THE RELATIONSHIP BETWEEN CHEMICAL STRUCTURE AND PHARMACOLOGICAL ACTIVITY OF FORTY-THREE NEW SYNTHETIC LOCAL ANESTHETICS

¹ From the Laboratory of Pharmacology, Yale University School of Medicine, New Haven, Connecticut

Forty-three compounds were studied for their local anesthetic properties, toxicity and relationship between chemical structure and pharmacological action. They consist of (A) alkamine esters of diphenylacetic acid, diphenylpropionic acid, benzilic acid and closely allied derivatives; (B) alkamine esters of phenyl alkyl and phenyl alkylene substituted acetic acid; (C) symmetrical alkamine esters of diphenylsuccinic acid; (D) para alkyl and alkamine carboxylates of alkamine benzyl ethers and diethyl benzylamine. All the groups contain highly active members.

(1) All members of group A are active. In general, increasing the length of the ester or alkamine groups increases toxicity and anesthetic potency, but there are several notable exceptions.

(2) Phenyl alkylene acetates are inactive if the alkylene group contains only two carbon atoms, but activity appears with a three carbon chain. Phenyl butyl acetates are as active as diphenyl acetates.

(3) Alkamine esters of diphenylsuccinic acid are characterized by relatively high thresholds of anesthetic activity but exceedingly long durations of action.

(4) Diethylaminoethylbenzyl ether has weak local anesthetic activity. Para substitution of ethyl and butyl carboxylate progressively potentiates anesthetic activity and decreases toxicity. Activity is lost if the p-ethyl carboxylate is converted to the p-diethylaminoethyl carboxylate and is only regained by increasing the length of the ester or alkamine chain. Lengthening the ether from ethyl to propyl diminishes activity whereas increasing the alkamine portion of the ether chain from diethyl to dibutyl enhances potency. Para alkamine carboxylates of diethylbenzylamine are active only after the carboxylate has been increased in molecular weight to the dibutylaminopropyl ester.