Synthesis and binding affinity studies of muscarinic receptor antagonists related to dehydrohimbacine

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.