Tropine benzilate (also known asglipin,BAT orT.B.) is an ester formed betweentropine andbenzilic acid.[1] Like its structural relatives such as atropine and scopolamine, tropine benzilate is considered amuscarinic antagonist, meaning it binds to and blocksmuscarinic acetylcholine receptors in the nervous system and various tissues.
The substance was first described in 1936 and was shown to relaxsmooth muscle and block signals from thevagus nerve.[2] It was also later shown to block stomach acid secretion in dogs.[3]
Another compound with which T.B. shares a striking similarity is calledTropenzile. T.B. sans the tertiary hydroxy group goes by nameTropacine.
Atropine andscopolamine (c.f.PC12047005) are natural alkaloids with a substantially similar structure to BAT, but differ in that they are formed fromtropic acid and notbenzilic acid. Tropic acid has a chiral carbon whereas benzilic acid is achiral. Whereas tropic acid is a natural product, benzilic acid is not known to exist in nature.
Tropine benzilate is less commonly sold as a tertiary amine, but is usually encountered as the quaternary amineFlutropium bromide. {It is worth making the distinction that although BAT can be used to make Flutropium bromide, one encounters the wrong stereochemistry about the bridgehead nitrogen when employing this method of synthesis. It is unknown what effect this would have on the resultant pharmacology. To make it correctly one has to use Norglipin [16444-19-2]. This same compound also finds use in the synthesis ofTrospium chloride.}
Alpha-stereochemistry is used to make BAT which mimicsatropine. Beta-stereochemistry would be more closely expected to mimictropacocaine, although alpha stereochemistry is stronger. Compared to tropacocaine, it is not known if beta-BAT has affinity toward biogenic amine transporters, although this was not documented to have been reported in the literature.
Lednicer teaches that amides are more resistant to metabolic degradation than esters because they are not subject toesterases. However, this was with reference tolocal anesthetics (e.g.lidocaine) andAntiarrhythmics. Although BAT-amide does not appear in the pubchem database, c.f.QNB-amide.[4] endo-8-Methyl-8-azabicyclo[3.2.1]octan-3-amine has instead found use in the synthesis of a compound that is calledSS16.[5] This is made from [3307-39-9].
The ester betweentropine andclofibric acid gave rise to a compound that is calledSM-25.[5] Many more such agents were described in the patent. A more well characterized compound appearing in the literature is calledSM-21 Maleate: [155059-42-0].[8][9][10][11][12][13] Another one is calledPG-9 Fb: [156143-26-9] Maleate salt: [155649-00-6].[14][15][16]
^Hromatka O, Csoklich C, Hofbauer I (November 1952). "Über den Tropin-benzilsäureester".Monatshefte für Chemie und verwandte Teile anderer Wissenschaften.83 (6):1321–1325.doi:10.1007/BF00913835.
^Kreitmair H (1936). "The pharmacological properties of the benzilic acid ester of tropin".Klinische Wochenschrift.15:676–678.doi:10.1007/BF01778785.ISSN0023-2173.
^Utepbergenova RK (1966). "Effect of a new cholinolytic glypine [diphenylglycolic acid tropine ester] on the secretory function of the stomach".Trudy Instituta Eksperimental'noi Meditsiny Akademii Meditsinskikh Nauk SSSR (in Russian).9 (3):28–30.ISSN0515-9261.
^Kiyoshi Taniguchi, et al. JPH09328469 (1997 to Fujisawa Pharmaceutical Co Ltd).
^abAlessandro Bartolini, et al. WO1994001435 (Abiogen Pharma SRL).
^Ghelardini et al (1997) Antinociceptive profile of 3-α-tropanyl-(2-Cl)-acid phenoxybutyrate (SM-21): a novel analgesic with a presynaptic cholinergic mechanism of action. J.Pharmacol.Exp.Ther. 282 430 PMID: 9223584
^Ghelardini et al (2000) Pharmacological identification of SM-21, the novel σ2 antagonist. Pharmacol.Biochem.Behav. 67 659 PMID: 11164098
^Matsumoto and Mack (2001) (±)-SM 21 attenuates the convulsive and locomotor stimulatory effects of cocaine in mice. Eur.J.Pharmacol. 417 R1 PMID: 11301071
^Matsumoto et al (2007) Effects of UMB24 and (+/-)-SM 21, putative σ2-preferring antagonists, on behavioral toxic and stimulant effects of cocaine in mice. PLoS One 86 86 PMID: 17241657
^Ishima and Hashimoto (2012) Potentiation of nerve growth factor-induced neurite outgrowth in PC12 cells by ifenprodil: the role of σ-1 and IP3 receptors. J Diabetes Res 7 e37989 PMID: 22655093
^Ghelardini, C., Galeotti, N., Gualtieri, F., Scapecchi, S., Bartolini, A. (December 1997). "3‐α‐tropanyl 2‐(4‐Cl‐phenoxy)butyrate (SM 21): A Review of the Pharmacological Profile of a Novel Enhancer of Cholinergic Transmission". CNS Drug Reviews. 3 (4): 346–362. doi:10.1111/j.1527-3458.1997.tb00332.x.
^Ghelardini, Carla; Galeotti, Nicoletta; Bartolini, Alessandro; Furukawa, Shoei; Nitta, Atsumi; Manetti, Dina; Gualtieri, Fulvio (1998). "Memory Facilitation and Stimulation of Endogenous Nerve Growth Factor Synthesis by the Acetylcholine Releaser PG-9". The Japanese Journal of Pharmacology. 78 (3): 245–251. doi:10.1254/jjp.78.245.
^Ghelardini C, Galeotti N, Gualtieri F, Marchese V, Bellucci C, Bartolini A. Antinociceptive and antiamnesic properties of the presynaptic cholinergic amplifier PG-9. J Pharmacol Exp Ther. 1998;284(3):806-16. PMID: 9495837.
^Ghelardini, C., Galeotti, N., Romanelli, M. N., Gualtieri, F., Bartolini, A. (March 2000). "Pharmacological Characterization of the Novel ACh Releaser α‐tropanyl 2‐(4‐bromophenyl)propionate (PG‐9)". CNS Drug Reviews. 6 (1): 63–78. doi:10.1111/j.1527-3458.2000.tb00138.x.
^Example 4 inUS 20080027094, Nakai H, Nishiyama T, Nakamura N, Fujita M, "Tropane Compounds and Pharmaceutical Compositions Comprising the Same as an Active Ingredient", published 31 January 2008, assigned to Ono Pharmaceutical Co., Ltd.
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