IDRA-21

IDRA-21是种AMPA受体（英语：AMPA receptor）的正別構調節劑（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。 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（英语：Aniracetam）10到30倍的效力，且在单次服用后，可产生长达48小时的持续效应，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。 正常情况下，IDRA-21或许不产生神经毒性，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。 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）。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，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。 正別構調節劑（英语：Allosteric modulator） 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.