N-Substituted derivatives of 4-piperidinyl benzilate: Affinities for brain muscarinic acetylcholine receptors

Abstract

N-Substituted derivatives of 4- piperidinyl benzilate were synthesized and their affinities for central muscarinic cholinergic receptors determined using an in vitro radioligand binding assay. 4- Piperidinyl benzilate exhibited a K i value of 2.0nM. N-Substitution with a methyl or an ethyl group increased the affinity to 0.2nM, whereas substitution with a n-propyl or isopropyl group decreased the binding affinity over 100 fold. Compounds with aralkyl substitutions at the nitrogen atom of piperidinyl benzilate were also synthesized and evaluated. The K i values (nM) obtained for these compounds were: benzyl, 0.2; p-nitrobenzyl, 13.0; p- flourobenzyl, 3.0; phenethyl, 8.0; p- nitrophenethyl, 15.0. These data suggest that a binding region near the piperidinyl nitrogen may tolerate bulky aromatic substitutions (e.g., benzyl or phenethyl) as well or better than straight chain or branched alkyl substitutions (e.g., n-propyl or isopropyl).