Synthesis and affinity studies of himbacine derived muscarinic receptor antagonists

A series of himbacine (1)-related analogues has been prepared featuring three different isomeric configurations with respect to the B-ring (a, b and natural c) and three different interconnecting two-carbon unsaturated units [natural (E)-ene, (Z)-ene, and yne]. The study of the binding affinities of the nine resulting compounds, including synthetic (+)-himbacine (3c), towards the M1–M4 muscarine receptor subtypes revealed that analogues 3a and 5c display a promising 10-fold selectivity for the M2 receptor as compared to the M1 receptor. [Copyright &y& Elsevier]