Sazetidine A

Sazetidine A
Identifiers
  • 6-[5-[(2S)-2-Azetidinylmethoxy]-3-pyridinyl]-5-hexyn-1-ol
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC15H20N2O2
Molar mass260.337 g·mol−1
3D model (JSmol)
  • OCCCCC#Cc1cc(cnc1)OCC2CCN2
  • InChI=1S/C15H20N2O2/c18-8-4-2-1-3-5-13-9-15(11-16-10-13)19-12-14-6-7-17-14/h9-11,14,17-18H,1-2,4,6-8,12H2/t14-/m0/s1
  • Key:WONBUILDJNKYCB-AWEZNQCLSA-N
  (verify)

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. ^ Turner JR, Wilkinson DS, Poole RL, Gould TJ, Carlson GC, Blendy JA (September 2013). "Divergent functional effects of sazetidine-a and varenicline during nicotine withdrawal". Neuropsychopharmacology. 38 (10): 2035–2047. doi:10.1038/npp.2013.105. PMC 3746688. PMID 23624742.
  2. ^ a b Xiao Y, Fan H, Musachio JL, Wei ZL, Chellappan SK, Kozikowski AP, et al. (October 2006). "Sazetidine-A, a novel ligand that desensitizes alpha4beta2 nicotinic acetylcholine receptors without activating them". Molecular Pharmacology. 70 (4): 1454–1460. doi:10.1124/mol.106.027318. PMID 16857741. S2CID 6599272.
  3. ^ Zwart R, Carbone AL, Moroni M, Bermudez I, Mogg AJ, Folly EA, et al. (June 2008). "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. doi:10.1124/mol.108.045104. PMID 18367540. S2CID 24632914.
  4. ^ Cucchiaro G, Xiao Y, Gonzalez-Sulser A, Kellar KJ (September 2008). "Analgesic effects of Sazetidine-A, a new nicotinic cholinergic drug". Anesthesiology. 109 (3): 512–519. doi:10.1097/ALN.0b013e3181834490. PMID 18719450. S2CID 22185882.
  5. ^ Kozikowski AP, Eaton JB, Bajjuri KM, Chellappan SK, Chen Y, Karadi S, et al. (August 2009). "Chemistry and pharmacology of nicotinic ligands based on 6-[5-(azetidin-2-ylmethoxy)pyridin-3-yl]hex-5-yn-1-ol (AMOP-H-OH) for possible use in depression". ChemMedChem. 4 (8): 1279–1291. doi:10.1002/cmdc.200900079. PMC 2955514. PMID 19569163.
  6. ^ Levin ED, Rezvani AH, Xiao Y, Slade S, Cauley M, Wells C, et al. (March 2010). "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. doi:10.1124/jpet.109.162073. PMID 20007754.
  7. ^ Zhang H, Tückmantel W, Eaton JB, Yuen P, Yu LF, Bajjuri KM, et al. (26 January 2012). "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. doi:10.1021/jm201157c. PMC 3292870. PMID 22171543.
  8. ^ Liu J, Yu LF, Eaton JB, Caldarone B, Cavino K, Ruiz C, et al. (27 October 2011). "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. doi:10.1021/jm200855b. PMC 3197876. PMID 21905669.
  9. ^ Yu LF, Tückmantel W, Eaton JB, Caldarone B, Fedolak A, Hanania T, et al. (26 January 2012). "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. doi:10.1021/jm201301h. PMC 3272775. PMID 22148173.
  10. ^ Yu LF, Eaton JB, Fedolak A, Zhang HK, Hanania T, Brunner D, et al. (26 November 2012). "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. doi:10.1021/jm301177j. PMC 3532055. PMID 23092294.
  11. ^ Yuan Y, Yu LF, Qiu X, Kozikowski AP, Van Breemen RB (January 2013). "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. doi:10.1016/j.jchromb.2012.11.011. PMC 3538945. PMID 23246847.
  12. ^ Yenugonda VM, Xiao Y, Levin ED, Rezvani AH, Tran T, Al-Muhtasib N, et al. (November 2013). "Design, synthesis and discovery of picomolar selective α4β2 nicotinic acetylcholine receptor ligands". Journal of Medicinal Chemistry. 56 (21): 8404–8421. doi:10.1021/jm4008455. PMID 24047231.
  13. ^ Kong H, Song JK, Yenugonda VM, Zhang L, Shuo T, Cheema AK, et al. (February 2015). "Preclinical studies of the potent and selective nicotinic α4β2 receptor ligand VMY-2-95". Molecular Pharmaceutics. 12 (2): 393–402. doi:10.1021/mp5003569. PMC 4319692. PMID 25533629.
  14. ^ Yu Z, Kong D, Liang Y, Zhao X, Du G (July 2021). "Protective effects of VMY-2-95 on corticosterone-induced injuries in mice and cellular models". Acta Pharmaceutica Sinica. B. 11 (7): 1903–1913. doi:10.1016/j.apsb.2021.03.002. PMC 8343195. 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; PMC 8343195.
  15. ^ Levin ED, Rezvani AH, Wells C, Slade S, Yenugonda VM, Liu Y, et al. (February 2019). "α4β2 Nicotinic receptor desensitizing compounds can decrease self-administration of cocaine and methamphetamine in rats". European Journal of Pharmacology. 845: 1–7. doi:10.1016/j.ejphar.2018.12.010. PMC 6353686. PMID 30529197.
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