In vitro interactions with the Cytochrome P450 system, toxicity, and local anaesthetic effects of Fomocaine Alkylmorpholine derivatives in rats.
Fomocaine (CAS 56583-43-8) is a basic ether-type local anaesthetic used in dermatological practice for surface anaesthesia. For many years, modifications of the fomocaine molecule have been pursued, e.g. to improve its affinity to the sodium channel and also in view of possible new (systemic) applications. In the present study fomocaine and eight fomocaine derivatives with an additional alkyl chain in 2- or 3-position of different length (C1 up to C4), or with a branched C3 chain in 3-position, respectively, at the morpholine ring were evaluated in vitro for possible structure-activity relationships with respect to the interactions with cytochrome P450 (CYP) mediated monooxygenase and oxidase functions using rat liver 9000 g supernatants or microsomes. Results were compared to in vivo data from rats on toxicity (LD50), paresis of the N. ischiadicus and surface and conduction anaesthesia (cornea, N. ischiadicus). In general, the influence of the derivatives on the CYP system was less than that of fomocaine, showing a further decline with enlarging chain length. Toxicity of the derivatives was comparable to that of fomocaine and lower only with the compound with a C4 alkyl chain in 2-position. The derivatives caused a stronger surface anaesthesia than fomocaine, exhibiting an additional increase with enlarging chain length. No clear-cut structure-activity relationships were observed with respect to paresis of the N. ischiadicus and to conduction anaesthesia. Especially the derivatives having a C2 or C4 chain in 2- or a C3 chain in 3-position, respectively, may be of interest for further investigations. In comparison to fomocaine they caused a stronger surface anaesthesia combined with a lower interaction capacity with the CYP system.
Lupp
Amelie
A
Institute of Pharmacology and Toxicology, Friedrich Schiller University, Jena, Germany. Amelie.Lupp@mti.uni-jena.de
Karge
Elke
E
Wange
Johannes
J
Eisentraut
Claudia
C
Zwenizner
Tobias
T
Oelschläger
Herbert
H
Fleck
Christian
C
D000765:Anesthesia, Conduction; D000772:Anesthesia, Local; D000779:Anesthetics, Local / Q000494:pharmacology* / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D007202:Indicators and Reagents; D007928:Lethal Dose 50; D015227:Lipid Peroxidation; D008163:Luminescent Measurements; D008165:Luminol; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology* / Q000633:toxicity*; D010243:Paralysis / Q000139:chemically induced / Q000473:pathology; D010647:Phenyl Ethers / Q000494:pharmacology* / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013748:Tetracaine / Q000633:toxicity; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D000779:Anesthetics, Local; D000975:Antioxidants; D005609:Free Radicals; D007202:Indicators and Reagents; D009025:Morpholines; D010647:Phenyl Ethers; D017392:Thiobarbituric Acid Reactive Substances; D013748:Tetracaine; C100275:fomocain; D008165:Luminol; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases