The preparation of novel histrionicotoxin analogues and their activity towards the α4β2 and α7 nicotinic acetylcholine receptors
| Autor: | Michael Sako, John H. Ryan, Simon Saubern, Mary Chebib, James M. MacDonald, Cecily Eldridge, Gracia X. J. Quek |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification Nitrile Stereochemistry Organic Chemistry Biochemistry Aldehyde Cycloaddition Nitrone 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine chemistry Drug Discovery Wittig reaction Binding site IC50 030217 neurology & neurosurgery Tricyclic |
| Zdroj: | Tetrahedron. 74:1245-1252 |
| ISSN: | 0040-4020 |
| Popis: | Four histrionicotoxin analogues were prepared in an efficient manner utilizing a nitrone dipolar cycloaddition reaction as the key step in forming tricyclic intermediate 13. The nitrile in intermediate 13 was reduced with DIBAL to an aldehyde which then underwent Z-selective Wittig reactions to produce intermediates containing the Z-alkene side-chain. Hydrogenation of the Z-alkenes produced saturated histrionicotoxin analogues whereas reduction with SmI2 afforded the unsaturated histrionicotoxin analogues. The histrionicotoxin analogues were shown to be potent non-competitive antagonists of the α4β2 and α7 nAChR's with the most potent analogue 3 displaying IC50's of 0.10 μM and 0.45 μM against the α4β2 and α7 nAChR's, respectively. The unsaturated analogues 15 and 18 displayed Hill slope (nH) of approximately 1 whilst the saturated analogues 16 and 3 had a nH of approximately 0.5, which may indicate that the saturated analogues are binding to more than one binding site. |
| Databáze: | OpenAIRE |
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