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 pKa 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]

Chemistry[edit]

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.[11][16][17]

Mecamylamine synthesis

Since there have been some studies to examine the differences between the pharmacological properties of the two mecamylamine enantiomers, and interest in the possible therapeutic application of one of these (see "Pharmacology and Clinical Applications", above), a few comments on the stereochemistry of mecamylamine may be useful.

The synthesis of "mecamylamine" reported by Stone et al., and shown in the reaction scheme above, began with racemic camphene.[11]

The attachment of the nitrogen substituent to C-2 via the Ritter reaction could, in principle, lead to two different geometrical isomers, endo- and exo-, depending on the geometry of addition of the nitrogen atom with respect to the two different bridges in the bicyclic part of the molecule. Each of these geometrical isomers would be racemic because the starting camphene was racemic. In practice, only one racemic geometrical isomer, believed to be the exo-isomer on theoretical grounds, was isolated from the reaction, and this substance was given the name "mecamylamine".[18] Racemic mecamylamine was also resolved into its two enantiomers using d-camphorsulfonic acid, and the resulting enantiomers then converted into their respective hydrochloride salts, with the following specific rotations and melting points:[11]

(+)-mecamylamine.HCl: [α] = + 20.6° (c = 1.5%, CHCl3); m.p. 262-264°.

(-)-mecamylamine.HCl: [α] = - 20.6° (c = 1.5%, CHCl3); m.p. 258°.

The melting point of the racemic HCl salt was 246-247°.

Many years later, Schonenberger and co-workers at the NIH separated racemic mecamylamine (which they obtained from Paul Anderson at Merck) into its enantiomers using a method different from that of Stone et al., noting that the latter method was inefficient in their hands.

The specific rotations and melting points obtained by these chemists are as follows:

(+)-mecamylamine.HCl: [α] = + 20.1° (c = 1.7%, CHCl3); m.p. 259-260°.

(-)-mecamylamine.HCl: [α] = - 20.0° (c = 2.2%, CHCl3); m.p. 259-260°.

It was noted in passing that the corresponding free bases had the opposite signs of optical rotation.

The NIH group also carried out a crystallographic analysis of the levorotatory hydrochloride, and established its absolute configuration to be (1S, 2R, 4R), in which the nitrogen is attached to the C-2 position.[19] This then corresponds to "exo-R-(-)-mecamylamine", the full IUPAC name becoming (1S, 2R, 4R)-N-methyl-(2,3,3-trimethylbicyclo[2.2.1]hept-2-yl)amine, and that of its enantiomer (1R, 2S, 4S)-N-methyl-(2,3,3-trimethylbicyclo[2.2.1]hept-2-yl)amine.[20][21]

The two exo-isomers of mecamylamine are shown below:

Mecamylamine exo.svg

To date (June 2012), syntheses of either of the two endo-isomers (see below) corresponding to mecamylamine have not been reported in the primary literature.

Mecamylamine endo.svg

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. ^ a b c d 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.
  16. ^ G. A. Stein, K. Pfister III, U.S. Patent 2,831,027 (1958)
  17. ^ 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. 
  18. ^ The trivial chemical name "3-amino-2,2,3-trimethylnorcamphane" was also used. Note the numbering differences with respect to the IUPAC name.
  19. ^ This is the isomer whose structure is shown in the box at upper right.
  20. ^ B. Schonenberger et al. (1986) Helv. Chim. Acta 69 283-287.
  21. ^ B. Schonenberger and A. Brossi (1986) Helv. Chim. Acta 69 1486-1497.
  • L. Barnhill (2007) letters JACAP 46 3-4