Pharmacological modulation of brain Nav1.2 and cardiac Nav1.5 subtypes by the local anesthetic ropivacaine

Objective The present study was aimed to investigate the pharmacological modulatory effects of ropivacaine,an amide-type local anesthetic,on rat Nav1.2（rNav1.2）and rNav1.5,the two Na＋channel isoforms heterologously expressed in Xenopus oocytes and in HEK293t cell line,respectively.Methods Two-electrode voltage-clamp（TEVC）and whole-cell patchclamp recordings were employed to record the whole-cell currents.Results Ropivacaine induced tonic inhibition of peak Na＋ currents of both subtypes in a dose-and frequency-dependent manner.rNav1.5 appeared to be more sensitive to ropivacaine.In addition,for both Na＋channel subtypes,the steady-state inactivation curves,but not the activation curves,were significantly shifted to the hyperpolarizing direction by ropivacaine.Use-dependent blockade of both rNav1.2 and rNav1.5 channels was induced by ropivacaine through a high frequency of depolarization,suggesting that ropivacaine could preferentially bind to the 2 inactivated Na＋channel isoforms.Conclusion The results will be helpful in understanding the pharmacological modulation by ropivacaine on Nav1.2 subtype in the central nervous system,and on Nav1.5 subtype abundantly expressed in the heart.

Improved Method for the Total Synthesis of Azaperone and Investigation of Its Electrochemical Behavior in Aqueous Solution

Azaperone,with anti-anxiety and anti-aggressive activities used in veterinary medicine,is a member of the butyrophenone class.It is ordinarily utilized for a wide range of indications,such as sedation,obstetrics,and anesthesia.In this research,an improved synthetic route is presented for azaperone using a phase-transfer catalyst(PTC).In general,it was synthesized as a dopamine antagonist in four steps.The bis(2-chloroethyl)amine intermediate is easily obtained after the conversion of the alcohol groups into the chloride leaving group using thionyl chloride(95%yields).The alkylation of commercially available 2-amino pyridine in the presence of PTC was then carried out,giving 1-(pyridin-2-yl)piperazine with 75%yield.1-(Pyridin-2-yl)piperazine was finally alkylated using 4-chloro-1-(4-fluorophenyl)butan-1-one to achieve azaperone with 60%yield.The butyrophenone intermediate was obtained via the Friedel-Crafts reaction of fluorobenzene with 4-chlorobutyryl chloride in the presence of AlCl3.High efficiency,gentle reaction conditions,and fast and simple procedure are the advantages of this method.Also,the electrochemical oxidation behaviour of azaperone was investigated using cyclic and differential pulse voltammetry techniques.Cyclic voltammetric studies indicated an irreversible process for azaperone electro-oxidation with a peak potential of 0.78 V in a phosphate buffer solution(pH=7.0)vs.Ag/AgCl(saturated KCl)electrode.The value of the peak current vs.the azaperone concentration was enhanced linearly in the range of 10―70μmol/L,and the detection limit was found to be 3.33μmol/L.