Skin permeability and analgesic activity effects of verbenone hydrazones

The present study aims to the development and synthesis of novel potential skin permeability enhancers based on derivatives of bicyclic terpenoid – verbenone. For this purpose, a series of hydrazones has been obtained via (‒)-verbenone condensation with hydrazides of para-substituted phenoxyacetic acids. The structure of synthesized compounds was characterized by ¹³C-NMR, ¹H-NMR, FT-IR and mass spectrometry.

The action mechanism of verbenone hydrazones on phospholipids of artificial membranes and lipids isolated from the rat stratum corneum was studied by fluorescence and FT-IR spectroscopy. When applying the fluorescent method, excimer/monomer emission intensity (I_E/I_M) ratio was calculated by measuring the relative intensities of pyrene excimer and monomer forms at 394 nm and 475 nm, respectively. According to our data, inclusion of verbenone hydrazones in phospholipid liposomes leads to growth of excimer to monomer ratio (I_E/I_M) indicating a decrease of membrane microviscosity. The disruption of hydrogen-bonded network formed by polar lipid groups was suggested as mechanism of action for verbenone derivatives confirmed by FT-IR analysis.

Given the above, (‒)-verbenone hydrazones was estimated after transdermal delivery as potential analgesic agents via chemical-induced pain models using capsaicin and allyl isothiocyanate (AITC) as algogens. All the tested compounds were found to suppress painful sensation produced by noxious stimuli which indicates TRP receptors as one of the pharmacological targets of verbenone hydrazones.