Chemistry:Sazetidine A

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Short description: Pharmaceutical drug

Sazetidine A
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
FormulaC15H20N2O2
Molar mass260.337 g·mol−1
3D model (JSmol)
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Sazetidine A (AMOP-H-OH & Saz-A) is a drug which acts as a subtype selective partial agonist[1] at α4β2 neural nicotinic acetylcholine receptors, acting as an agonist at (α4)2(β2)3 pentamers, but as an antagonist at (α4)3(β2)2 pentamers.[2][3] It has potent analgesic effects in animal studies comparable to those of epibatidine, but with less toxicity,[4] and also has antidepressant action.[5][2]

Saz-A is based on an 20th century agent called A-85380 that had Ki value of ca. 50 pM for the α4β2 nAChR.

Saz-A was able to attenuate nicotine self-administration in rats & holds promise for a new therapy to aid smoking cessation.[6]

The potential metabolic liability of the acetylenic bond, which may be oxidized to generate a labile, highly reactive oxirene, thereby possibly giving rise to toxicity, discouraged further advancement of Saz-A down the drug discovery pipeline.[7] The cited reference directs to a NNRTI called DPC-963. This has a structure that most strongly resembles efavirenz. It is noteworthy making the observation that the Sonogashira coupling has been used in the synthesis of a range of pharmaceuticals. In any event the alkyne moiety was replaced by a cycopropane along with diminution of the sidechain to 2 carbon atoms to yield a compound called 12a.

Additional attempts at modifying the alkyne moiety into an isoxazole heterocycle resulted in LF-3-88 & LF-3-80.[8][9][10][11]

Finally, replacement of the omega-butanol sidechain in Saz-A with a phenyl gave a compound called VMY-2-95 [1434047-61-6].[12][13][14]

YL-2-203 is another codename that was disclosed as part of the drug discovery effort.[15] However, YL-2-203 did not cause robust decreases in drug and alcohol self-administration in the same way as Saz-A or VMY-2-95 did.

References

  1. ↑ "Divergent functional effects of sazetidine-a and varenicline during nicotine withdrawal". Neuropsychopharmacology 38 (10): 2035–2047. September 2013. doi:10.1038/npp.2013.105. PMID 23624742. 
  2. ↑ 2.0 2.1 "Sazetidine-A, a novel ligand that desensitizes alpha4beta2 nicotinic acetylcholine receptors without activating them". Molecular Pharmacology 70 (4): 1454–1460. October 2006. doi:10.1124/mol.106.027318. PMID 16857741. 
  3. ↑ "Sazetidine-A is a potent and selective agonist at native and recombinant alpha 4 beta 2 nicotinic acetylcholine receptors". Molecular Pharmacology 73 (6): 1838–1843. June 2008. doi:10.1124/mol.108.045104. PMID 18367540. 
  4. ↑ "Analgesic effects of Sazetidine-A, a new nicotinic cholinergic drug". Anesthesiology 109 (3): 512–519. September 2008. doi:10.1097/ALN.0b013e3181834490. PMID 18719450. 
  5. ↑ "Chemistry and pharmacology of nicotinic ligands based on 6-[5-(azetidin-2-ylmethoxy)pyridin-3-ylhex-5-yn-1-ol (AMOP-H-OH) for possible use in depression"]. ChemMedChem 4 (8): 1279–1291. August 2009. doi:10.1002/cmdc.200900079. PMID 19569163. 
  6. ↑ "Sazetidine-A, a Selective α4β2 Nicotinic Receptor Desensitizing Agent and Partial Agonist, Reduces Nicotine Self-Administration in Rats". The Journal of Pharmacology and Experimental Therapeutics 332 (3): 933–939. March 2010. doi:10.1124/jpet.109.162073. PMID 20007754. 
  7. ↑ "Chemistry and Behavioral Studies Identify Chiral Cyclopropanes as Selective α4β2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile". Journal of Medicinal Chemistry 55 (2): 717–724. 26 January 2012. doi:10.1021/jm201157c. PMID 22171543. 
  8. ↑ "Discovery of Isoxazole Analogues of Sazetidine-A as Selective α4β2-Nicotinic Acetylcholine Receptor Partial Agonists for the Treatment of Depression". Journal of Medicinal Chemistry 54 (20): 7280–7288. 27 October 2011. doi:10.1021/jm200855b. PMID 21905669. 
  9. ↑ "Identification of Novel α4β2-Nicotinic Acetylcholine Receptor (nAChR) Agonists Based on an Isoxazole Ether Scaffold that Demonstrate Antidepressant-like Activity". Journal of Medicinal Chemistry 55 (2): 812–823. 26 January 2012. doi:10.1021/jm201301h. PMID 22148173. 
  10. ↑ "Discovery of Highly Potent and Selective α4β2-Nicotinic Acetylcholine Receptor (nAChR) Partial Agonists Containing an Isoxazolylpyridine Ether Scaffold that Demonstrate Antidepressant-like Activity. Part II". Journal of Medicinal Chemistry 55 (22): 9998–10009. 26 November 2012. doi:10.1021/jm301177j. PMID 23092294. 
  11. ↑ "Pharmacokinetics and brain penetration of LF-3-88, (2-[5-[5-(2(S)-azetidinylmethoxyl)-3-pyridyl-3-isoxazolyl]ethanol), a selective α4β2-nAChR partial agonist and promising antidepressant"]. Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences 912: 38–42. January 2013. doi:10.1016/j.jchromb.2012.11.011. PMID 23246847. 
  12. ↑ "Design, synthesis and discovery of picomolar selective α4β2 nicotinic acetylcholine receptor ligands". Journal of Medicinal Chemistry 56 (21): 8404–8421. November 2013. doi:10.1021/jm4008455. PMID 24047231. 
  13. ↑ "Preclinical studies of the potent and selective nicotinic α4β2 receptor ligand VMY-2-95". Molecular Pharmaceutics 12 (2): 393–402. February 2015. doi:10.1021/mp5003569. PMID 25533629. 
  14. ↑ "Protective effects of VMY-2-95 on corticosterone-induced injuries in mice and cellular models". Acta Pharmaceutica Sinica. B 11 (7): 1903–1913. July 2021. doi:10.1016/j.apsb.2021.03.002. PMID 34386327.  Erratum in: Acta Pharm Sin B. 2023 Feb;13(2):899–901. doi:10.1016/j.apsb.2022.11.017. Erratum in: Acta Pharm Sin B. 2023 Aug;13(8):3579–80. doi:10.1016/j.apsb.2023.05.002. PMID 34386327; Template:PMCID.
  15. ↑ "α4β2 Nicotinic receptor desensitizing compounds can decrease self-administration of cocaine and methamphetamine in rats". European Journal of Pharmacology 845: 1–7. February 2019. doi:10.1016/j.ejphar.2018.12.010. PMID 30529197. 



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