Davasaicin

DA-5018, a recently synthesized capsaicin analog, appears to possess potent analgesic activity when administered topically. The objective of this study is to test the feasibility of the topical administration of this compound. Specifically, our goal was to identify vehicle system that permit a reasonable transdermal permeation of the compound in mice. Among the vehicles examined, isopropyl myristate (IPM) showed the largest in vitro permeability across the intact skin (83.6 +/- 5.42 microl/cm2/h). However, due to the limited solubility of DA-5018 in IPM (0.53 mg/ml), the maximal flux from the IPM medium remained at only 44.3 +/- 2.87 microg/cm2/hr. In order to increase the flux, addition of better solvents for DA-5018 was attempted, under the assumption that flux is the result of both solubility and permeability. Ethoxydiglycol (EG) and oleic acid (OA) were selected as examples of good solvents. The addition of EG or OA to IPM at a 1:1 volume ratio resulted in a comparable increase in the solubility of the compound (i.e., to 61.1 and 50.2 mg/ml for EG and OA, respectively). However, the addition of EG at a 1:1 volume ratio, for example, increased the flux 6.3 fold (i.e., 279 microg/cm2/hr), while OA, at a 1:1 volume ratio, decreased the flux 5 fold (i.e., 9.26 microg/cm2/hr). The mechanism of this discrepancy between EG and OA was investigated by measuring the permeabilty of DA-5018 across the stratum corneum-removed skin of the mouse, under the hypothesis that the viable skin layer may serve as a barrier for the permeation of lipophilic substances such as DA 5018. The permeability of DA-5018, from the medium of EG or OA, across the viable skin differed greatly for EG (0.41 microl/cm2/hr) and OA (0.086 microl/cm2/hr), suggesting that a higher permeability across the viable skin layer is needed for the second solvents. The maximum flux across the intact skin was achieved for DA-5018 when EG was added to IPM at a 1:1 volume ratio. Thus, the use of a binary system appears to be the bes approach for realizing the transdermal delivery of DA-5018 at a reasonable rate.

Heterologously expressed vanilloid receptor 1 (VR1), a cloned cDNA encoding for capsaicin (CAP)-sensitive currents, resembles the native CAP channels in cultured sensory neurons in channel property. But, the pharmacological profile of VR1 to various CAP analogs is not known. The stable expression of VR1 in human embryonic kidney (HEK) cells was generated and confirmed by reverse transcription-polymerase chain reaction and Western blots. VR1 expressed in HEK cells retained single-channel properties similar to those of the native channels. When concentration-response relationships were compared, CAP and DA-5018.HCl, a synthetic analog of CAP, exhibited a greater potency in activating VR1 than the native channels in sensory neurons. In contrast, resiniferatoxin and its analog, phorbol 12-phenylacetate 13-acetate 20-homovanillate, was more potent in activating the CAP-activated channels in cultured sensory neurons than VR1. Thus, the difference in pharmacological profiles of VR1 and the native channels suggests the possible presence of subtypes of the CAP receptor or regulatory mechanisms associated with VR1.