Benzylidene ketal derivatives as M2 muscarinic receptor antagonists

C D Boyle; S Chackalamannil; L Y Chen; S Dugar; P Pushpavanam; W Billard; H Binch 3rd; G Crosby; M Cohen-Williams; V L Coffin; R A Duffy; V Ruperto; J E Lachowicz

doi:10.1016/s0960-894x(00)00553-9

Benzylidene ketal derivatives as M2 muscarinic receptor antagonists

Bioorg Med Chem Lett. 2000 Dec 18;10(24):2727-30. doi: 10.1016/s0960-894x(00)00553-9.

Authors

C D Boyle¹, S Chackalamannil, L Y Chen, S Dugar, P Pushpavanam, W Billard, H Binch 3rd, G Crosby, M Cohen-Williams, V L Coffin, R A Duffy, V Ruperto, J E Lachowicz

Affiliation

¹ Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. [email protected]

PMID: 11133078
DOI: 10.1016/s0960-894x(00)00553-9

Abstract

Benzylidene ketal derivatives were investigated as selective M2 receptor antagonists for the treatment of Alzheimer's disease. Compound 10 was discovered to have subnanomolar M2 receptor affinity and 100-fold selectivity against other muscarinic receptors. Also, 10 demonstrated in vivo efficacy in rodent models of muscarinic activity and cognition.

MeSH terms

Acetylcholine / metabolism
Alzheimer Disease / drug therapy
Animals
Benzylidene Compounds / chemical synthesis
Benzylidene Compounds / metabolism*
Benzylidene Compounds / pharmacokinetics*
Brain / metabolism
Cholinergic Agonists / chemical synthesis
Cholinergic Agonists / metabolism
Cholinergic Agonists / pharmacokinetics
Cognition / drug effects
Drug Stability
Humans
Memory / drug effects
Muscarinic Antagonists / chemical synthesis
Muscarinic Antagonists / metabolism
Muscarinic Antagonists / pharmacokinetics
Protein Binding
Rats
Receptor, Muscarinic M2
Receptors, Muscarinic / metabolism*
Structure-Activity Relationship

Substances

Benzylidene Compounds
Cholinergic Agonists
Muscarinic Antagonists
Receptor, Muscarinic M2
Receptors, Muscarinic
Acetylcholine