The synthesis and nicotinic binding activity of (±)-epiquinamide and (±)-C(1)-epiepiquinamide

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 17, 2006, Pages 4648-4651

  Kanakubo, Akira ^a   Gray, Diane ^a   Innocent, Neal ^b   Wonnacott, Susan ^b   Gallagher, Timothy ^a  

^a UNIVERSITY OF BRISTOL   (United Kingdom)

^b University of Bath   (United Kingdom)

Author keywords

Epiepiquinamide; Epiquinamide; Nicotinic agonist

Indexed keywords

EPIBATIDINE; EPIEPIQUINAMIDE; EPIQUINAMIDE; NICOTINE; NICOTINIC AGENT; QUINOLIZIDINE DERIVATIVE; TRITIUM; UNCLASSIFIED DRUG;

ARTICLE; BINDING AFFINITY; BRAIN MEMBRANE; CURTIUS REARRANGEMENT; DRUG BINDING; DRUG SYNTHESIS; NONHUMAN; RAT; STATISTICAL SIGNIFICANCE;

ANIMALS; BINDING SITES; ESTERS; MOLECULAR STRUCTURE; NICOTINE; QUINOLIZINES; RATS;

EID: 33746703748     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.05.100     Document Type: Article

References (18)

1. Jensen A.A., Frolund B., Lijefors T., and Krogsgaard-Larsen P. J. Med. Chem. 48 (2005) 4705
2. Coe J.W., Vetelino M.G., Bashore C.G., Wirtz M.C., Brooks P.R., Arnold E.P., Lebel L.A., Fox C.B., Sands S.B., Davis T.I., Schulz D.W., Rollema H., Tingley F.D., and O'Neill B.T. Bioorg. Med. Chem. Lett. 15 (2005) 2974
3. Coe J.W., Brooks P.R., Vetelino M.G., Wirtz M.C., Arnold E.P., Huang J.H., Sands S.B., Davis T.I., Lebel L.A., Fox C.B., Shrikhande A., Heym J.H., Schaeffer E., Rollema H., Lu Y., Mansbach R.S., Chambers L.K., Rovetti C.C., Schulz D.W., Tingley F.D., and O'Neill B.T. J. Med. Chem. 48 (2005) 3474
4. Nicotine:. Benowitz N.L. Ann. Rev. Pharmacol. Toxicol. 36 (1996) 597
5. Epibatidine:. Badio B., and Daly J.W. Mol. Pharmacol. 45 (1994) 563
6. Anatoxin-a:. Wonnacott S., and Gallagher T. Mar. Drugs 4 (2006) 228
7. For an overview of the role of natural products as nicotinic ligands, see:. Daly J.W. Cell. Mol. Neurobiol. 25 (2005) 513
8. Fitch R.W., Garraffo H.M., Spande T.F., Yeh H.J.C., and Daly J.W. J. Nat. Prod. 66 (2003) 1345
9. Fitch R.W., Xiao Y.X., Kellar K.J., and Daly J.W. Proc. Natl. Acad. Sci. U.S.A. 100 (2003) 4909
10. Wijdeven M.A., Botman P.N.M., Wijtmans R., Schoemaker H.E., Rutjes F.P.J.T., and Blaauw R.H. Org. Lett. 7 (2005) 4005
11. Huang P.-Q., Guo Z.-Q., and Ruan Y.-P. Org. Lett. 8 (2006) 1435
12. We focused initially on the synthesis of racemic 1 and 2 because of (i) the absolute configuration of natural 1 is unknown (ii) 2 is novel and was of unknown activity, and (iii) the possibility that biological activity may reside in only one enantiomer of either or both of 1 and 2.
13. Bicyclic ester 5 has also been used as an intermediate for the synthesis of the lupin alkaloid thermopsine, and the relative stereochemistry of 5 was established by X-ray crystallographic analysis:. Gray D., and Gallagher T. Angew. Chem. Int. Ed. 45 (2006) 2419 The synthesis of ester 5 in enantiomerically pure form has now been achieved but in light of the biological data reported here, it has not yet been applied to an asymmetric synthesis of epiquinamide 1
14. For the use of 9-FM to aid isolation and purification of Curtius rearrangement products, see:. Spino C., and Gobdout C. J. Am. Chem. Soc. 125 (2003) 11207
15. 8 Other routes to esters 5 and 9 and related compounds have been reported by others and these are detailed in Ref. 8.
16. 13C NMR data for 1 and 2 are available as Supplementary data.
17. -10 M. However, epiquinamide 1 and C(1)-epiepiquinamide 2 showed no significant level of activity in this assay (see Fig. 1).
18. The effect of amide variants of acetylcholine on activity at nAChR has been studied:. Barlow R.B., Bremner J.B., and Soh K.S. Br. J. Pharmacol. 62 (1978) 39 Replacement of the ester moiety of acetylcholine by an amide, by analogy to epiquinamide, reduces activity on guinea-pig ileum (which corresponds to α3-containing neuronal nAChR) over 1000-fold and on frog rectus (i.e., muscle nAChR) over 50-fold