Mecamylamine

Mecamylamine
Clinical data
Trade namesInversine, Vecamyl
AHFS/Drugs.comConsumer Drug Information
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding40%
Identifiers
IUPAC name
  • (1S,2R,4R)-N,2,3,3-Tetramethylbicyclo[2.2.1]heptan-2-amine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.433
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Chemical and physical data
FormulaC11H21N
Molar mass167.296 g·mol−1
3D model (JSmol)
SMILES
  • N([C@@]2([C@@H]1CC[C@@H](C1)C2(C)C)C)C
InChI
  • InChI=1S/C11H21N/c1-10(2)8-5-6-9(7-8)11(10,3)12-4/h8-9,12H,5-7H2,1-4H3/t8-,9+,11+/m0/s1 checkY
  • Key:IMYZQPCYWPFTAG-IQJOONFLSA-N checkY
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Mecamylamine (INN, BAN; or mecamylamine hydrochloride (USAN); brand names Inversine, Vecamyl[1]) is a non-selective, non-competitive antagonist of the nicotinic acetylcholine receptors (nAChRs) that was introduced in the 1950s as an antihypertensive drug.[2] In the United States, it was voluntarily withdrawn from the market in 2009 but was brought to market in 2013 as Vecamyl and eventually was marketed by Turing Pharmaceuticals.[3][4]

Chemically, mecamylamine is a secondary aliphatic amine, with a pKaH of 11.2[5]

Pharmacology and clinical applications

Mecamylamine has been used as an orally-active ganglionic blocker in treating autonomic dysreflexia and hypertension,[6] but, like most ganglionic blockers, it is more often used now as a research tool.

Mecamylamine is also sometimes used as an antiaddictive drug to help people stop smoking tobacco,[7] and is now more widely used for this application than it is for lowering blood pressure. This effect is thought to be due to its blocking α3β4 nicotinic receptors in the brain. It has also been reported to bring about sustained relief from tics in Tourette syndrome when a series of more usually used agents had failed.

In a recent double-blind, placebo-controlled Phase II trial in Indian patients with major depression, (S)-mecamylamine (TC-5214) appeared to have efficacy as an augmentation therapy. This is the first substantive evidence that shows that compounds where the primary pharmacology is antagonism to neuronal nicotinic receptors will have antidepressant properties.[8][9] TC-5214 is currently in Phase III of clinical development as an add-on treatment and on stage II as a monotherapy treatment for major depression. The first results reported from the Phase III trials showed that TC-5214 failed to meet the primary goal and the trial did not replicate the effects that had been encouraging in the Phase II trial.[10][11] Development is funded by Targacept and AstraZeneca.[12] It did not produce meaningful, beneficial results on patients as measured by changes on the Montgomery-Asberg Depression Rating Scale after eight weeks of treatment as compared with placebo.

(S)-(+)-Mecamylamine dissociates more slowly from α4β2 and α3β4 receptors than does the (R)-(−)-enantiomer.[13]

A large SAR study of mecamylamine and its analogs was reported by a group from Merck in 1962.[14] Another, more recent SAR study was undertaken by Suchocki et al.[15]

A comprehensive review of the pharmacology of mecamylamine was published in 2001.[16]

Toxicology

The LD50 for the HCl salt[17] in mice: 21 mg/kg (i.v.); 37 mg/kg (i.p.); 96 mg/kg (p.o.).[18]

History

Mecamylamine was brought to market by Merck & Co. in the 1950s; in 1996 Merck sold the asset to Layton Bioscience.[19] In 2002, Targacept acquired it from Layton, intending to repurpose it for CNS conditions.[20] Targacept voluntarily withdrew mecamylamine from the market in 2009[21] for reasons not related to safety or efficacy.[22] Manchester Pharmaceuticals brought the drug back to market in 2013.[23] Retrophin acquired Manchester in 2014[24] and after Martin Shkreli was forced out of Retrophin, in 2014 his new company, Turing Pharmaceuticals, acquired the rights to mecamylamine from Retrophin.[25]

See also

References

  1. ↑ "Mecamylamine". drugs.com. Retrieved May 15, 2015.
  2. ↑ Bacher I, Wu B, Shytle DR, George TP (November 2009). "Mecamylamine - a nicotinic acetylcholine receptor antagonist with potential for the treatment of neuropsychiatric disorders". Expert Opinion on Pharmacotherapy. 10 (16): 2709–21. doi:10.1517/14656560903329102. PMID 19874251. S2CID 25690407.
  3. ↑ "Drug Profile: Mecamylamine - Targacept".
  4. ↑ "Drugs@FDA: FDA Approved Drug Products". www.accessdata.fda.gov. Retrieved 2017-10-16.
  5. ↑ Schanker LS, Shore PA, Brodie BB, Hogben CA (1957). "Absorption of drugs from the stomach. I. The rat". J. Pharmacol. Exp. Ther. 120 (4): 528–39. PMID 13476377.
  6. ↑ T. O. Soine (1966). C. O. Wilson, O. Gisvold and R. F. Doerge (ed.). Textbook of Organic Medicinal and Pharmaceutical Chemistry (5th ed.). Philadelphia: Lippincott. pp. 468–546.
  7. ↑ Shytle RD, Penny E, Silver AA, Goldman J, Sanberg PR (July 2002). "Mecamylamine (Inversine): an old antihypertensive with new research directions". J Hum Hypertens. 16 (7): 453–7. doi:10.1038/sj.jhh.1001416. PMID 12080428.
  8. ↑ Lippiello PM, Beaver JS, Gatto GJ, et al. (2008). "TC-5214 (S-(+)-mecamylamine): a neuronal nicotinic receptor modulator with antidepressant activity". CNS Neurosci Ther. 14 (4): 266–77. doi:10.1111/j.1755-5949.2008.00054.x. PMC 6494058. PMID 19040552.
  9. ↑ Rabenstein RL, Caldarone BJ, Picciotto MR (December 2006). "The nicotinic antagonist mecamylamine has antidepressant-like effects in wild-type but not beta2- or alpha7-nicotinic acetylcholine receptor subunit knockout mice". Psychopharmacology. 189 (3): 395–401. doi:10.1007/s00213-006-0568-z. PMID 17016705. S2CID 6395092.
  10. ↑ John Carroll. "Key AZ/Targacept depression drug flunks first Phase III test". Fiercebiotech.com. Retrieved 2011-11-09.
  11. ↑ "Targacept Shares Fall After Depression Medicine Misses Goal". News.businessweek.com. 2007-01-15. Retrieved 2011-11-09.
  12. ↑ "AstraZeneca Pipeline as of the 27th of January 2011". Retrieved 2011-11-09.
  13. ↑ Papke RL, Sanberg PR, Shytle RD (May 2001). "Analysis of mecamylamine stereoisomers on human nicotinic receptor subtypes". J. Pharmacol. Exp. Ther. 297 (2): 646–56. PMID 11303054.
  14. ↑ Stone CA, Torchiana ML, Meckelnberg KL, Stavorski J, Sletzinger M, Stein GA, Ruyle WV, Reinhold DF, Gaines WA, Arnold H, Pfister K, et al. (1962). "Chemistry and Structure-Activity Relationships of Mecamylamine and Derivatives". J Med Pharm Chem. 91 (4): 665–90. doi:10.1021/jm01239a001. PMID 14061006.
  15. ↑ Suchocki, J. A.; May, E. L.; Martin ,T. J.; George, C.; Martin, B. R. (1991). "Synthesis of 2-exo- and 2-endo-mecamylamine analogs. Structure-activity relationships for nicotinic antagonism in the central nervous system". Journal of Medicinal Chemistry. 34 (3): 1003–1010. doi:10.1021/jm00107a019. PMID 2002445.
  16. ↑ Young, J. M.; et al. (2001). "Mecamylamine: New therapeutic uses and toxicity/risk profile". Clin. Ther. 23 (4): 532–565. doi:10.1016/s0149-2918(01)80059-x. PMID 11354389.
  17. ↑ In view of the time period when these data were generated, they presumably refer to the HCl salt of the racemic drug
  18. ↑ Spinks, A.; et al. (1958). "The pharmacological actions of pempidine and its ethyl homologue". Br. J. Pharmacol. Chemother. 13 (4): 501–520. doi:10.1111/j.1476-5381.1958.tb00246.x. PMC 1481871. PMID 13618559.
  19. ↑ Shytle, RD; Penny, E; Silver, AA; Goldman, J; Sanberg, PR (July 2002). "Mecamylamine (Inversine): an old antihypertensive with new research directions". Journal of Human Hypertension. 16 (7): 453–7. doi:10.1038/sj.jhh.1001416. PMID 12080428.
  20. ↑ "Press release: Targacept, Inc. Acquires Marketed Drug To Expand Its CNS Portfolio | Evaluate". Targacept via Evaluate. August 27, 2002.
  21. ↑ "Notification letter from Targacept" (PDF). FDA. June 4, 2009.
  22. ↑ "Determination That INVERSINE (Mecamylamine Hydrochloride) Tablet and Six Other Drug Products Were Not Withdrawn From Sale for Reasons of Safety or Effectiveness". Federal Register. 28 July 2011.
  23. ↑ "Press release: Manchester Announces FDA Approval of Vecamyl". Manchester Pharamceuticals via Evaluate. May 1, 2013.
  24. ↑ Fidler, Ben (13 February 2014). "Retrophin Shares Boom Following Manchester Pharma Buyout". Xconomy.
  25. ↑ Fidler, Ben (10 August 2015). "Shkreli Leads $90M Round for New Startup, Turing Pharma | Xconomy". Xconomy.
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