Mecamylamine

Mecamylamine
Mecamylamine
Systematic (IUPAC) name
(2R)-N,2,3,3-tetramethylbicyclo[2.2.1]heptan-2-amine
Clinical data
AHFS/Drugs.com Consumer Drug Information
Pregnancy cat.  ?
Legal status ℞ Prescription only
Routes Oral
Pharmacokinetic data
Protein binding 40%
Identifiers
CAS number 60-40-2 YesY
ATC code C02BB01
PubChem CID 4032
DrugBank APRD00458
ChemSpider 5036243 YesY
UNII 6EE945D3OK YesY
ChEMBL CHEMBL1398031 N
Chemical data
Formula C11H21N 
Mol. mass 167.291 g/mol
SMILES eMolecules & PubChem
 N(what is this?)  (verify)

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

Uses

Mecamylamine has been used as a ganglionic blocker in treating hypertension, 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,[2] 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.

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.[3][4] 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.[5][6] Development is funded by Targacept and AstraZeneca.[7] 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 alpha-4 beta-2 and alpha-3 beta-4 receptors than does the (R)-(-)-enantiomer.[8] The pKa value is 11.2.

A small SAR study was undertaken by Suchocki et al.[9]

Chemistry

Mecamylamine is synthesized from camphene, which is reacted under Ritter reaction conditions with hydrogen cyanide in concentrated sulfuric acid, giving N-(2,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)formamide, the reduction of which by lithium aluminum hydride leads to mecamylamine.[10][11]

Mecamylamine synthesis.png

References

  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. http://informahealthcare.com/doi/abs/10.1517/14656560903329102. 
  2. ^ 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. 
  3. ^ 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. 
  4. ^ 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. 
  5. ^ "Key AZ/Targacept depression drug flunks first Phase III test". Fiercebiotech.com. http://www.fiercebiotech.com/story/key-aztargacept-depression-drug-flunks-first-phase-iii-test/2011-11-08. Retrieved 2011-11-09. 
  6. ^ "Targacept Shares Fall After Depression Medicine Misses Goal". News.businessweek.com. 2007-01-15. http://news.businessweek.com/article.asp?documentKey=1376-LUBZKL6JIJVL01-1OBSNUJNAR30QM320MFNHCQ74T. Retrieved 2011-11-09. 
  7. ^ "AstraZeneca Pipeline as of the 27th of January 2011". http://www.astrazeneca.com/cs/Satellite?blobcol=urldata&blobheader=application%2Fpdf&blobheadername1=Content-Disposition&blobheadername2=MDT-Type&blobheadervalue1=inline%3B+filename%3DDownload-pipeline-summary.pdf&blobheadervalue2=abinary%3B+charset%3DUTF-8&blobkey=id&blobtable=MungoBlobs&blobwhere=1285619440126&ssbinary=true. Retrieved 2011-11-09. 
  8. ^ 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. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11303054. 
  9. ^ "JMC 1991". Pubs.acs.org. http://pubs.acs.org/doi/abs/10.1021/jm00107a019. Retrieved 2011-11-09. 
  10. ^ G.A. Stein, K. Pfister III, U.S. Patent 2,831,027 (1958)
  11. ^ Stein, G. A.; Sletzinger, M.; Arnold, H.; Reinhold, D.; Gaines, W.; Pfister, K. (1956). Journal of the American Chemical Society 78 (7): 1514. doi:10.1021/ja01588a070. 
v · d · eSympatholytic (and closely related) antihypertensives (C02)
Sympatholytics
(antagonize α-adrenergic
vasoconstriction)
Central
Adrenergic release inhibitors
Bethanidine • Bretylium • Debrisoquine • Guanadrel • Guanazodine • Guanethidine • Guanoclor • Guanoxan • Guanazodine • Guanoxabenz • Guanoxan
Mecamylamine • Pentolinium • Trimethaphan
Peripheral
Indirect
Tyrosine hydroxylase inhibitor
Direct
Non-selective α blocker
Other antagonists
dual (Bosentan) • selective (Ambrisentan, Sitaxentan)

M: VAS

anat(a:h/u/t/a/l,v:h/u/t/a/l)/phys/devp/cell/prot

noco/syva/cong/lyvd/tumr, sysi/epon, injr

proc, drug(C2s+n/3/4/5/7/8/9)
v · d · eAntiaddictives (N07B)
Nicotine dependence/
(Nicotinic agonist)

Nicotine • Dianicline • Varenicline • Lobeline • Mecamylamine • Scopolamine

NDRI (Bupropion) • AA (Clonidine) • CB1 (Surinabant)
Alcohol dependence
Opioid dependence
Stimulant dependence
Benzodiazepine dependence
Cocaine dependence
Sedative-Hypnotic dependence

M: CNS

anat(n/s/m/p/4/e/b/d/c/a/f/l/g)/phys/devp

noco(m/d/e/h/v/s)/cong/tumr, sysi/epon, injr

proc, drug(N1A/2AB/C/3/4/7A/B/C/D)

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Look at other dictionaries:

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  • mecamylamine — noun Etymology: from Mecamylamine, a trademark Date: 1955 a drug that is used orally in the form of its hydrochloride C11H21N•HCl as a ganglionic blocking agent to effect a rapid lowering of severely elevated blood pressure …   New Collegiate Dictionary

  • mecamylamine — noun An anti addictive drug, an amino derivative of norbornane, used as a nicotine antagonist …   Wiktionary

  • mecamylamine — mec·a·myl·a·mine .mek ə mil ə .mēn n a drug administered orally in the form of its hydrochloride C11H21N·HCl as a ganglionic blocking agent to effect a rapid lowering of severely elevated blood pressure …   Medical dictionary

  • mecamylamine — mec·a·myl·amine …   English syllables

  • mecamylamine — …   Useful english dictionary

  • mecamylamine hydrochloride — A secondary amine that blocks transmission of impulses at autonomic ganglia (similar to but more effective than hexamethonium); used in the management of severe hypertension. * * * mec·a·myl·amine hy·dro·chlo·ride (mek″ə milґə… …   Medical dictionary

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  • Nicotinic antagonist — A nicotinic antagonist is a type of anticholinergic that inhibits the action at nicotinic acetylcholine receptors. These compounds are mainly used for peripheral muscle paralysis in surgery, but some centrally acting compounds such as bupropion,… …   Wikipedia

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