Saunders_1990_J.Med.Chem_33_1128

Reference

Title : Novel quinuclidine-based ligands for the muscarinic cholinergic receptor - Saunders_1990_J.Med.Chem_33_1128
Author(s) : Saunders J , Cassidy M , Freedman SB , Harley EA , Iversen LL , Kneen C , MacLeod AM , Merchant KJ , Snow RJ , Baker R
Ref : Journal of Medicinal Chemistry , 33 :1128 , 1990
Abstract :

Recent clinical studies on Alzheimer's patients have implied that only agents displaying high efficacy at the cortical muscarinic receptor have yielded encouraging results. This paper describes the design, synthesis, and biochemical characterization of novel quinuclidine-based muscarinic agonists which can readily penetrate into the central nervous system and which are capable of displaying high efficacy at cortical sites. With use of a biochemical assay capable of measuring receptor affinity and predicting cortical efficacy, it has been discovered that an oxadiazole ring and related heterocycles can function as bioisosteric replacements for the ester moiety found in several known muscarinic ligands. Within this series there exist compounds which span the efficacy range from high-efficacy agonist through partial agonists to antagonists with affinity comparable or superior to that of classical quaternary ammonium ligands. Consistent with recent molecular biology studies, structure-activity trends are interpreted in terms of separate binding sites for agonists and antagonists with H-bonding interactions characterizing agonist behavior and lipophilic binding characterizing antagonist behavior. Thus the aminooxadiazole moiety has structural features which are optimized for an agonist profile.

PubMedSearch : Saunders_1990_J.Med.Chem_33_1128
PubMedID: 2319559

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Citations formats

Saunders J, Cassidy M, Freedman SB, Harley EA, Iversen LL, Kneen C, MacLeod AM, Merchant KJ, Snow RJ, Baker R (1990)
Novel quinuclidine-based ligands for the muscarinic cholinergic receptor
Journal of Medicinal Chemistry 33 :1128

Saunders J, Cassidy M, Freedman SB, Harley EA, Iversen LL, Kneen C, MacLeod AM, Merchant KJ, Snow RJ, Baker R (1990)
Journal of Medicinal Chemistry 33 :1128