Synthesis Of Novel 4-Aryl-1,4-dihydropyridines And Local Anesthetic Effect Analysis

ObjectiveThis study firstly successfully synthesized 4 kinds of 4-aryl-1,4-dihydrogenpyridine compounds.Compared with the clinical commonly used local anesthetics,and through the further analysis of the local anesthesia effect and toxic reaction,provides the theoretical basis and experimental basis for the searching of a better local anesthetics.MethodsCompounds 1-4 were synthesized according to a reported procedure[9].A mixture of ammonium acetate(10 mmol),aromatic aldehyde(10 mmol)and ethyl acetoacetate(10 mmol)in ethanol(100 mL)was refluxed for 2-3 h and then cooled to room temperature.According to the evaporation of chloroform solution,Suitable single crystals of compound 4 come to hand.Through establishing a variety of animal models compared the effect of 4-aryl-1,4-dihydrogenpyridine with commonly used local anesthetics lidocaine,tetracaine,ropivacaine,bupivacaine in surface anesthesia,local infiltration anesthesia,peripheral nerve block,and the effect of spinal anesthesia.By establishing rat local anesthetics neurotoxicity and cardiac toxicity model,compared 4-aryl-1,4-dihydrogenpyridine compounds with commonly used anesthetics in toxicity reaction and fat emulsion of reversal effect.Results1.Achieved four kinds of 4-aryl-1,4-dihydrogenpyridine compounds.Named respectively as 4-aryl-1,4-dihydrogenpyridine compound1;4-aryl-1,4-dihydrogenpyridine compound 2;4-axyl-1,4-dihydrogenpyridine compound 3;4-aryl-1,4-dihydrogenpyridine compound 4.2.Though researching surface anesthesia and local infiltration anesthesia animals model,found that only 4-aryl-1,4-dimethylaminopyridine 4 have anesthetic effect.The surface anesthetic effect was similar to tetracaine and superior to bupivacine and lidocaine(P<0.05).There was no significant difference in hexagonal cell ratio(6A),corneal cells coefficient of variation(CV),the density of corneal endothelial cells(CD)and the central corneal thickness compared with the normal control group.Local infiltration anesthesia effect of 4-aryl-1,4-dihydrogenpyridine 4 is better than that of lidocaine,ropivacaine,bupivacine(P<0.05).3.Blocking rat’s tail nerve used respectively by 4-aryl-1,4-dihydrogenpyridine compand 4,ropivacaine,bupivacaine,the result showed anesthetic length of 4-aryl-1,4-dihydrogenpyridine compand 4 was longer than that of ropivacaine and bupivacaine.The differences are statistically significance(P<0.05).4.By establishing the rat model of spinal anesthesia compared the effect of 4-aryl-1,4-dihydrogenpyridine compound 4 with ropivacaine,bupivacaine,showed analgesic effect and duration of 4-aryl-1,4-dihydrogenpyridine compound 4 was better than that of ropivacaine,bupivacaine.Compared with the other two drugs,4-aryl-1,4-dihydrogenpyridine compound 4 can lower the secretion of TNF alpha and IL-2 in rat cerebrospinal fluid and inhibit Caspase3 activity.Their differences are statistical significance(P<0.05).5.4-aryl-1,4-dihydrogenpyridine compound 4 also possesses the local anesthetics common toxicity reaction.Poisonous dose can cause different extent of cardiac toxic reactions and central nervous system toxic reactions.Fat emulsion can reverse the rat 4-aryl-1,4-dihydrogenpyridine compound 4 poisoning adverse cardiac reactions and central nervous system toxic reactions such as convulsions(P<0.05).conclusionThis study successful synthesized four kinds of 4-aryl-1,4-dihydrogenpyridine compounds 1～4.Only 4-aryl-1,4-dihydrogenpyridine compound 4 possesses anesthetic activity.Its effect of surface anesthesia,local infiltration anesthesia,nerve block anesthesia,spinal anethesia are good.But it has cardiac toxicity and central nervous system toxicity.Fat emulsion can reverse cardiac and central nervous system toxic reactions from overdosed 4-aryl-1,4-dihydrogenpyridine 4.