The Hedgehog (HH) pathway has been linked to the formation of basal cell carcinoma (BCC), medulloblastoma, and other cancers. The recently approved orally active drugs vismodegib (GDC‐0449) and sonidegib (LDE–225) were not only efficacious for the treatment of advanced or metastatic BCC by antagonizing the smoothened (SMO) receptor, but also produced important side effects, limiting their use for less invasive BCC. Herein, we compared a large series of SMO antagonists, including GDC‐0449 and LDE‐225, the clinically tested BMS‐833923, CUR‐61414, cyclopamine, IPI‐926 (saridegib), itraconazole, LEQ‐506, LY‐2940680 (taladegib), PF‐04449913 (glasdegib), and TAK‐441 as well as preclinical candidates (PF‐5274857, MRT‐83) in two SMO‐dependent cellular assays and for G‐protein activation. We report marked differences in inhibitor potencies between compounds as well as a notable disparity between the G‐protein assay and the cellular tests, suggesting that classification of drugs is assay dependent. Furthermore, we explored topical efficacies of SMO antagonists on depilated mice using Gli1 and Ptch1 mRNA quantification in skin as biomarkers of the HH signaling inhibition. This topical model rapidly discriminated drugs in terms of efficacies and potencies for inhibition of both biomarkers. SMO antagonists showed also a large variation in their blood and skin partition, suggesting that some drugs are more favorable for topical application. Overall, our data suggested that in vitro and in vivo efficacious drugs such as LEQ‐506 and TAK‐441 may be of interest for topical treatment of less invasive BCC with minimal side effects.

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We report the discovery of a new family of α(2) adrenergic receptor antagonists derived from atipamezole. Affinities of the compounds at human α(2) and α(1b) receptors as well as their functional activities at hα(2A) receptors were determined in competition binding and G-protein activation assays, respectively. Central α(2) antagonist activities were confirmed in mice after oral administration. Further studies on a selected example: (+)-4-(1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-1H-imidazole, (+)-1 (F 14805), were undertaken to probe the potential of the series. On the one hand, (+)-1 increased the release of noradrenaline in mouse frontal cortex following acute systemic administration, the magnitude of this effect being much larger than that obtained with reference agents. On the other, (+)-1 produced minimal cardiovascular effects in intact, anesthetized rat, a surprising outcome that might be explained by its differential action at peripheral and central α(2) receptors. A strategy for improving the therapeutic window of α(2) antagonists is put forward.

Objective Deleterious effects of pollutants and ultraviolet radiation on the skin can be attenuated using formulations containing antioxidants. However, these have disadvantages, including chemical instability, photodegradation, poor bioavailability or biological activity. Here, two commercial formulations were evaluated: one optimized to stabilize and deliver ascorbic acid (AA) at 15% and the other containing a glucoside form of AA, namely ascorbic acid 2‐glucoside (AA2G), at 1.8% and at a physiological pH. We compared the skin delivery, antioxidative effects and chemical stability of AA2G with AA in their respective formulations. Methods Skin delivery was measured using fresh viable human skin explants, and oxidative stress was measured using a human reconstructed epidermal (RHE) model according to levels of malondialdehyde (MDA), superoxide dismutase (SOD) and catalase. Results Ascorbic acid 2‐glucoside was completely metabolized to AA by the skin before entering the receptor compartment. The skin contained parent and AA, indicating a reserve of AA2G was present for further metabolism. For AA2G and AA, maximum flux of AA‐equivalents was at 12 h, with continued absorption over 24 h. The absolute amount in µg was higher in the skin after application of AA than after application of AA2G. This may suggest a greater antioxidative effect; however, according to all three measurements of oxidative stress, the protective effect of AA and AA2G was similar. Unlike AA, AA2G was chemically stable under storage conditions. Conclusion A lower concentration of AA2G is as effective as the active metabolite, AA, in terms of antioxidant effects. AA2G was chemically stable and can be applied at a lower concentration than AA, thus avoiding the need for an acidic formulation with a pH below 3.5.

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N-methyl-D-aspartate (NMDA) receptor channels are implicated in a wide range of physiological and pathophysiological processes, and a large number of pharmacological agents have been introduced that target the receptor via diverse mechanisms of action. Amongst others, subunit selectivity (in particular for the NR2B receptor subunit) and rapid unblocking kinetics have been put forward as favourable pharmacological properties of NMDA receptor-targeting drugs. Here, we describe a pharmacological characterization of human recombinant NMDA receptors expressed in Xenopus oocytes in an electrophysiological set-up. Using this approach, we compare inhibitor potencies of several known NMDA receptor ligands as well as unblocking kinetic properties of selected compounds. All compounds tested had similar potencies at receptors containing NR2A or NR2B receptors with the exception of traxoprodil, which was selective for NR2B. The rank order of potency was (+)MK-801 > phencyclidine (PCP) ≈ traxoprodil > memantine ≈ ketamine > duloxetine. In line with its proposed rapid dissociation properties, the relatively well-tolerated drug memantine exhibits markedly faster unblocking than ketamine and PCP, similar to the low-affinity compound, duloxetine. Electrophysiological recording in Xenopus oocytes thus allows a relatively convenient comparison of key pharmacological parameters at recombinant human NMDA receptors.

Objective We investigated the dermal bioavailability and antioxidative properties of a sunscreen formulation containing two antioxidants, oxothiazolidine (OTZ) and δ‐tocopheryl glucoside (DTG). OTZ reacts directly with reactive oxygen species to form taurine, while DTG is metabolized in δ‐tocopherol to achieve antioxidative activities. Methods After topical application to a hair follicle‐derived reconstructed human epidermis (RHE) model, followed by solar‐simulated radiation, kinetics of bioavailability and antioxidative responses were measured over 24 h. Markers for oxidative stress were malondialdehyde (MDA), superoxide dismutase (SOD) and catalase activities. Results The two antioxidants had different bioavailability profiles: OTZ was rapidly and extensively absorbed, whereas DTG was slowly absorbed and converted to δ‐tocopherol. Compared to OTZ alone, the protection against effects on MDA levels and SOD and catalase activities was higher when DTG was used alone or in combination with OTZ. When used in combination, the degree of protection increased over time and remained constant over 24 h with maximal protection 2 h post‐irradiation. DTG slowly penetrated into the skin and was present in the skin at all post‐irradiation timepoints, thus allowing a slow but constant supply of δ‐tocopherol over at least 24 h. By contrast, the oxidative protection by OTZ was immediate but short‐lived due to its rapid penetration through the RHE and into the receptor fluid. Conclusion These results indicate a complementary sunlight protective action of OTZ and DTG with an immediate delivery of OTZ just after topical application of the formulation, and a prolonged skin delivery of δ‐tocopherol from the slower penetration and metabolism of DTG.