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-phenoxyetlhyldialkylamine 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

Investigations on the drug-protein interaction of certain new potential local anaesthetics

Generally, plasma proteins owe their binding capacity to the presence of aminoacid units which enter into intra- and intermolecular hydrophobic bonding with a diverse range of endo- and exogenous chemical substances. The intermolecular interactions between the hydrophobic areas of drug molecules and those of plasma proteins play an important role in drug-macromolecular complex formation and stabilization. This largely accounts for the carrier capacity of proteins for lipid soluble drugs. Albumin may be particularly responsible for the binding of local anaesthetics in plasma, but another binding factor may be lipoproteins present in blood cell membranes- Thus, and due to the special importance of the drug protein binding phenomenon and its influence on the biological response, this investigation has been commenced on the purpose of establishing whether the degree of drug-protein interaction could be correlated with the duration of action of certain new potential local anaesthetics. These are derivatives of 2-phenoxyethyldialkylamine hydrochloride. Equilibrium dialysis, being generally the most reliable of the various methods available, was chosen as a means of determining the extent of drug-protein binding, and bovine serum albumin [BSA] of molecular weight around 70,000 was employed. An ultraviolet assay method was used to measure the concentration of free, unbound local anaesthetic molecules in the protein-free compartment, once equilibrium had been attained. It was found that the affinity of the test compounds for BSA does not parallel their duration of action produced in the guinea pig intradermal wheal test Moreover, the ability of BSA to bind these local anaesthetics appeared not to depend on the number of binding sites on the protein molecule, but rather on the proportion of unionised lipophilic species. This suggests that ionic forces probably play no essential part in the binding process

Pharmacological studies on novel basic aminoalkyl aryl ethers as potential local anesthetics

Following our previous investigations on certain new aminoalkyi aryl ethers, which showed promising and outstanding local anaesthetic properties, the local anaesthetic activity and duration of action of a further selection of four novel derivatives of the above-mentioned series, used as hydrochloride salts, have been determined by the in vivo rat sciatic nerve test. These are: N N-dimethyl-2- [2,6-di-tert-butylphenoxy] ethylamine; N, N-dimethyl-2- [4-butoxyphenoxy] elhylamine; N, N-dimethyl-2- [2,6-di-.sec-butylphenoxy]ethylamine; and N, N diethyl-2-[4-sec-butylphenoxy]ethylamine. The tests have been performed by adouble blind, controlled trial [at the later stage] and in two stages. Bupivacaine hydrochloride has been employed as the standard and normal saline as the control. The complete loss of motor function of the injected limb of the animal is considered as a positive response, which is assessed by observing the animal gait and ability to climb up a sloping wire mesh. The test compounds have exhibited shorter duration of motor paralysis than that of the standard and comparable rates of both onset of action, and recovery time from full analgesia. They also have shown neither apparent systemic nor local side effects such as edema, swelling, induration, ulceration, necrosis, or irritation

new biological screening system for local anesthetics by inhibition mobility of tetrahymena pyriformis

An alternative in vitro approach to drug screening has been the use of human cell cultures for antiviral agents and microbial cell cultures for the assessment of the carcinogenic potential of selected compounds. A number of protozoan species have been also used as drug screens for anti-protozoal agents. The ciliated protozoan Tetrahymena pyriformis species has been widely utilised as a drug screen for a variety of pharmacologically active agents. Accordingly, it was decided to investigate whether T. pyriformis could be used as a preliminary drug screen for evaluation of the local anaesthetic activity and duration of action of certain commercially available local anaesthetics. In this communication, the results of this new in vitro biological drug screen are reported. It is based on the complete protozoan cell immobilization by the anaesthetic solution. A positive inverse correlation was observed between the lowest concentration [minimum inhibitory concentration =MIC] that wholly inhibits the mobility of all cells of T. pyriformis and the duration of action of the test compounds. Generally, MIC was high for the short-acting anaesthetics and low for the long-acting ones. The results suggest the suitability of this new microbiological assay system for the evaluation of local anaesthetic activity and duration of action and possibly irritancy and toxicity of other local anaesthetics as well as potentially active therapeutic agents which possess surface activity

Toxicological studies on certain amino alkyl ethers as potential long-acting local anesthetics

The acute intravenous toxicities of a selection of three potential long-acting local anaesthetics belonging to the series of 2- phenoxyethyldial kylamine were determined in mice. Two of the compounds were tertiary amines and the third a quaternary ammonium derivative. The I.V. median lethal dose, [LD 50] of one of the tertiary compounds, 21A [N- diethyl-2- [2,6- diisopropyl] ethylamine hydrochloride was over 2.5 times that of lignocaine, while the other, 30A [N, N- diethyl-2- [4-sec-butyl] ethylamine hydrochloride] had an LD 50 of 1.5 times. On the other hand, the quaternary ammonium derivative FA [benzyl-N-N- dimethyl -2- [2- tert- butyl] ethylamine chloride] was more toxic, with an LD 50 value of one quarter of the standard. The test compounds, particularly compound 21A, seem to have good properties that would warrant further investigation as potential long-acting local anaesthetic agents