Mecamylamine

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Mecamylamine
Mecamylamine3.svg
Clinical data
Trade names Inversine, Vecamyl
AHFS/Drugs.com Consumer Drug Information
Routes of
administration
Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding 40%
Identifiers
  • (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 InfoCard 100.000.433 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C11H21N
Molar mass 167.296 g·mol−1
3D model (JSmol)
  • N([C@@]2([C@@H]1CC[C@@H](C1)C2(C)C)C)C
  • 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 Yes check.svgY
  • Key:IMYZQPCYWPFTAG-IQJOONFLSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

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 [2] In the United States, it was voluntarily withdrawn from the market in 2009 but was brought to market in 2013 as Vecamyl and eventually was marketed by Turing Pharmaceuticals.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]

Contents

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

Medical uses

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.[ medical citation needed ]

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.

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. [13] [14] Development is funded by Targacept and AstraZeneca. [15] 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. 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. [16] [17] Development is funded by Targacept and AstraZeneca. [18] 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.

Overdose

The LD50 for the HCl salt [19] in mice: 21 mg/kg (i.v.); 37 mg/kg (i.p.); 96 mg/kg (p.o.). [20]

Pharmacology

(S)-(+)-Mecamylamine dissociates more slowly from α4β2 and α3β4 receptors than does the (R)-(−)-enantiomer. [21]

A large SAR study of mecamylamine and its analogs was reported by a group from Merck in 1962. [22] Another, more recent SAR study was undertaken by Suchocki et al. [23]

A comprehensive review of the pharmacology of mecamylamine was published in 2001. [24]

History

Mecamylamine was brought to market by Merck & Co. in the 1950s; in 1996 Merck sold the asset to Layton Bioscience. [25] In 2002, Targacept acquired it from Layton, intending to repurpose it for CNS conditions. [26] Targacept voluntarily withdrew mecamylamine from the market in 2009 [27] for reasons not related to safety or efficacy. [28] Manchester Pharmaceuticals brought the drug back to market in 2013. [29] Retrophin acquired Manchester in 2014 [30] and after Martin Shkreli was forced out of Retrophin, in 2014 his new company, Turing Pharmaceuticals, acquired the rights to mecamylamine from Retrophin. [31]

See also

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References

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  8. 1 2 3 Lippiello PM, Beaver JS, Gatto GJ, James JW, Jordan KG, Traina VM, et al. (2008). "TC-5214 (S-(+)-mecamylamine): a neuronal nicotinic receptor modulator with antidepressant activity". CNS Neuroscience & Therapeutics. 14 (4): 266–277. doi:10.1111/j.1755-5949.2008.00054.x. PMC   6494058 . PMID   19040552.
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  12. "AstraZeneca Pipeline as of the 27th of January 2011" . Retrieved 2011-11-09.
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  14. Hirschler B (8 November 2011). "AstraZeneca, Targacept drug fails depression test". Reuters.
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  17. Hirschler B (8 November 2011). "AstraZeneca, Targacept drug fails depression test". Reuters.
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  19. In view of the time period when these data were generated, they presumably refer to the HCl salt of the racemic drug
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  25. 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): 453–457. doi:10.1038/sj.jhh.1001416. PMID   12080428.
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