Relationships between chemical structure and inhibition of human placental choline acetyltransferase by keto analogs of acetylcholine.

Seven keto analogs of acetylcholine were synthesized and evaluated as inhibitors of human placental choline placental choline acetyltransferase. Their potencies for inhibition of horse serum cholinesterase and stimulation of cholinergic receptors in the longitudinal ileal muscle of the guinea pig were investigated. The most potent and selective inhibitor of choline acetyltransferase was (2-benzoylethyl)trimethylammonium chloride with an I50 of 3 X 10(-6) M. It exhibited considerably low activities at muscarinic and nicotinic receptors and cholinesterases. Its high potency for inhibiting choline acetyltransferase was atrributed to: (a) its cationic terminal, a site for an electron acceptor interaction; (b) an aryl moiety for hydrophobic and electron donor contributions; and (c) a positive charge on the carbon atom adjacent to the benzene ring due to the presence of the carbonyl group, which interacts with the nucleophilic residue on the enzyme.