THE INTERACTION BETWEEN CHOLINESTERASES AND A SERIES OF LOCAL ANESTHETICS

¹ Department of Pharmacology, University of Toronto

The interactions between two homologous series of procaine analogues and cholinesterases were investigated. The local anesthetics were esters of substituted benzoic acids ("Series 0" consisting of Win 2559, 3606, 3459 (Ravocaine), 3706 (Sympocaine), and 5303), and thio esters of substituted benzoic acids ("Series S" consisting of Win 3260, 3800, 5334, and 4510). Procaine and dibucaine served as controls. The preparations of esterase were purified human serum cholinesterase (pseudocholinesterase) and a suspension of guinea pig brain for acetylcholine esterase.

Serum cholinesterase hydrolysed the compounds of Series 0 at about half the rate that it destroyed procaine but hydrolysed the compounds of Series S at an extremely slow rate. Acetylcholine esterase did not hydrolyse any of the compounds investigated.

The enzymatic hydrolysis of the compounds of Series 0 and of procaine was inhibited by dibucaine.

All the local anesthetics were strong inhibitors of the hydrolysis of benzoylcholine by serum cholinesterase. Their inhibiting action occurred instantaneously. Physostigmine, neostigmine, Ro 2-0638, and TEPP inhibited serum cholinesterase only after some delay. Acetylcholine esterase was less inhibited by local anesthetics than serum cholinesterase.

Local anesthetic potency was strongly related to affinity for serum cholinesterase and less so to affinity for acetylcholine esterase. It is suggested that this relationship mirrors to some extent the combination of local anesthetics with cellular receptors capable of combining with acetylcholine. The strong but delayed action of the classical inhibitors is explained in the literature as due to the formation of a fairly stable complex consisting of esterase and a fragment of the inhibitor. It may be concluded that the classical inhibitors should not block very strongly a receptor protein unless this protein has cholinesterase activity. This restriction does not seem to exist for the local anesthetics since the fast inhibition of esterase by these drugs suggests that the intact molecule is responsible for their action.