Study of local anesthetic activity of some derivatives of 3-amino-benzo-[d]-isothiazole.
On the basis of computer prediction of biological activity by PASS and toxicity by DEREK, the most prospective 18 alkylaminoacyl derivatives of 3-amino-benzo-[d]-isothiazole were selected. Their local anesthetic action was assessed using an in vitro preparation of the isolated peroneal nerve of the frog. The local anesthetics action of the compounds was assessed according to the time required for each compound to reduce the amplitude of the evoked compound action potential (CAP). Lidocaine was used as the control compound. The results show that the tested compounds can be divided into three groups: (a) compounds with action similar to lidocaine, (b) compounds with action lower than lidocaine and (c) compounds which block completely the evoked CAP, but after the compound was removed and replaced with normal saline showed no recovery of the potential at all. QSAR studies showed that polarizability, polarity and presence of five-membered rings in molecules have a positive influence on local anesthetic activity, while contributions of aromatic CH and singly bonded nitrogen are negative. Since estimations from PASS probabilities to find local anesthetic activity in the most active compounds were less than 50%, these compounds may be considered as new chemical entities (NCEs).
Geronikaki
A
A
School of Pharmacy, Department of Pharmaceutical Chemistry, Aristotelian University, Thessaloniki 54124, Greece. geronik@pharm.auth.gr
Vicini
P
P
Theophilidis
G
G
Lagunin
A
A
Poroikov
V
V
Dearden
J C
JC
D000200:Action Potentials; D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D003198:Computer Simulation; D005544:Forecasting; D015394:Molecular Structure; D010543:Peroneal Nerve / Q000187:drug effects / Q000502:physiology; D021281:Quantitative Structure-Activity Relationship; D011898:Ranidae; D012984:Software; D013844:Thiazoles / Q000494:pharmacology*
D000779:Anesthetics, Local; D013844:Thiazoles