Tropine benzilate

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Tropine benzilate
Tropine benzilate.svg
Clinical data
Other namesTropine benzylate, BAT, TB, #9447, BETE, BTE, Glykin, Glypin
Identifiers
  • endo-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 2-hydroxy-2,2-diphenylacetate
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.125.953 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C22H25NO3
Molar mass 351.446 g·mol−1
3D model (JSmol)
  • CN1[C@@H]2CC[C@H]1CC(C2)OC(=O)C(C3=CC=CC=C3)(C4=CC=CC=C4)O
  • InChI=1S/C22H25NO3/c1-23-18-12-13-19(23)15-20(14-18)26-21(24)22(25,16-8-4-2-5-9-16)17-10-6-3-7-11-17/h2-11,18-20,25H,12-15H2,1H3/t18-,19+,20?
  • Key:XXVZGWNHSCGMCT-YOFSQIOKSA-N

Tropine benzilate also known as glipin is an ester formed between tropine and benzilic acid. [1] Like its structural relatives such as atropine and scopolamine, tropine benzilate is considered a muscarinic antagonist, meaning it binds to and blocks muscarinic acetylcholine receptors in the nervous system and various tissues.

Contents

The substance was first described in 1936 and was shown to relax smooth muscle and block signals from the vagus nerve. [2] It was also later shown to block stomach acid secretion in dogs. [3]

It is a chemical deliriant similar to two related substances, namely 3-quinuclidinyl benzilate (aka QNB or BZ) and CS-27349. Atropine and scopolamine (c.f. PC12047005) are natural alkaloids with a substantially similar structure to BAT, but differ in that they are formed from tropic acid and not benzilic acid. Tropic acid has a chiral carbon whereas benzilic acid is achiral.

Tropine benzilate is less commonly sold as a tertiary amine, but is usually encountered as the quaternary amine Flutropium 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.}

Alpha-stereochemistry is used to make BAT which mimics atropine. Beta-stereochemistry would be more closely expected to mimic tropacocaine, although alpha stereochemistry is stronger.

Further reading

Lednicer teaches that amides are more resistant to metabolic degradation than esters because they are not subject to esterases. However, this was with reference to local anesthetics (e.g. lidocaine) and Antiarrhythmics. 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 called SS16. [5] This is made from [3307-39-9] . {While beta-stereochemistry is chemically easier to manufacture, alpha-stereochemistry gives superior pharmacology.}

SM-21 Maleate: [155059-42-0] SM-21.svg
SM-21 Maleate: [155059-42-0]
PG-9 PG-9 (chemical).svg
PG-9

The ester between tropine and clofibric acid gave rise to a compound that is called SM-25. [5] Many more such agents were described in the patent. A more well characterized compound appearing in the literature is called SM-21. [6] [7] [8] [9] [10] [11] Another one is called PG-9 Fb: [156143-26-9] Maleate salt: [155649-00-6]. [12] [13] [14]

Synthesis

Tropine benzilate may be synthesized by reacting tropine with methyl benzilate in a transesterification reaction. [15]

See also

References

  1. ↑ 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.
  2. ↑ Kreitmair H (1936). "The pharmacological properties of the benzilic acid ester of tropin". Klinische Wochenschrift. 15: 676–678. doi:10.1007/BF01778785. ISSN   0023-2173.
  3. ↑ 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. ISSN   0515-9261.
  4. ↑ Kiyoshi Taniguchi, et al. JPH09328469 (1997 to Fujisawa Pharmaceutical Co Ltd).
  5. 1 2 Alessandro Bartolini, et al. WO1994001435 (Abiogen Pharma SRL).
  6. ↑ 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
  7. ↑ Ghelardini et al (2000) Pharmacological identification of SM-21, the novel σ2 antagonist. Pharmacol.Biochem.Behav. 67 659 PMID: 11164098
  8. ↑ Matsumoto and Mack (2001) (±)-SM 21 attenuates the convulsive and locomotor stimulatory effects of cocaine in mice. Eur.J.Pharmacol. 417 R1 PMID: 11301071
  9. ↑ 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
  10. ↑ 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
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ Example 4 in US 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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