Truxillic Acid Derivatives, Neuromuscular Blocking Agents with Very High Affinity for the Allosteric Binding Site of Muscarinic Acetylcholine Receptors

Abstract

Bis-quaternary salts of 3-piperidinopropyl esters of α-truxillic acid were synthesized in order to study their allosteric action on muscarinic acetylcholine receptor. Using radioligand binding studies, it has been demonstrated that most of prepared compounds bind with high affinity to the allosteric binding site of M2 muscarinic receptor subtype (Kd values in the range 1-10 nM). Bulky substitution of the quaternary ammonium center led to effective positive modulators of [3H]N-methylscopolamine binding to M2 receptors. Due to its high allosteric potency, the structure of phenacyl derivative seems to be the most promising candidate for future design of photoaffinity probes or radiolabelled ligands for mapping the allosteric binding site.