Truxillic acid derivatives, neuromuscular blocking agents with very high affinity for the allosteric binding site of muscarinic acetylcholine receptors

Bis-quaternary salts of 3-piperidinopropyl esters of alpha-truxillic acid w ere synthesized in order to study their allosteric action on muscarinic ace tylcholine receptor. Using radioligand binding studies, it has been demonst rated that most of prepared compounds bind with high affinity to the allost eric binding site of M-2 muscarinic receptor subtype (K-d values in the ran ge 1-10 nM). Bulky substitution of the quaternary ammonium center led to ef fective positive modulators of [H-3]N-melhylscopolamine binding to M-2 rece ptors. Due to its high allosteric potency, the structure of phenacyl deriva tive seems to be the most promising candidate for future design of photoaff inity probes or radiolabelled ligands for mapping the allosteric binding si te.