Local anaesthetic effects and toxicity of seven new diethanolamine and morpholine derivatives of fomocaine. Testing in rats compared with procaine and tetracaine.
Fomocaine (CAS 56583-43-8) is a local anaesthetic (LA) with long lasting surface effect and low toxicity. Nevertheless, it is not optimal yet. Therefore, 7 newly synthesised derivatives, 4 diethanolamines (OE 6000, OE 7000, OE 8000, OE 9000) and 3 morpholines (OE 500, OE 1000, OE 5000) were compared with procaine-HCl (CAS 51-05-8) and tetracaine-HCl (CAS 136-47-0) in rats. Based on standard methods for the testing of LA effects and using two methods for characterising side effects and toxicity of LA (paresis of the N. ischiadicus, LD50) it can be concluded that: a) The very good surface anaesthesia caused by especially fomocaine and tetracaine could be stated but concerning conduction anaesthesia procaine is better qualified. b) Concerning conduction anaesthesia, diethanolamine derivatives are more potent compared to morpholine derivatives. c) Surface anaesthesia shows a different picture: the effect of fomocaine is in between. d) The paresis of the N. ischiadicus as a first sign of toxic side effects indicated that low effect is combined with short paresis. e) Compared to the LD50 of fomocaine, the toxicity of OE 500 and OE 5000 is only one half. On the basis of the experiments with fomocaine derivatives, distinct structure-activity relationships could be demonstrated for fomocaine derivatives concerning a) LA effects and b) toxicity. Altogether OE 9000 could be a promising candidate for systemic use.
Fleck
Christian
C
Institute of Pharmacology and Toxicology, Friedrich Schiller University, Jena, Germany. Christian.Fleck@mti.uni-jena.de
Karge
Elke
E
Loy
Steffi
S
Wennek-Klose
Janett
J
Listing
Monika
M
Oelschläger
Herbert
H
D000287:Administration, Topical; D000765:Anesthesia, Conduction; D000779:Anesthetics, Local / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003315:Cornea / Q000187:drug effects; D004983:Ethanolamines / Q000138:chemical synthesis* / Q000633:toxicity; D008297:Male; D009025:Morpholines / Q000138:chemical synthesis* / Q000633:toxicity; D010243:Paralysis / Q000139:chemically induced; D010647:Phenyl Ethers / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D011343:Procaine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013748:Tetracaine / Q000494:pharmacology
D000779:Anesthetics, Local; D004983:Ethanolamines; D009025:Morpholines; D010647:Phenyl Ethers; D013748:Tetracaine; C100275:fomocain; D011343:Procaine