哌卡嗪

哌卡嗪（INN：pecazine）又名甲哌啶嗪（英語：mepazine），商品名Pacatal，为MALT1（英语：MALT1）蛋白酶的变构抑制剂，是一种已经淘汰的吩噻嗪类抗精神病药。 哌卡嗪最早由Wilhelm Schuler（英语：Wilhelm Schuler）和Otto Nieschulz于1953年合成得到，并迅速被作为镇静剂（字面意义上镇静剂，非广义上的安眠药或抑制剂）应用于精神科实践当中。尽管哌卡嗪强力的副交感神经抑制作用和抗胆碱作用导致本身镇静效果较弱和锥体外系症状风险低，但其仍被视作是氯丙嗪的替代品。 然而早在1958年，就有研究报告称哌卡嗪治疗精神分裂的效果不及其他吩噻嗪类药物，并对其临床应用地位提出质疑。随后到了1960年，一项双盲随机对照实验发现哌卡嗪甚至不及安慰剂有效。后续研究发现，哌卡嗪与其结构类似物异丙嗪一样，本质上不具备抗精神病活性。 20世纪50年代，因哌卡嗪与多例顆粒性白血球缺乏症（英语：Agranulocytosis）报告有关，导致其被撤出市场。进入21世纪后，因其对MALT1（英语：MALT1）蛋白酶和RANKL（破骨细胞分化因子）有抑制作用而重新引起研究者研究兴趣。 英国药理学会（英语：British Pharmacological Society）. pecazine. The International Union of Basic and Clinical Pharmacology (IUPHAR) / British Pharmacological Society (BPS) Guide to PHARMACOLOGY.  Bowens HA. The ataractic drugs: the present position of chlorpromazine, Frenquel, Pacatal, and reserpine in the psychiatric hospital. Am J Psychiatry. December 1956, 113 (6): 530–9. PMID 13372821. doi:10.1176/ajp.113.6.530.  Hutchinson JT, Jacobs EH. The place of pacatal in psychiatry. Postgrad Med J. November 1958, 34 (397): 605–8. PMC 2501585 . PMID 13591077. doi:10.1136/pgmj.34.397.605.  Casey JF, Lasky JJ, Klett CJ, Hollister LE. Treatment of schizophrenic reactions with phenothiazine derivatives. A comparative study of chlorpromazine, triflupromazine, mepazine, prochlorperazine, perphenazine, and phenobarbital. Am J Psychiatry. August 1960, 117: 97–105. PMID 13808146. doi:10.1176/ajp.117.2.97.  Whittier JR, Klein DF, Levine G, Weiss D. Mepazine (pacatal): clinical trial with placebo control and psychological study. Psychopharmacologia. June 1960, 1 (4): 280–7. PMID 13844495. S2CID 28787741. doi:10.1007/BF00404225.  Lassen JB. Inhibition and potentiation of apomorphine-induced hypermotility in rats by neuroleptics. Eur. J. Pharmacol. April 1976, 36 (2): 385–93. PMID 1278230. doi:10.1016/0014-2999(76)90092-3.  Biezanek A, Gore CP. Agranulocytosis during treatment with pacatal. Lancet. November 1956, 271 (6952): 1081. PMID 13377680. doi:10.1016/s0140-6736(56)90213-6.  Feldman PE, Bertone J, Panthel H. Fatal agranulocytosis during treatment with pacatal. Am J Psychiatry. March 1957, 113 (9): 842–3. PMID 13402978. doi:10.1176/ajp.113.9.842.  Drake M, Honey NK. Agranulocytosis during mepazine therapy. Med. J. Aust. November 1957, 44 (20): 726–7. PMID 13492769. S2CID 22232507. doi:10.5694/j.1326-5377.1957.tb60246.x.  Sherman S, Baur E, Klahre H, Lever PG. Agranulocytosis after 10(N-methyl-piperdyl-3-methyl)phenothiazine, with recovery. N. Engl. J. Med. February 1958, 258 (6): 287. PMID 13504461. doi:10.1056/NEJM195802062580608.  Nagel D, Spranger S, Vincendeau M, Grau M, Raffegerst S, Kloo B, Hlahla D, Neuenschwander M, Peter von Kries J, Hadian K, Dörken B, Lenz P, Lenz G, Schendel DJ, Krappmann D. Pharmacologic inhibition of MALT1 protease by phenothiazines as a therapeutic approach for the treatment of aggressive ABC-DLBCL. Cancer Cell. December 2012, 22 (6): 825–37. PMID 23238017. doi:10.1016/j.ccr.2012.11.002 .  Schlauderer F, Lammens K, Nagel D, Vincendeau M, Eitelhuber AC, Verhelst SH, Kling D, Chrusciel A, Ruland J, Krappmann D, Hopfner KP. Structural analysis of phenothiazine derivatives as allosteric inhibitors of the MALT1 paracaspase. Angew. Chem. Int. Ed. Engl. September 2013, 52 (39): 10384–7. PMID 23946259. doi:10.1002/anie.201304290.