Synthesis and muscarinic M2 subtype antagonistic activity of unnatural ent-himbacine and an enantiomeric pair of (2'S,6'R)-diepihimbacine.
The title three compounds ent-1, 6, and ent-6 were synthesized by coupling the chiral sulfone 4 or ent-4 with the chiral piperidinaldehyde 5 or ent-5, which were readily prepared following the synthetic routes previously established by the novel total synthesis of natural himbacine 1. Their muscarinic M2 subtype binding affinity was evaluated in comparison to that of 1, disclosing that the stereochemistry of both the tricyclic moiety and the piperidine part of 1 plays crucial roles in its potent activity.
Takadoi
Masanori
M
Discovery Research Laboratories, Kyorin Pharmaceutical Company Ltd., 2399-1Nogi, Nogi-machi, Tochigi, Japan. masanori.takadoi@mb2.kyorin-pharm.co.jp
Terashima
Shiro
S
D000470:Alkaloids / Q000138:chemical synthesis* / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects; D005663:Furans; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D009281:Naphthalenes; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000470:Alkaloids; D005663:Furans; D018727:Muscarinic Antagonists; D009281:Naphthalenes; D010880:Piperidines; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; C048172:himbacine