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 α3β4nicotinic 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.
A large SAR study of mecamylamine and its analogs was reported by a group from Merck in 1962.[14] Another, more recent SAR study was undertaken by Suchocki et al.[15]
A comprehensive review of the pharmacology of mecamylamine was published in 2001.[16]
Toxicology
The LD50 for the HCl salt[17] in mice: 21 mg/kg (i.v.); 37 mg/kg (i.p.); 96 mg/kg (p.o.).[18]
History
Mecamylamine was brought to market by Merck & Co. in the 1950s; in 1996 Merck sold the asset to Layton Bioscience.[19] In 2002, Targacept acquired it from Layton, intending to repurpose it for CNS conditions.[20] Targacept voluntarily withdrew mecamylamine from the market in 2009[21] for reasons not related to safety or efficacy.[22] Manchester Pharmaceuticals brought the drug back to market in 2013.[23]Retrophin acquired Manchester in 2014[24] and after Martin Shkreli was forced out of Retrophin, in 2014 his new company, Turing Pharmaceuticals, acquired the rights to mecamylamine from Retrophin.[25]
^"Mecamylamine". drugs.com. Retrieved May 15, 2015.
^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): 2709–2721. doi:10.1517/14656560903329102. PMID 19874251. S2CID 25690407.
^"Drugs@FDA: FDA Approved Drug Products". www.accessdata.fda.gov. Retrieved 2017-10-16.
^Schanker LS, Shore PA, Brodie BB, Hogben CA (August 1957). "Absorption of drugs from the stomach. I. The rat". The Journal of Pharmacology and Experimental Therapeutics. 120 (4): 528–539. PMID 13476377.
^Soine TO (1966). Wilson CO, Gisvold O, Doerge RF (eds.). Textbook of Organic Medicinal and Pharmaceutical Chemistry (5th ed.). Philadelphia: Lippincott. pp. 468–546.
^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.
^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. PMC6494058. 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. 189 (3): 395–401. doi:10.1007/s00213-006-0568-z. PMID 17016705. S2CID 6395092.
^Carroll J (8 November 2011). "Key AZ/Targacept depression drug flunks first Phase III test". Fiercebiotech.com. Retrieved 2011-11-09.
^Hirschler B (8 November 2011). "AstraZeneca, Targacept drug fails depression test". Reuters.
^"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". The Journal of Pharmacology and Experimental Therapeutics. 297 (2): 646–656. PMID 11303054.
^Stone CA, Torchiana ML, Meckelnberg KL, Stavorski J, Sletzinger M, Stein GA, et al. (July 1962). "Chemistry and Structure-Activity Relationships of Mecamylamine and Derivatives". Journal of Medicinal and Pharmaceutical Chemistry. 91 (4): 665–690. doi:10.1021/jm01239a001. PMID 14061006.
^Suchocki JA, May EL, Martin TJ, George C, Martin BR (March 1991). "Synthesis of 2-exo- and 2-endo-mecamylamine analogues. Structure-activity relationships for nicotinic antagonism in the central nervous system". Journal of Medicinal Chemistry. 34 (3): 1003–1010. doi:10.1021/jm00107a019. PMID 2002445.
^Young JM, Shytle RD, Sanberg PR, George TP (April 2001). "Mecamylamine: new therapeutic uses and toxicity/risk profile". Clinical Therapeutics. 23 (4): 532–565. doi:10.1016/s0149-2918(01)80059-x. PMID 11354389.
^In view of the time period when these data were generated, they presumably refer to the HCl salt of the racemic drug
^Spinks A, Young EH, Farrington JA, Dunlop D (December 1958). "The pharmacological actions of pempidine and its ethyl homologue". British Journal of Pharmacology and Chemotherapy. 13 (4): 501–520. doi:10.1111/j.1476-5381.1958.tb00246.x. PMC1481871. PMID 13618559.
^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.
^"Press release: Targacept, Inc. Acquires Marketed Drug To Expand Its CNS Portfolio | Evaluate". Targacept via Evaluate. August 27, 2002.
^"Notification letter from Targacept" (PDF). FDA. June 4, 2009.
^"Determination That INVERSINE (Mecamylamine Hydrochloride) Tablet and Six Other Drug Products Were Not Withdrawn From Sale for Reasons of Safety or Effectiveness". Federal Register. 28 July 2011.
^"Press release: Manchester Announces FDA Approval of Vecamyl". Manchester Pharamceuticals via Evaluate. May 1, 2013.
^Fidler B (13 February 2014). "Retrophin Shares Boom Following Manchester Pharma Buyout". Xconomy.
^Fidler B (10 August 2015). "Shkreli Leads $90M Round for New Startup, Turing Pharma | Xconomy". Xconomy.
August 18, 2023
mecamylamine, mecamylamine, hydrochloride, usan, brand, names, inversine, vecamyl, selective, competitive, antagonist, nicotinic, acetylcholine, receptors, nachrs, that, introduced, 1950s, antihypertensive, drug, united, states, voluntarily, withdrawn, from, m. 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 MecamylamineClinical dataTrade namesInversine VecamylAHFS Drugs comConsumer Drug InformationRoutes ofadministrationOralATC codeC02BB01 WHO Legal statusLegal statusIn general Prescription only Pharmacokinetic dataProtein binding40 IdentifiersIUPAC name 1S 2R 4R N 2 3 3 Tetramethylbicyclo 2 2 1 heptan 2 amineCAS Number6147 18 8 YPubChem CID4032IUPHAR BPS3990DrugBankDB00657 YChemSpider5036243 YUNII6EE945D3OKChEMBLChEMBL1398031 NCompTox Dashboard EPA DTXSID0023240ECHA InfoCard100 000 433Chemical and physical dataFormulaC 11H 21NMolar mass167 296 g mol 13D model JSmol Interactive imageSMILES N C 2 C H 1CC C H C1 C2 C C C CInChI 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 YKey IMYZQPCYWPFTAG IQJOONFLSA N Y N Y what is this verify Chemically mecamylamine is a secondary aliphatic amine with a pKaH of 11 2 5 Contents 1 Pharmacology and clinical applications 2 Toxicology 3 History 4 See also 5 ReferencesPharmacology and clinical applications EditMecamylamine 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 a3b4 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 S Mecamylamine dissociates more slowly from a4b2 and a3b4 receptors than does the R enantiomer 13 A large SAR study of mecamylamine and its analogs was reported by a group from Merck in 1962 14 Another more recent SAR study was undertaken by Suchocki et al 15 A comprehensive review of the pharmacology of mecamylamine was published in 2001 16 Toxicology EditThe LD50 for the HCl salt 17 in mice 21 mg kg i v 37 mg kg i p 96 mg kg p o 18 History EditMecamylamine was brought to market by Merck amp Co in the 1950s in 1996 Merck sold the asset to Layton Bioscience 19 In 2002 Targacept acquired it from Layton intending to repurpose it for CNS conditions 20 Targacept voluntarily withdrew mecamylamine from the market in 2009 21 for reasons not related to safety or efficacy 22 Manchester Pharmaceuticals brought the drug back to market in 2013 23 Retrophin acquired Manchester in 2014 24 and after Martin Shkreli was forced out of Retrophin in 2014 his new company Turing Pharmaceuticals acquired the rights to mecamylamine from Retrophin 25 See also EditBupropion ScopolamineReferences Edit Mecamylamine drugs com Retrieved May 15 2015 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 2721 doi 10 1517 14656560903329102 PMID 19874251 S2CID 25690407 Drug Profile Mecamylamine Targacept AdisInsight Springer Nature Switzerland AG Drugs FDA FDA Approved Drug Products www accessdata fda gov Retrieved 2017 10 16 Schanker LS Shore PA Brodie BB Hogben CA August 1957 Absorption of drugs from the stomach I The rat The Journal of Pharmacology and Experimental Therapeutics 120 4 528 539 PMID 13476377 Soine TO 1966 Wilson CO Gisvold O Doerge RF eds Textbook of Organic Medicinal and Pharmaceutical Chemistry 5th ed Philadelphia Lippincott pp 468 546 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 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 amp Therapeutics 14 4 266 277 doi 10 1111 j 1755 5949 2008 00054 x PMC 6494058 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 189 3 395 401 doi 10 1007 s00213 006 0568 z PMID 17016705 S2CID 6395092 Carroll J 8 November 2011 Key AZ Targacept depression drug flunks first Phase III test Fiercebiotech com Retrieved 2011 11 09 Hirschler B 8 November 2011 AstraZeneca Targacept drug fails depression test Reuters 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 The Journal of Pharmacology and Experimental Therapeutics 297 2 646 656 PMID 11303054 Stone CA Torchiana ML Meckelnberg KL Stavorski J Sletzinger M Stein GA et al July 1962 Chemistry and Structure Activity Relationships of Mecamylamine and Derivatives Journal of Medicinal and Pharmaceutical Chemistry 91 4 665 690 doi 10 1021 jm01239a001 PMID 14061006 Suchocki JA May EL Martin TJ George C Martin BR March 1991 Synthesis of 2 exo and 2 endo mecamylamine analogues Structure activity relationships for nicotinic antagonism in the central nervous system Journal of Medicinal Chemistry 34 3 1003 1010 doi 10 1021 jm00107a019 PMID 2002445 Young JM Shytle RD Sanberg PR George TP April 2001 Mecamylamine new therapeutic uses and toxicity risk profile Clinical Therapeutics 23 4 532 565 doi 10 1016 s0149 2918 01 80059 x PMID 11354389 In view of the time period when these data were generated they presumably refer to the HCl salt of the racemic drug Spinks A Young EH Farrington JA Dunlop D December 1958 The pharmacological actions of pempidine and its ethyl homologue British Journal of Pharmacology and Chemotherapy 13 4 501 520 doi 10 1111 j 1476 5381 1958 tb00246 x PMC 1481871 PMID 13618559 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 Press release Targacept Inc Acquires Marketed Drug To Expand Its CNS Portfolio Evaluate Targacept via Evaluate August 27 2002 Notification letter from Targacept PDF FDA June 4 2009 Determination That INVERSINE Mecamylamine Hydrochloride Tablet and Six Other Drug Products Were Not Withdrawn From Sale for Reasons of Safety or Effectiveness Federal Register 28 July 2011 Press release Manchester Announces FDA Approval of Vecamyl Manchester Pharamceuticals via Evaluate May 1 2013 Fidler B 13 February 2014 Retrophin Shares Boom Following Manchester Pharma Buyout Xconomy Fidler B 10 August 2015 Shkreli Leads 90M Round for New Startup Turing Pharma Xconomy Xconomy Retrieved from https en wikipedia org w index php title Mecamylamine amp oldid 1170676345, wikipedia, wiki, book, books, library,
