MT-45 (IC-6) is anopioidanalgesic drug invented in the 1970s byDainippon Pharmaceutical Co.[1] It is chemically a 1-substituted-4-(1,2-diphenylethyl)piperazine derivative, which is structurally unrelated to most other opioid drugs. Racemic MT-45 has around 80% the potency ofmorphine, with almost all opioid activity residing in the (S) enantiomer (the opposite stereochemistry from the related druglefetamine).[2][3] It has been used as alead compound from which a large family of potent opioid drugs[4] have been developed, including full agonists, partial agonists, and antagonists at the three mainopioid receptor subtypes.[5][6][7][8][9][10] Fluorinated derivatives of MT-45 such as 2F-MT-45 are significantly more potent asμ-opioid receptor agonists, and one of its main metabolites 1,2-diphenylethylpiperazine also blocksNMDA receptors.[11]
Recreational use of MT-45 has been associated with unconsciousness andoverdose, as well as a range of unusual side effects not typically seen with other opioid agonists, includinghearing loss, hair depigmentation,alopecia,cataracts, and skin and nail reactions such asdermatitis andMees lines. The cause for this is unclear, although a structural similarity to a withdrawn drugtriparanol which caused similar side effects has been noted.[12][13][14][15][16][17]
The CanadianControlled Drugs and Substances Act was amended in 2016 to include the substance as a Schedule I substance. Possession without legal authority can result in maximum 7 years imprisonment. Further,Health Canada amended theFood and Drug Regulations in May 2016 to classify MT-45 as a restricted drug.[20] Only those with a law enforcement agency, person with an exemption permit or institutions with Minister's authorization may possess the drug in Canada.
In the United States, the DEA placed MT-45 in Schedule 1 of the Controlled Substance Act. This took effect on January 12, 2018.[21]
^US patent 3957788, Haruki Nishimura, Hitoshi Uno, Kagayaki Natsuka, Noriaki Shimokawa, Masanao Shimizu, Hideo Nakamura, "1-Substituted-4-(1,2-diphenylethyl)piperazine derivatives and their salts", published 1975-15-01, issued 1976-18-05
^Natsuka K, Nakamura H, Uno H, Umemoto S (December 1975). "Studies on 1-substituted 4-(1,2-diphenylethyl)piperazine derivatives and their analgesic activities. 1".Journal of Medicinal Chemistry.18 (12):1240–4.doi:10.1021/jm00246a014.PMID1195277.
^Nakamura H, Shimizu M (May 1976). "Comparative study of 1-cyclohexyl-4-(1,2-diphenylethyl)-piperazine and its enantiomorphs on analgesic and other pharmacological activities in experimental animals".Archives Internationales de Pharmacodynamie et de Thérapie.221 (1):105–21.PMID962421.
^Natsuka K, Nakamura H, Negoro T, Uno H, Nishimura H (December 1978). "Studies on 1-substituted 4-(1,2-diphenylethyl)piperazine derivatives and their analgesic activities. 2. Structure-activity relationships of 1-cycloalkyl-4-(1,2-diphenylethyl)piperazines".Journal of Medicinal Chemistry.21 (12):1265–9.doi:10.1021/jm00210a017.PMID722735.
^Shimokawa N, Nakamura H, Shimakawa K, Minami H, Nishimura H (January 1979). "Studies on analgesic agents. 1.1a Preparation of 1,2-diphenyl-2-(4-substituted 1-piperazinyl)ethanol derivatives and structure-activity relationships".Journal of Medicinal Chemistry.22 (1):58–63.doi:10.1021/jm00187a014.PMID106119.
^Nakamura H, Ishii D, Yokoyama Y, Motoyoshi S, Natsuka K, Shimizu M (September 1980). "Analgesic and other pharmacological activities of a new narcotic antagonist analgesic (−)-1-(3-methyl-2-butenyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]-piperazine and its enantiomorph in experimental animals".The Journal of Pharmacy and Pharmacology.32 (9):635–42.doi:10.1111/j.2042-7158.1980.tb13020.x.PMID6107365.S2CID27764413.
^Nozaki M, Niwa M, Imai E, Hori M, Fujimura H (1983). "(1,2-Diphenylethyl) piperazines as potent opiate-like analgesics; the unusual relationships between stereoselectivity and affinity to opioid receptor".Life Sciences.33 (Suppl 1):431–4.doi:10.1016/0024-3205(83)90534-9.PMID6319898.
^Natsuka K, Nakamura H, Nishikawa Y, Negoro T, Uno H, Nishimura H (October 1987). "Synthesis and structure-activity relationships of 1-substituted 4-(1,2-diphenylethyl)piperazine derivatives having narcotic agonist and antagonist activity".Journal of Medicinal Chemistry.30 (10):1779–87.doi:10.1021/jm00393a017.PMID3656354.
^Helander A, Bradley M, Hasselblad A, Norlén L, Vassilaki I, Bäckberg M, Lapins J (April 2017). "Acute skin and hair symptoms followed by severe, delayed eye complications in subjects using the synthetic opioid MT-45".The British Journal of Dermatology.176 (4):1021–1027.doi:10.1111/bjd.15174.PMID27976363.S2CID39249889.
^Helander A, Bradley M, Lapins J (August 2017). "'Is nitrogen mustard contamination responsible for the reported MT-45 toxicity?' Reply from the authors".The British Journal of Dermatology.177 (2): 595.doi:10.1111/bjd.15676.PMID28626874.S2CID26911685.
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