MT-45 explained

MT-45 (IC-6) is an opioid analgesic drug invented in the 1970s by Dainippon 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 of morphine, with almost all opioid activity residing in the (S) enantiomer (the opposite stereochemistry from the related drug lefetamine).[2] [3] It has been used as a lead compound from which a large family of potent opioid drugs[4] have been developed, including full agonists, partial agonists, and antagonists at the three main opioid receptor subtypes.[5] [6] [7] [8] [9] [10] Fluorinated derivatives of MT-45 such as 2F-MT-45 are significantly more potent as μ-opioid receptor agonists, and one of its main metabolites 1,2-diphenylethylpiperazine also blocks NMDA receptors.[11]

Side effects

Recreational use of MT-45 has been associated with unconsciousness and overdose, as well as a range of unusual side effects not typically seen with other opioid agonists, including hearing loss, hair depigmentation, alopecia, cataracts, and skin and nail reactions such as dermatitis and Mees lines. The cause for this is unclear, although a structural similarity to a withdrawn drug triparanol which caused similar side effects has been noted.[12] [13] [14] [15] [16] [17]

Legality

MT-45 became a class A drug in the UK on 11 March 2015.[18]

MT-45 is banned in the Czech Republic.[19]

The Canadian Controlled 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 the Food 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]

See also

Notes and References

  1. US . 3957788 . patent . 1-Substituted-4-(1,2-diphenylethyl)piperazine derivatives and their salts . 1975-15-01 . 1976-18-05 . Haruki Nishimura, Hitoshi Uno, Kagayaki Natsuka, Noriaki Shimokawa, Masanao Shimizu, Hideo Nakamura.
  2. Natsuka K, Nakamura H, Uno H, Umemoto S . Studies on 1-substituted 4-(1,2-diphenylethyl)piperazine derivatives and their analgesic activities. 1 . Journal of Medicinal Chemistry . 18 . 12 . 1240–4 . December 1975 . 1195277 . 10.1021/jm00246a014.
  3. Nakamura H, Shimizu M . 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 . May 1976 . 962421 .
  4. US Patent 4080453
  5. Natsuka K, Nakamura H, Negoro T, Uno H, Nishimura H . 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 . December 1978 . 722735 . 10.1021/jm00210a017.
  6. Shimokawa N, Nakamura H, Shimakawa K, Minami H, Nishimura H . 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 . January 1979 . 106119 . 10.1021/jm00187a014.
  7. Nakamura H, Ishii D, Yokoyama Y, Motoyoshi S, Natsuka K, Shimizu M . 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 . September 1980 . 6107365 . 10.1111/j.2042-7158.1980.tb13020.x. 27764413 .
  8. Nozaki M, Niwa M, Imai E, Hori M, Fujimura H . (1,2-Diphenylethyl) piperazines as potent opiate-like analgesics; the unusual relationships between stereoselectivity and affinity to opioid receptor . Life Sciences . 33 . 431–4 . 1983 . Suppl 1 . 6319898 . 10.1016/0024-3205(83)90534-9.
  9. Natsuka K, Nakamura H, Nishikawa Y, Negoro T, Uno H, Nishimura H . 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 . October 1987 . 3656354 . 10.1021/jm00393a017.
  10. Natsuka K, Nishikawa Y, Nakamura H . Roles of two basic nitrogen atoms in 1-substituted 4-(1,2-diphenylethyl)piperazine derivatives in production of opioid agonist and antagonist activities . Chemical & Pharmaceutical Bulletin . 47 . 12 . 1790–3 . December 1999 . 10748722 . 10.1248/cpb.47.1790. free .
  11. Baptista-Hon DT, Smith M, Singleton S, Antonides LH, Nic Daeid N, McKenzie C, Hales TG . Activation of μ-opioid receptors by MT-45 (1-cyclohexyl-4-(1,2-diphenylethyl)piperazine) and its fluorinated derivatives . British Journal of Pharmacology. 177 . 15 . 3436–48 . August 2020 . 32246840 . 10.1111/bph.15064. 7348096 . free .
  12. Helander A, Bäckberg M, Beck O . MT-45, a new psychoactive substance associated with hearing loss and unconsciousness . Clinical Toxicology . 52 . 8 . 901–4 . 2014 . 25175898 . 10.3109/15563650.2014.943908 . 37311206 .
  13. Helander A, Bradley M, Hasselblad A, Norlén L, Vassilaki I, Bäckberg M, Lapins J . 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 . April 2017 . 27976363 . 10.1111/bjd.15174 . 39249889 .
  14. Wallach JV, Morris H, Brandt SD . Is nitrogen mustard contamination responsible for the reported MT-45 toxicity? . The British Journal of Dermatology . 177 . 2 . 594–595 . August 2017 . 28369837 . 10.1111/bjd.15507 . 30128050 .
  15. Helander A, Bradley M, Lapins J . 'Is nitrogen mustard contamination responsible for the reported MT-45 toxicity?' Reply from the authors . The British Journal of Dermatology . 177 . 2 . 595 . August 2017 . 28626874 . 10.1111/bjd.15676 . 26911685 .
  16. Solimini R, Pichini S, Pacifici R, Busardò FP, Giorgetti R . Pharmacotoxicology of Non-fentanyl Derived New Synthetic Opioids . Frontiers in Pharmacology . 2018 . 9 . 654 . 29973882 . 10.3389/fphar.2018.00654 . 6020781 . free .
  17. McKenzie C, Sutcliffe OB, Read KD, Scullion P, Epemolu O, Fletcher D, Helander A, Beck O, Rylski A, Antonides LH, Riley J, Smith SA, Nic Daeid N . 6 . Chemical synthesis, characterisation and in vitro and in vivo metabolism of the synthetic opioid MT-45 and its newly identified fluorinated analogue 2F-MT-45 with metabolite confirmation in urine samples from known drug users . Forensic Toxicology . 36 . 2 . 359–374 . 2018 . 29963206 . 6002428 . 10.1007/s11419-018-0413-1 .
  18. Web site: Circular 003/2015: a change to the Misuse of Drugs Act 1971: control of MT-45 and 4,4'-DMAR . UK Home Office . 20 February 2015 . 11 March 2015.
  19. Web site: Látky, o které byl doplněn seznam č. 4 psychotropních látek (příloha č. 4 k nařízení vlády č. 463/2013 Sb.) . Ministerstvo zdravotnictví . cs . 2016-02-06 . 2016-03-09 . https://web.archive.org/web/20160309174659/http://www.mzcr.cz/Admin/_upload/files/3/Nov%C3%A9%20PL.pdf . dead .
  20. http://www.gazette.gc.ca/rp-pr/p2/2016/2016-06-01/html/sor-dors106-eng.php Regulations Amending the Food and Drug Regulations (Parts G and J — Lefetamine, AH-7921, MT-45 and W-18)
  21. Web site: 2017 - Final Order: Placement of MT-45 into Schedule I.

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