Collect. Czech. Chem. Commun. 1999, 64, 1980-1992

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

Marek Urbanskýa,*, Jan Proškab, Jan Říčnýc and Pavel Drašara

a Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic
b Research Institute for Pharmacy and Biochemistry, Kouřimská 17, 130 60 Prague 3, Czech Republic
c Institute of Physiology, Academy of Sciences of the Czech Republic, Vídeňská 1083, 142 20 Prague 4, Czech Republic


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.

Keywords: Allosteric binding; Cooperativity; Muscarinic receptors; Nicotinic receptors; Truxillic acid; Quaternary ammonium salts; Cyclobutanes.