SAR studies on the potent and selective muscarinic antagonist 2-ethylthio-2,2-diphenylacetic acid N,N-diethylaminoethyl ester.
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.
Scapecchi
S
S
Dipartimento di Scienze Farmaceutiche, Università di Firenze, Italy.
Angeli
P
P
Dei
S
S
Ghelardini
C
C
Gualtieri
F
F
Marucci
G
G
Paparelli
F
F
Romanelli
M N
MN
Teodori
E
E
D000700:Analgesics / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D013329:Structure-Activity Relationship
D000700:Analgesics; D018727:Muscarinic Antagonists