropsychiatric diseases. Here，we summarized the progress of biological functions and developed ligands of sigma-1 receptors，and discussed the potential applications of novel allosteric modulator in some neuropsychiatric diseases.

Key words: sigma-1 receptor, allosteric modulation, neuropsychiatric disease

中图分类号:

R964

王允，镇学初. 新型Sigma-1 受体变构调节剂的发现和潜在应用[J]. 神经药理学报, 2018, 8(1): 35-44.

WANG Yun，ZHEN Xue-chu. An Update on Allosteric Modulator of Sigma-1 Receptors: Potential Applications[J]. Acta Neuropharmacologica, 2018, 8(1): 35-44.

参考文献

[1] Ajmo C T, Vernon D O, Collier L, et al. Sigma receptor activation reduces infarct size at 24 hours after permanent middle cerebral artery occlusion in rats[J].Current Neurovascular Research, 2006, 3: 89-98.

[2] Matthew J Robson, Ryan C Turner, Zachary J Naser, et al. SN79, a sigma receptor antagonist, attenuates methamphetamine-induced astrogliosis through a blockade of OSMR/gp130 signaling and STAT3 phosphorylation[J].Experimental neurology, 2014, 254:180-189.

[3] Schmidt H R, Zheng S, Gurpinar E, et al. Crystal structure of the human sigma1 receptor[J].Nature, 2016, 532: 527-530.

[4] Assaf Alon, Hayden R Schmidt, Michael D Wood, et al. Identification of the gene that codes for the sigma2 receptor[J].Proceedings of the National Academy of Sciences of the United States of America, 2017, 114(27): 7160-7165.

[5] Zhao Jing, Ha Yon-ju, Gregory I Liou, et al. Sigma receptor ligand, (+)-pentazocine, suppresses inflammatory responses of retinal microglia[J].Invest Ophthalmol Vis Sci, 2014, 55(6): 3375-3384.

[6] Hall A.A., Herrera Y., Ajmo C.T., et al. Sigma receptors suppress multiple aspects of microglial activation[J].Glia, 2009, 57: 744-754.

[7] Cobos E J, Entrena J M, Nieto F R, et al. Pharmacology and therapeutic potential of sigma(1) receptor ligands[J].Current Neuropharmacology, 2008, 6: 344-366.

[8] Mollyy Johannessen, Dominique Fontanilla, Timur Mavlyutov, et al. Antagonist action of progesterone at sigma-receptors in the modulation of voltage-gated sodium channels[J].Am J Physiol Cell Physiol, 2011, 300:C328-337.

[9] Schwarz S, Pohl P, and Zhou G Z. Steroid binding at sigma-"opioid" receptors[J].Science, 1989, 246: 1635-1638.

[10] Kenji Hashimoto. Activation of sigma-1 receptor chaperone in the treatment of neuropsychiatric diseases and its clinical implication[J].Journal of pharmacological Sciences, 2015, 127(1): 6-9.

[11] Rikki Waterhouse, Raymond C Chang, Nana Atuehene, et al. In vitro and in vivo binding of neuroactive steroids to the sigma-1 receptor as measured with the positron emission tomography radioligand [18F]FPS[J].Synapse, 2007, 61: 540-546.

[12] Dominique Fontanilla, Molly Johannessen, Abdol R Hajipour, et al. The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator[J].Science, 2009, 323(5916):934-937.

[13] Maho Kinoshita, Yoshikazu Matsuoka, Takeshi Suzuki, et al.Sigma-1 receptor alters the kinetics of Kv1.3 voltage gated potassium channels but not the sensitivity to receptor ligands[J].Brain Res, 2012, 1452: 1-9.

[14] Dilshan Balasuriya, Lauren D'Sa, Ronel Talker, et al. A direct interaction between the sigma-1 receptor and the hERG voltage-gated K+ channel revealed by atomic force microscopy and homogeneous time-resolved fluorescence (HTRF(R)) [J].J Biol Chem, 2014, 289: 32353-32363.

[15] Said Kourrich, Teruo Hayashi, Jian-ying Chuang, et al. Dynamic interaction between sigma-1 receptor and Kv1.2 shapes neuronal and behavioral responses to cocaine[J].Cell, 2013, 152(1-2): 236-247.

[16] Marzia Martina, Turcotte M.E., Halman S., et al. The sigma-1 receptor modulates NMDA receptor synaptic transmission and plasticity via SK channels in rat hippocampus[J].The Journal of physiology, 2007, 578: 143-157.

[17] Olivier Soriani, Frank Le Foll, Francois Roman, et al. A-Current down-modulated by sigma receptor in frog pituitary melanotrope cells through a G protein-dependent pathway[J].J Pharmacol Exp Ther, 1999, 289(1): 321-328.

[18] Tchedre K T, Huang R Q, Dibas A, et al. Sigma-1 receptor regulation of voltage-gated calcium channels involves a direct interaction[J].Invest Ophthalmol Vis Sci, 2008, 49(11): 4993-5002.

[19] Cheng Zheng-xiang, Lan Dan-mei, Wu Pei-ying, et al. Neurosteroid dehydroepiandrosterone sulphate inhibits persistent sodium currents in rat medial prefrontal cortex via activation of sigma-1 receptors[J].Experimental Neurology, 2008, 210(1): 128-136.

[20] Molly Johannessen, Subramaniam Ramachandran, Logan Riemer, et al. Voltage-gated sodium channel modulation by sigma-receptors in cardiac myocytes and heterologous systems[J].Am J Physiol Cell Physiol, 2009, 296: C1049-1057.

[21] Mohan Pabba M, Adrian Y C Wong, Nina Ahlskog, et al. NMDA receptors are upregulated and trafficked to the plasma membrane after sigma-1 receptor activation in the rat hippocampus[J].J Neurosci, 2014, 34(34): 11325-11338.

[22] Benjamin Gronier, Guy Debonnel. Involvement of sigma receptors in the modulation of the glutamatergic/NMDA neurotransmission in the dopaminergic systems[J].Eur J Pharmacol, 1999, 368: 183-196.

[23] Magali Peeters, Pascal Romieu, Tangui Maurice, et al. Involvement of the sigma 1 receptor in the modulation of dopaminergic transmission by amantadine[J].The European Journal of Neuroscience, 2004, 19: 2212-2220.

[24] Tetsuya Kobayashi, Kiyoshi Matsuno, Masaaki Murai, et al. Sigma 1 receptor subtype is involved in the facilitation of cortical dopaminergic transmission in the rat brain[J].Neurochem Res, 1997, 22(9): 1105-1109.

[25] Lin M T, Beal M F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases[J].Nature, 2006, 443: 787-795.

[26]Arindam Pal, Dominique Fontanilla, Anupama Gopalakrishnan, et al. The sigma-1 receptor protects against cellular oxidative stress and activates antioxidant response elements[J].Eur J Pharmacol, 2012, 682(1-3): 12-20.

[27] Tuerhong Tuerxun, Tadahiro Numakawa, Naoki Adachi, et al. SA4503, a sigma-1 receptor agonist, prevents cultured cortical neurons from oxidative stress-induced cell death via suppression of MAPK pathway activation and glutamate receptor expression[J].Neurosci Lett, 2010, 469(3): 303-308.

[28]Tomohisa Mori, Teruo Hayashi, Eri Hayashi, et al. Sigma-1 receptor chaperone at the ER-mitochondrion interface mediates the mitochondrion-ER-nucleus signaling for cellular survival[J].PLoS One, 2013, 8: e76941.

[29] Teruo Hayashi, Su Tsung-Ping. Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival[J].Cell, 2007, 131(3): 596-610.

[30] Nino Natsvlishvili, Nino Goguadze, Elene Zhuravliova, et al.Sigma-1 receptor directly interacts with Rac1-GTPase in the brain mitochondria[J].BMC Biochemistry, 2015, 16: 11.

[31] Heather L Osborn-Heaford, Alan J Ryan, Shubha Murthy, et al. Mitochondrial Rac1 GTPase import and electron transfer from cytochrome c are required for pulmonary fibrosis[J].J Biol Chem, 2012, 287: 3301-3312.

[32] Hideaki Tagashira, Md Shenuarin Bhuiyan, Norifumi Shioda, et al. Fluvoxamine rescues mitochondrial Ca2+ transport and ATP production through sigma(1)-receptor in hypertrophic cardiomyocytes[J].Life Sci, 2014, 95(2): 89-100.

[33] Kissaou T Tchedre, Thomas Yorio. Sigma-1 receptors protect RGC-5 cells from apoptosis by regulating intracellular calcium, Bax levels, and caspase-3 activation[J].Invest Ophthalmol Vis Sci, 2008, 49: 2577-2588.

[34] Yang Su-fang, Anish Bhardwaj, Cheng Jian, et al. Sigma receptor agonists provide neuroprotection in vitro by preserving bcl-2[J].Anesthesia and Analgesia, 2007, 104: 1179-1184, tables of contents.

[35] Katnik C, Guerrero W R, Pennypacker K R, et al. Sigma-1 receptor activation prevents intracellular calcium dysregulation in cortical neurons during in vitro ischemia[J].J Pharmacol Exp Ther, 2006, 319: 1355-1365.

[36] Karsten Ruscher, Mehrdad Shamloo, Mattias Rickhag, et al. The sigma-1 receptor enhances brain plasticity and functional recovery after experimental stroke[J].Brain, 2011, 134(3): 732-746.

[37] Marco Peviani, Eleonora Salvaneschi, Leonardo Bontempi, et al. Neuroprotective effects of the Sigma-1 receptor (S1R) agonist PRE-084, in a mouse model of motor neuron disease not linked to SOD1 mutation[J].Neurobiol Dis, 2014, 62: 218-232.

[38] Anis Klouz, Jean-Paul Tillement, Marie-Francoise Boussard, et al. [3H]BHDP as a novel and selective ligand for sigma1 receptors in liver mitochondria and brain synaptosomes of the rat[J].FEBS Lett, 2003, 553(03): 157-162.

[39] Wang Li-yun, Martin Bronwen, Randall Brenneman, et al. Allosteric modulators of g protein-coupled receptors: future therapeutics for complex physiological disorders[J].J Pharmacol Exp Ther, 2009, 331(2): 340-348.

[40] Stephan Urwyler. Allosteric modulation of family C G-protein-coupled receptors: from molecular insights to therapeutic perspectives[J].Pharmacol Rev, 2011, 63(1): 59-126.

[41] Alice Cavanaugh, Huang Ying, Gerda E Breitwieser. Behind the curtain: cellular mechanisms for allosteric modulation of calcium-sensing receptors[J].British Journal of Pharmacology, 2012, 165: 1670-1677.

[42] Bernard Lagane, Javier Garcia-Perez, Esther Kellenberger. Modeling the allosteric modulation of CCR5 function by Maraviroc[J].Drug Discovery Today Technologies, 2013,10(2): e297-305.

[43] Enrique J Cobos, Jose M Baeyens, Esperanza Del Pozo. Phenytoin differentially modulates the affinity of agonist and antagonist ligands for sigma 1 receptors of guinea pig brain[J].Synapse, 2005, 55: 192-195.

[44] Cobos E J, Lucena G, Baeyens J M, et al. Differences in the allosteric modulation by phenytoin of the binding properties of the sigma1 ligands [3H](+)-pentazocine and [3H]NE-100[J].Synapse, 2006, 59: 152-161.

[45] Guo Lin, Zhao Jiang-hao, Jin Guo-zhang, et al.SKF83959 is a potent allosteric modulator of sigma-1 receptor[J].Mol Pharmacol, 2013, 83: 577-586.

[46] Zhou Shang-lin, Chu Hong-yuan, Jin Guo-zhang, et al. Effects of SKF83959 on the excitability of hippocampal CA1 pyramidal neurons: a modeling study[J].Acta Pharmacol Sin, 2014, 35: 738-751.

[47] Fang Xing, Guo Lin, Xu Jia-Jia, et al. SKF83959 is a novel triple reuptake inhibitor that elicits anti-depressant activity[J].Acta Pharmacol Sin, 2013, 34: 1149-1155.

[48] Chu Hong-yuan, Wu Qian-qian, Zhou Shang-lin, et al. SKF83959 suppresses excitatory synaptic transmission in rat hippocampus via a dopamine receptor-independent mechanism[J].J Neurosci Res, 2011, 89: 1259-1266.

[49] Chu Hong-yuan, Gu Qin-hua, Jin Guo-zhang, et al. Electrophysiological effects of SKF83959 on hippocampal CA1 pyramidal neurons: potential mechanisms for the drug's neuroprotective effects[J].PLoS One, 2010, 5(10): e13118.

[50] Chen Xue-qin, Zhang Jing, John L Neumeyer, et al. Arylbenzazepines are potent modulators for the delayed rectifier K+ channel: a potential mechanism for their neuroprotective effects[J].PLoS One, 2009, 4: e5811.

[51] 镇学初, 张翱, 郭琳.苯并氮杂卓内化合物在制备预防或治疗癫痫药物中的应用[P].中国专利No 201210337109, 2013.

[52] Zhang Jing, Huang Ji-ye, Song Zi-lan, et al. Structural manipulation on the catecholic fragment of dopamine D(1) receptor agonist 1-phenyl-N-methyl-benzazepines[J].European J Medicinal Chemistry, 2014, 85: 16-26.

[53] Guo Lin, Chen Yan-ke, Zhao Rui, et al. Allosteric modulation of sigma-1 receptors elicits anti-seizure activities[J].British J Pharmacology, 2015, 172: 4052-4065.

[54] Edijs Vavers, Baiba Svalbe, Lasma Lauberte, et al. The activity of selective sigma-1 receptor ligands in seizure models in vivo[J].Behavioural Brain Research, 2017, 328: 13-18.

[55] Anders A Jensen, Hans Brauner-Osborne. Allosteric modulation of the calcium-sensing receptor[J].Current Neuropharmacology, 2007, 5(3): 180-186.

[56]Marcia M Moraes, Marcella C Galvao, Danilo Cabral, et al. Propentofylline prevents sickness behavior and depressive-like behavior induced by lipopolysaccharide in rats via neuroinflammatory pathway[J].PLoS One, 2017, 12: e0169446.

[57] Michael T Heneka, Markus P Kummer, Eicke Latz. Innate immune activation in neurodegenerative disease[J].Nature Reviews Immunology, 2014, 14: 463-477.

[58] Zhang Hai, Ma Li-qun, Wang Fang, et al. Chronic SKF83959 induced less severe dyskinesia and attenuated L-DOPA-induced dyskinesia in 6-OHDA-lesioned rat model of Parkinson's disease[J].Neuropharmacology, 2007, 53: 125-133.

[59] Christopher Bown, Wang Jun-feng, Glenda MacQueen, et al. Increased temporal cortex ER stress proteins in depressed subjects who died by suicide[J].Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology, 2000, 22: 327-332.

[60] Aliza J Ferrari, Fiona J Charlson, Rosana Elizabeth Norman, et al. The epidemiological modelling of major depressive disorder: application for the Global Burden of Disease Study 2010[J].PLoS One, 2013, 8: e69637.

[61] Andre Tadic, Stefanie Wagner, Stanislav Gorbulev, et al. Peripheral blood and neuropsychological markers for the onset of action of antidepressant drugs in patients with Major Depressive Disorder[J].BMC Psychiatry, 2011, 11: 16.

[62] Matthew A Timberlake, Yogesh Dwivedi. Altered expression of endoplasmic reticulum stress associated genes in hippocampus of learned helpless rats: relevance to depression pathophysiology[J].Frontiers in Pharmacology, 2015, 6: 319.

[63] Philip Gold, Julio Licinio, Maria G Pavlatou. Pathological parainflammation and endoplasmic reticulum stress in depression: potential translational targets through the CNS insulin, klotho and PPAR-gamma systems[J].Mol Psychiatry, 2013, 18: 154-165.