IDRA-21

IDRA-21
法律规范状态
法律规范	美：试验用新药;
识别信息
	IUPAC命名法 7-chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide; ;
CAS号	22503-72-6
PubChem CID	3688;
IUPHAR/BPS	4219;
ChemSpider	3560 ;
UNII	689UW7PT68;
ChEMBL	ChEMBL77862 ;
CompTox Dashboard（英语：CompTox Chemicals Dashboard） (EPA)	DTXSID70936887 ;
化学信息
化学式	C8H9ClN2O2S
摩尔质量	232.68 g·mol−1
3D模型（JSmol（英语：JSmol））	交互式图像;
	SMILES CC1NC2=C(C=C(C=C2)Cl)S(=O)(=O)N1;
	InChI InChI=1S/C8H9ClN2O2S/c1-5-10-7-3-2-6(9)4-8(7)14(12,13)11-5/h2-5,10-11H,1H3 ; Key:VZRNTCHTJRLTMU-UHFFFAOYSA-N ;

IDRA-21是种AMPA受体（英语：AMPA receptor）的正别构调节剂（英语：Allosteric modulator），也是苯丙噻二嗪（英语：Benzothiadiazine）的衍生物，也是一种手性分子，(+)-IDRA-21是其活性形式。^[1]

在动物实验中，IDRA-21表现出了有促进学习的效果，并能明显改善学习和记忆。在逆转阿普唑仑或东莨菪碱诱发的认知障碍方面，有着约比茴拉西坦10到30倍的效力，^[2]^[3]且在单次服用后，可产生长达48小时的持续效应，^[4]其作用机制，被认为是通过促进大脑突触间的诱导LTP达到的。^[5]

正常情况下，IDRA-21或许不产生神经毒性，^[6]但可能会加重中风或癫痫发作后，因全身缺血所造成的神经元损伤。^[7]

与安帕金（英语：Ampakine）或苯甲酰哌啶衍生的AMPA受体增效剂相比，IDRA-21药效优于CX-516（英语：CX-516），低于CX-546（英语：CX-546）。^[8]与IDRA-21相比，效力更好的苯丙噻二嗪（英语：Benzothiadiazine）类衍生物已被开发出来，^[9]^[10]但这些衍生物，各所获的研究程度并不一样，苯甲酰基哌啶（benzoylpiperidine）和苯甲酰基吡咯烷CX系列（benzoylpyrrolidine CX-series）药物，在临床开发中更受青睐，这或是由于它们在高剂量使用时，具有更有利的毒性特征。^[11]

另见

正别构调节剂（英语：Allosteric modulator）

参考文献

^ Uzunov DP, Zivkovich I, Pirkle WH, Costa E, Guidotti A. Enantiomeric resolution with a new chiral stationary phase of 7-chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine S,S-dioxide, a cognition-enhancing benzothiadiazine derivative. Journal of Pharmaceutical Sciences. August 1995, 84 (8): 937–42. PMID 7500277. doi:10.1002/jps.2600840807.
^ Thompson DM, Guidotti A, DiBella M, Costa E. 7-Chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine S,S-dioxide (IDRA 21), a congener of aniracetam, potently abates pharmacologically induced cognitive impairments in patas monkeys. Proceedings of the National Academy of Sciences of the United States of America. August 1995, 92 (17): 7667–71. Bibcode:1995PNAS...92.7667T. PMC 41206 . PMID 7644474. doi:10.1073/pnas.92.17.7667 .
^ Zivkovic I, Thompson DM, Bertolino M, Uzunov D, DiBella M, Costa E, Guidotti A. 7-Chloro-3-methyl-3-4-dihydro-2H-1,2,4 benzothiadiazine S,S-dioxide (IDRA 21): a benzothiadiazine derivative that enhances cognition by attenuating DL-alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid (AMPA) receptor desensitization. The Journal of Pharmacology and Experimental Therapeutics. January 1995, 272 (1): 300–9. PMID 7815345.
^ Buccafusco JJ, Weiser T, Winter K, Klinder K, Terry AV. The effects of IDRA 21, a positive modulator of the AMPA receptor, on delayed matching performance by young and aged rhesus monkeys. Neuropharmacology. January 2004, 46 (1): 10–22. PMID 14654093. S2CID 26443642. doi:10.1016/j.neuropharm.2003.07.002.
^ Arai A, Guidotti A, Costa E, Lynch G. Effect of the AMPA receptor modulator IDRA 21 on LTP in hippocampal slices. NeuroReport. September 1996, 7 (13): 2211–5. PMID 8930991. S2CID 35888339. doi:10.1097/00001756-199609020-00031.
^ Impagnatiello F, Oberto A, Longone P, Costa E, Guidotti A. 7-Chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine S,S-dioxide: a partial modulator of AMPA receptor desensitization devoid of neurotoxicity. Proceedings of the National Academy of Sciences of the United States of America. June 1997, 94 (13): 7053–8. Bibcode:1997PNAS...94.7053I. PMC 21283 . PMID 9192690. doi:10.1073/pnas.94.13.7053 .
^ Yamada KA, Covey DF, Hsu CY, Hu R, Hu Y, He YY. The diazoxide derivative IDRA 21 enhances ischemic hippocampal neuron injury. Annals of Neurology. May 1998, 43 (5): 664–9. PMID 9585363. S2CID 39977647. doi:10.1002/ana.410430517.
^ Nagarajan N, Quast C, Boxall AR, Shahid M, Rosenmund C. Mechanism and impact of allosteric AMPA receptor modulation by the ampakine CX546. Neuropharmacology. November 2001, 41 (6): 650–63. PMID 11640919. S2CID 7796112. doi:10.1016/S0028-3908(01)00133-2.
^ Phillips D, Sonnenberg J, Arai AC, Vaswani R, Krutzik PO, Kleisli T, et al. 5'-alkyl-benzothiadiazides: a new subgroup of AMPA receptor modulators with improved affinity. Bioorganic & Medicinal Chemistry. May 2002, 10 (5): 1229–48. CiteSeerX 10.1.1.113.7845 . PMID 11886787. doi:10.1016/S0968-0896(01)00405-9.
^ Arai AC, Xia YF, Kessler M, Phillips D, Chamberlin R, Granger R, Lynch G. Effects of 5'-alkyl-benzothiadiazides on (R,S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor biophysics and synaptic responses. Molecular Pharmacology. September 2002, 62 (3): 566–77. PMID 12181433. S2CID 16182942. doi:10.1124/mol.62.3.566.
^ Black MD. Therapeutic potential of positive AMPA modulators and their relationship to AMPA receptor subunits. A review of preclinical data. Psychopharmacology. April 2005, 179 (1): 154–63. PMID 15672275. S2CID 5869366. doi:10.1007/s00213-004-2065-6.

[1] Uzunov DP, Zivkovich I, Pirkle WH, Costa E, Guidotti A. Enantiomeric resolution with a new chiral stationary phase of 7-chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine S,S-dioxide, a cognition-enhancing benzothiadiazine derivative. Journal of Pharmaceutical Sciences. August 1995, 84 (8): 937–42. PMID 7500277. doi:10.1002/jps.2600840807.

[2] Thompson DM, Guidotti A, DiBella M, Costa E. 7-Chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine S,S-dioxide (IDRA 21), a congener of aniracetam, potently abates pharmacologically induced cognitive impairments in patas monkeys. Proceedings of the National Academy of Sciences of the United States of America. August 1995, 92 (17): 7667–71. Bibcode:1995PNAS...92.7667T. PMC 41206 . PMID 7644474. doi:10.1073/pnas.92.17.7667 .

[3] Zivkovic I, Thompson DM, Bertolino M, Uzunov D, DiBella M, Costa E, Guidotti A. 7-Chloro-3-methyl-3-4-dihydro-2H-1,2,4 benzothiadiazine S,S-dioxide (IDRA 21): a benzothiadiazine derivative that enhances cognition by attenuating DL-alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid (AMPA) receptor desensitization. The Journal of Pharmacology and Experimental Therapeutics. January 1995, 272 (1): 300–9. PMID 7815345.

[4] Buccafusco JJ, Weiser T, Winter K, Klinder K, Terry AV. The effects of IDRA 21, a positive modulator of the AMPA receptor, on delayed matching performance by young and aged rhesus monkeys. Neuropharmacology. January 2004, 46 (1): 10–22. PMID 14654093. S2CID 26443642. doi:10.1016/j.neuropharm.2003.07.002.

[5] Arai A, Guidotti A, Costa E, Lynch G. Effect of the AMPA receptor modulator IDRA 21 on LTP in hippocampal slices. NeuroReport. September 1996, 7 (13): 2211–5. PMID 8930991. S2CID 35888339. doi:10.1097/00001756-199609020-00031.

[6] Impagnatiello F, Oberto A, Longone P, Costa E, Guidotti A. 7-Chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine S,S-dioxide: a partial modulator of AMPA receptor desensitization devoid of neurotoxicity. Proceedings of the National Academy of Sciences of the United States of America. June 1997, 94 (13): 7053–8. Bibcode:1997PNAS...94.7053I. PMC 21283 . PMID 9192690. doi:10.1073/pnas.94.13.7053 .

[7] Yamada KA, Covey DF, Hsu CY, Hu R, Hu Y, He YY. The diazoxide derivative IDRA 21 enhances ischemic hippocampal neuron injury. Annals of Neurology. May 1998, 43 (5): 664–9. PMID 9585363. S2CID 39977647. doi:10.1002/ana.410430517.

[8] Nagarajan N, Quast C, Boxall AR, Shahid M, Rosenmund C. Mechanism and impact of allosteric AMPA receptor modulation by the ampakine CX546. Neuropharmacology. November 2001, 41 (6): 650–63. PMID 11640919. S2CID 7796112. doi:10.1016/S0028-3908(01)00133-2.

[9] Phillips D, Sonnenberg J, Arai AC, Vaswani R, Krutzik PO, Kleisli T, et al. 5'-alkyl-benzothiadiazides: a new subgroup of AMPA receptor modulators with improved affinity. Bioorganic & Medicinal Chemistry. May 2002, 10 (5): 1229–48. CiteSeerX 10.1.1.113.7845 . PMID 11886787. doi:10.1016/S0968-0896(01)00405-9.

[10] Arai AC, Xia YF, Kessler M, Phillips D, Chamberlin R, Granger R, Lynch G. Effects of 5'-alkyl-benzothiadiazides on (R,S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor biophysics and synaptic responses. Molecular Pharmacology. September 2002, 62 (3): 566–77. PMID 12181433. S2CID 16182942. doi:10.1124/mol.62.3.566.

[11] Black MD. Therapeutic potential of positive AMPA modulators and their relationship to AMPA receptor subunits. A review of preclinical data. Psychopharmacology. April 2005, 179 (1): 154–63. PMID 15672275. S2CID 5869366. doi:10.1007/s00213-004-2065-6.

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