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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 pK_a 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]

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:

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.

References[edit]

^ 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.
^ L. S. Schanker et al. (1957) J. Pharmacol. Exp. Ther. 120 528.
^ 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.
^ 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.
^ 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.
^ 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.
^ John Carroll. "Key AZ/Targacept depression drug flunks first Phase III test". Fiercebiotech.com. Retrieved 2011-11-09.
^ "Targacept Shares Fall After Depression Medicine Misses Goal". News.businessweek.com. 2007-01-15. Retrieved 2011-11-09.
^ "AstraZeneca Pipeline as of the 27th of January 2011". Retrieved 2011-11-09.
^ 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.
^ ^a ^b ^c ^d C. A. Stone et al. (1962) J. Med. Pharm. Chem. 5 665-690.
^ 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.
^ J. M. Young et al. (2001) Clin. Ther. 23 532-565.
^ 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.
^ A. Spinks et al. (1958) Br. J. Pharmacol. Chemother. 13 501-520.
^ G. A. Stein, K. Pfister III, U.S. Patent 2,831,027 (1958)
^ 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.
^ The trivial chemical name "3-amino-2,2,3-trimethylnorcamphane" was also used. Note the numbering differences with respect to the IUPAC name.
^ This is the isomer whose structure is shown in the box at upper right.
^ B. Schonenberger et al. (1986) Helv. Chim. Acta 69 283-287.
^ B. Schonenberger and A. Brossi (1986) Helv. Chim. Acta 69 1486-1497.

L. Barnhill (2007) letters JACAP 46 3-4

UpToDate Contents

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1. 鼻炎の概要 an overview of rhinitis

English Journal

Simultaneous quantification of nicotine, cotinine, trans-3'-hydroxycotinine, norcotinine and mecamylamine in human urine by liquid chromatography-tandem mass spectrometry.

Scheidweiler KB, Shakleya DM, Huestis MA.SourceChemistry and Drug Metabolism, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.
Clinica chimica acta; international journal of clinical chemistry.Clin Chim Acta.2012 Jun 14;413(11-12):978-84. Epub 2012 Feb 27.
BACKGROUND: Mecamylamine is a nicotine antagonist under investigation in combination with nicotine replacement for smoking treatment.METHODS: A simple, rapid and reliable liquid chromatography tandem mass spectrometry (LCMSMS) method was developed and validated for quantifying nicotine, cotinine, tr
PMID 22394455

A fluorinated quinuclidine benzamide named LMA 10203 acts as an agonist of insect nicotinic acetylcholine receptors.

Mathé-Allainmat M, Bodereau-Dubois B, Lapied B, Lebreton J, Thany SH.SourceUniversité de Nantes, CEISAM UMR 6230, UFR des Sciences et des Techniques, 2 rue de la Houssinière BP 92208, Nantes F-44000, France.
Insect biochemistry and molecular biology.Insect Biochem Mol Biol.2012 Jun;42(6):417-25. Epub 2012 Mar 5.
In the present study, we take advantage of the fact that cockroach dorsal unpaired median neurons express different nicotinic acetylcholine receptor subtypes to demonstrate that simple quinuclidine benzamides such as the 2-fluorinated benzamide LMA 10203, could act as an agonist of cockroach α-bung
PMID 22421703

Nicotine effects on human endothelial intercellular communication via α4β2 and α3β2 nicotinic acetylcholine receptor subtypes.

Duerrschmidt N, Hagen A, Gaertner C, Wermke A, Nowicki M, Spanel-Borowski K, Stepan H, Mohr FW, Dhein S.SourceClinic for Cardiac Surgery, Heart Centre, University of Leipzig, Strümpellstr. 39, 04289, Leipzig, Germany.
Naunyn-Schmiedeberg's archives of pharmacology.Naunyn Schmiedebergs Arch Pharmacol.2012 Jun;385(6):621-32. Epub 2012 Feb 22.
Since previous in vitro experiments revealed that nicotine can impair endothelial intercellular communication via the downregulation of connexin43 (Cx43), we wanted to find out which nicotinic acetylcholine receptors are involved in the molecular mechanism of communication failure. Cultured human en
PMID 22349182

Nicotine-induced changes of brain β-endorphin.

Gudehithlu KP, Duchemin AM, Tejwani GA, Neff NH, Hadjiconstantinou M.SourceDepartment of Pharmacology, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
Neuropeptides.Neuropeptides.2012 Jun;46(3):125-31. Epub 2012 Apr 4.
A consensus has emerged that endogenous opioid peptides and their receptors play an important role in the psychoactive properties of nicotine. Although behavioral studies have shown that β-endorphin contributes to the rewarding and emotional effects of nicotine, whether the drug alters the function
PMID 22483037

Japanese Journal

ラット脳の線条体において,ペントバルビタールは一酸化窒素の放出を減少させるが,ケタミンはコリン作動性神経制御と無関係に一酸化窒素の放出を増大させる

KIMURA KUROIWA Kaori,ADACHI Yushi U.,MIMURO Soichiro,KAWAMATA Mikito,SATO Shigehito,MATSUDA Naoyuki
Experimental animals 61(2), 165-170, 2012-04-01
… Neostigmine (1 and 10 μM) and mecamylamine (100 μM) were added to the perfusate. … Mecamylamine and calcium-free perfusion had no effect on baseline NOx concentrations and Ket-induced NOx increases. …
NAID 10030555974

Critical roles of mecamylamine-sensitive mushroom body neurons in insect olfactory learning

Watanabe Hidehiro,Matsumoto Chihiro Sato,Nishino Hiroshi,Mizunami Makoto
Neurobiology of Learning and Memory 95(1), 1-13, 2011-01
… In cockroaches, a type of nicotinic ACh receptor specifically antagonized by mecamylamine (MEC) has been characterized. …
NAID 120002834739

Related Pictures

★リンクテーブル★

リンク元	「ニコチン受容体」「メカミラミン」

「ニコチン受容体」

Mecamylamine
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
ATC code	C02BB01
PubChem	CID 4032
IUPHAR ligand	3990
DrugBank	DB00657
ChemSpider	5036243
UNII	6EE945D3OK
ChEMBL	CHEMBL1398031
Chemical data
Formula	C11H21N
Mol. mass	167.291 g/mol
	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 ; Key:IMYZQPCYWPFTAG-IQJOONFLSA-N ;
(what is this?) (verify)

　　[★]

英: nicotinic receptor
同: ニコチン性受容体、ニコチン性アセチルコリン受容体
関: アセチルコリン受容体、アドレナリン受容体

イオンチャネル型受容体
リガンドの結合により開口して、Na⁺をはじめとする陽イオンを透過させる
fast EPSPを発生する

神経筋接合部の運動終板に存在するニコチン性受容体：N_M受容体
神経筋接合部では、4種類5個のサブユニットからなる→五量体

α₁, α₁, β₁, γ, δ ← 胎児

α₁, α₁, β₁, ε, δ ← 成人

自律神経節、副腎髄質に存在するニコチン性受容体：N_N受容体

GOO. 155

受容体		サブユニット	局在	透過するイオン	作動薬	阻害薬
N_M受容体	胎児	(α₁)₂, β₁, γ, δ	骨格筋の神経筋接合部	Na⁺, K⁺	アセチルコリンニコチンスキサメトニウムデカメトニウム	ベクロニウムパンクロニウムアトラクリニウム d-ツボクラリン
N_M受容体	成人	(α₁)₂, β₁, ε, δ	骨格筋の神経筋接合部	Na⁺, K⁺	アセチルコリンニコチンスキサメトニウムデカメトニウム	ベクロニウムパンクロニウムアトラクリニウム d-ツボクラリン
N_N受容体		(α₃)₂, (β₄)₃	自律神経節副腎髄質	Na⁺, K⁺	アセチルコリンニコチン epibatidine dimethylphenylpiperazinium	triethaphan mecamylamine
CNS		(α₄)₂, (β₄)₃	postjunctional prejunctional	Na⁺, K⁺	cytisine, epibatidine anatoxin A	mecamylamine dihydro-β-erythrodine erysodine lophotoxin
CNS		(α₇)₅	postsynaptic presynaptic	Ca²⁺	anatoxin A	methyllycaconitine α-bungarotoxin α-conotoxin IMI

「メカミラミン」

　　[★]

英: mecamylamine、
同: メカミン
化: 塩酸メカミラミン mecamylamine hydrochloride、塩酸メカミン mecamine hydrochloride
商: INVERSINE

[pmid19874251-1] 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.

[pmid12080428-4] 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.

[pmid19040552-5] 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.

[pmid17016705-6] 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.

[pmid11303054-10] 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.

[Stone-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.

[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.

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mecamylamine