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 M(1)-M(4) muscarine receptor subtypes revealed that analogues 3a and 5c display a promising 10-fold selectivity for the M(2) receptor as compared to the M(1) receptor.
Department of Organic Chemistry, Ghent University, Krijgslaan 281, Belgium.
Ling-Jie
LJ
Gao
Magali
M
Waelbroeck
Sven
S
Hofman
Dirk
D
Van Haver
Marco
M
Milanesio
Davide
D
Viterbo
Pierre J
PJ
De Clercq
D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells / Q000378:metabolism; D006224:Cricetinae; D005663:Furans; D006801:Humans; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D009281:Naphthalenes; D010880:Piperidines; D011485:Protein Binding; D011976:Receptors, Muscarinic / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D000470:Alkaloids; D005663:Furans; D018727:Muscarinic Antagonists; D009281:Naphthalenes; D010880:Piperidines; D011976:Receptors, Muscarinic; C048172:himbacine