SAR Studies on the Potent and Selective Muscarinic Antagonist 2‐Ethylthio‐2,2‐diphenylacetic Acid N,N‐Diethylaminoethyl Ester

Abstract

Molecular modification of the potent and selective muscarinic antagonist 2-ethylthio-2,2-diphenylacetic acid N,N-diethylaminoethyl ester was performed in order to identify M2 selective antagonists able to cross the blood brain barrier and potentially useful in the treatment of Alzheimer's disease. Modifications included substitution or hydrogenation of one of the phenyl rings as well as their incorporation in a tricyclic system. In general the changes introduced were detrimental for both affinity and selectivity. Only a modest M2 selectivity is present in some compounds that, on the other hand, carry a quaternary ammonium group which precludes their penetration into the brain.

Therapeutic Opportunities for Muscarinic Receptors in the Central Nervous System

“…In contrast, S -ET-126 ( 37 ) is functionally an M 1 antagonist in tissues with 8-fold selectivity over M 2 activity and even less M 3 antagonist activity . Extensive molecular modification of 2-ethylthio diphenylacetate 38 did not lead to improved M 2 selectivity in functional tissue assays …”

“…118 Extensive molecular modification of 2-ethylthio diphenylacetate 38 did not lead to improved M 2 selectivity in functional tissue assays. 119 Highest M 2 selectivity was usually found among quaternary derivatives. Binding studies in cloned muscarinic receptor subtypes have not confirm the M 2 subtype selectivity of 38.…”