RELATIONSHIPS BETWEEN LIPOPHILIC CHARACTER AND BIOLOGICAL ACTIVITY OF NEW POTENTIAL LONG-ACTING LOCAL ANESTHETICS

The partition coefficients (P-values) of certain new potential, stereoselective, reversible, long-acting local anesthetics have been determined in an n-octanol/ phosphate buffer system. These are derivatives of 2-phenoxyethyldialkylamine hydrochloride, and almost all of them are readily soluble in water. Their aqueous solutions have shown different absorption maxima, and these have been used quantitatively to determine the concentration of solute in aqueous phase using the Beer-Lambert equation and the calibration curve, which has been a straight line within the test concentrations. The values of P have been calculated as the ratio of the concentration of solute in the octanol phase divided by the concentration in the aqueous phase the former value has been obtained from mass balance. The mass balance is confirmed by obtaining the absorption measurements of the organic phase. The guinea pig intradermal wheal test has been used to determine the anesthetic properties of the test agents. They have exhibited better anesthetic profiles than those of the bupivacaine standard. Moreover, they have displayed no apparent side-effects neither locally nor systemically. Although there has been no sharp general correlation between the P-values and duration of action (WT), it is observed, in many cases, that derivatives with low P-values have shorter WT than those with high P-values. Therefore, it seems that the duration of action of these compounds is not influenced only by this property, i.e. P-values, and other factors such as physicochemical, pharmacokinetic, and pharmacodynamic parameters as well as non-specific binding characteristics at adjacent tissues are also involved. Thus, the action of these new compounds is due to the molecule as a whole and not to any one particular physical or chemical property. Furthermore, these are reversible and stereoselective agents.