Synthesis and binding affinity studies of muscarinic receptor antagonists related to dehydrohimbacine
| Autor: | Noël Hosten, Ling-Jie Gao, Gunther Van Cauwenberge, Dirk Van Haver, Pierre J. De Clercq, Magali Waelbroeck |
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| Jazyk: | angličtina |
| Rok vydání: | 2003 |
| Předmět: | |
| Zdroj: | ARKIVOC, Vol 2003, Iss 4, Pp 22-45 (2003) |
| ISSN: | 1551-7012 1551-7004 |
| Popis: | The intramolecular Diels-Alder reaction of bromo-substituted nonatrienoate 24 leads to a mixture of the anti-adducts 25a and 25b, in which the trans-fused lactone 25b, the result of an expected exo-addition, predominates (6.2: 1 stereoselectivity). Further introduction of a 2,6-trans-disubstituted piperidine ring ( 26 and 27) via palladium catalyzed cross-coupling reactions (Stille and Sonogashira) affords intermediates that are easily transformed into dehydrohimbacine derivatives 14a, 14b, 15a, and 15b. Binding affinity studies for the muscarine receptors M-1, M-2, M-3, and M-4 show that 15a possesses a 18-fold selectivity for the M-2 relative to the M-1 receptor, but with concomittant loss in affinity compared to the naturally occurring (+)- himbacine ( 1), a recognized muscarinic receptor antagonist. |
| Databáze: | OpenAIRE |
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