Mecamylamine

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Mecamylamine
Mecamylamine3.svg
Systematic (IUPAC) name
(1S,2R,4R)-N,2,3,3-tetramethylbicyclo[2.2.1]heptan-2-amine
Clinical data
AHFS/Drugs.com Consumer Drug Information
Legal status
  • Prescription only
Routes Oral
Pharmacokinetic data
Protein binding 40%
Identifiers
CAS number 60-40-2 YesY
ATC code C02BB01
PubChem CID 4032
IUPHAR ligand 3990
DrugBank DB00657
ChemSpider 5036243 YesY
UNII 6EE945D3OK YesY
ChEMBL CHEMBL1398031 N
Chemical data
Formula C11H21N 
Mol. mass 167.291 g/mol
 N (what is this?)  (verify)

Mecamylamine (Inversine) is a nonselective and noncompetitive antagonist of nicotinic acetylcholine receptors that was introduced in the 1950s as an antihypertensive drug.[1]

Chemically, it is a secondary aliphatic amine, with a pKaH of 11.2[2]

Pharmacology and Clinical Applications[edit]

Mecamylamine has been used as an orally-active ganglionic blocker in treating autonomic dysreflexia and hypertension,[3] but, like most ganglionic blockers, it is more often used now as a research tool.

Mecamylamine is also sometimes used as an anti-addictive drug to help people stop smoking tobacco,[4] 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's Disorder when a series of more usually used agents had failed [22].

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.[5][6] 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.[7][8] Development is funded by Targacept and AstraZeneca.[9] 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.[10]

A large SAR study of mecamylamine and its analogs was reported by a group from Merck in 1962.[11] Another, more recent SAR study was undertaken by Suchocki et al.[12]

A comprehensive review of the pharmacology of mecamylamine was published in 2001.[13]

Toxicology[edit]

LD50 for the HCl salt[14] in mice: 21 mg/kg (i.v.); 37 mg/kg (i.p.); 96 mg/kg (p.o.).[15]

References[edit]

  1. ^ 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. 
  2. ^ L. S. Schanker et al. (1957) J. Pharmacol. Exp. Ther. 120 528.
  3. ^ T. O. Soine (1966), Textbook of Organic Medicinal and Pharmaceutical Chemistry, 5th Ed., (C. O. Wilson, O. Gisvold and R. F. Doerge, Eds.), pp. 468-546, Philadelphia: Lippincott.
  4. ^ 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. 
  5. ^ 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. PMID 19040552. 
  6. ^ 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 (Berl.) 189 (3): 395–401. doi:10.1007/s00213-006-0568-z. PMID 17016705. 
  7. ^ John Carroll. "Key AZ/Targacept depression drug flunks first Phase III test". Fiercebiotech.com. Retrieved 2011-11-09. 
  8. ^ "Targacept Shares Fall After Depression Medicine Misses Goal". News.businessweek.com. 2007-01-15. Retrieved 2011-11-09. 
  9. ^ "AstraZeneca Pipeline as of the 27th of January 2011". Retrieved 2011-11-09. 
  10. ^ 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. 
  11. ^ C. A. Stone et al. (1962) J. Med. Pharm. Chem. 5 665-690.
  12. ^ 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. 
  13. ^ J. M. Young et al. (2001) Clin. Ther. 23 532-565.
  14. ^ In view of the time period when these data were generated, they presumably refer to the HCl salt of the racemic drug - see discussion of stereochemical issues in "Chemistry" section.
  15. ^ A. Spinks et al. (1958) Br. J. Pharmacol. Chemother. 13 501-520.
  • L. Barnhill (2007) letters JACAP 46 3-4