Vedaclidine
Vedaclidine (INN,[1]: 180 codenamed LY-297,802, NNC 11-1053) is an experimental analgesic drug which acts as a mixed agonist–antagonist at muscarinic acetylcholine receptors, being a potent and selective agonist for the M1 and M4 subtypes, yet an antagonist at the M2, M3 and M5 subtypes.[2][3] It is orally active and an effective analgesic over 3× the potency of morphine, with side effects such as salivation and tremor only occurring at many times the effective analgesic dose.[4][5][6] Human trials showed little potential for development of dependence or abuse,[7] and research is continuing into possible clinical application in the treatment of neuropathic pain and cancer pain relief.[8]
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Other names | (S)-3-[4-(butylthio)-1,2,5-thiadiazol-3-yl]quinuclidine |
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Formula | C13H21N3S2 |
Molar mass | 283.45 g·mol−1 |
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Synthesis
Ex 1: The Knoevenagel condensation between 3-Quinuclidone [3731-38-2] (1) & ethyl cyanoacetate [105-56-6] (2) gives Ethyl (1-azabicyclo[2.2.2]octan-3-ylidine)cyanoacetate, CID:54445383 (3). The catalytic hydrogenation of the olefin group gave Ethyl (1-azabicyclo[2.2.2]octan-3-yl)cyanoacetate [141593-50-2] (4). The reaction with sodium in ethanol, followed by addition of isoamylnitrite [110-46-3] led to (1-Azabicyclo[2.2.2]octan-3-yl)hydroxyiminoacetonitrile, CID:73192825 (5). Halogenation with Disulfur dichloride [10025-67-9] in DMF gave 3-(3-Chloroquinuclidine-3-yl)-4-chloro-1,2,5-thiadiazole, CID:9795252 (6).
Ex 5: Catalytic hydrogenation went on to give 3-Chloro-4-quinuclidin-3-yl-1,2,5-thiadiazole, CID:9942707 (7).
Ex 10: The reaction with sodium hydrogen sulfide in the presence of potassium carbonate, followed by addition of 1-bromobutane completed the synthesis of Vedaclidine (8).
See also
References
- "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names (Rec. INN): List 38" (PDF). World Health Organization. 1997. Retrieved 18 November 2016.
- Shannon HE, Womer DE, Bymaster FP, Calligaro DO, DeLapp NC, Mitch CH, et al. (1997). "In vivo pharmacology of butylthio[2.2.2] (LY297802 / NNC11-1053), an orally acting antinociceptive muscarinic agonist". Life Sciences. 60 (13–14): 969–76. doi:10.1016/s0024-3205(97)00036-2. PMID 9121363.
- Womer DE, Shannon HE (September 2000). "Reversal of pertussis toxin-induced thermal allodynia by muscarinic cholinergic agonists in mice". Neuropharmacology. 39 (12): 2499–504. doi:10.1016/S0028-3908(00)00068-X. PMID 10974334. S2CID 31065787.
- Swedberg MD, Sheardown MJ, Sauerberg P, Olesen PH, Suzdak PD, Hansen KT, et al. (May 1997). "Butylthio[2.2.2] (NNC 11-1053/LY297802): an orally active muscarinic agonist analgesic". The Journal of Pharmacology and Experimental Therapeutics. 281 (2): 876–83. PMID 9152397.
- Shannon HE, Sheardown MJ, Bymaster FP, Calligaro DO, Delapp NW, Gidda J, et al. (May 1997). "Pharmacology of butylthio[2.2.2] (LY297802/NNC11-1053): a novel analgesic with mixed muscarinic receptor agonist and antagonist activity". The Journal of Pharmacology and Experimental Therapeutics. 281 (2): 884–94. PMID 9152398.
- Shannon HE, Jones CK, Li DL, Peters SC, Simmons RM, Iyengar S (September 2001). "Antihyperalgesic effects of the muscarinic receptor ligand vedaclidine in models involving central sensitization in rats". Pain. 93 (3): 221–7. doi:10.1016/S0304-3959(01)00319-0. PMID 11514081. S2CID 10256837.
- Petry NM, Bickel WK, Huddleston J, Tzanis E, Badger GJ (April 1998). "A comparison of subjective, psychomotor and physiological effects of a novel muscarinic analgesic, LY297802 tartrate, and oral morphine in occasional drug users". Drug and Alcohol Dependence. 50 (2): 129–36. doi:10.1016/S0376-8716(98)00026-X. PMID 9649964.
- Tata AM (June 2008). "Muscarinic acetylcholine receptors: new potential therapeutic targets in antinociception and in cancer therapy". Recent Patents on CNS Drug Discovery. 3 (2): 94–103. doi:10.2174/157488908784534621. PMID 18537768.
- Olesen, P., Sauerberg, P., Treppendahl, S., Larsson, O., Sheardown, M., Suzdak, P., Mitch, C., Ward, J., Bymaster, F., Shannon, H., Swedberg, M. (January 1996). "3-(3-Alkylthio-1,2,5-thiadiazol-4-yl)-1-azabicycles. Structure—activity relationships for antinociception mediated by central muscarinic receptors". European Journal of Medicinal Chemistry. 31 (3): 221–230. doi:10.1016/0223-5234(96)89138-0. ISSN 0223-5234.
- Per Sauerberg & Preben H. Olesen, WO 1992003433 (Novo Nordisk AS).
- Franklin Porter Bymaster, et al. WO 1995005379 (Novo Nordisk AS).