am-630 and Skin-Diseases

A set of CB2R ligands, based on the thiophene scaffold, was synthesized and evaluated in in vitro assays. Compounds 8c-i, k, l, bearing the 3-carboxylate and 2-(adamantan-1-yl)carboxamido groups together with apolar alkyl/aryl substituents at 5-position or at 4- and 5-positions of the thiophene ring possess high CB2R affinity at low nanomolar concentration, good receptor selectivity, and agonistic functional activity. The full agonist 8g, showing the best balance between receptor affinity and selectivity, was tested in vitro in an experimental model of allergic contact dermatitis and proved to be able to block the release of MCP-2 in HaCaT cells at 10 μM concentration.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Cell Line; Cell Survival; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Immunosuppressive Agents; Inflammation; Keratinocytes; Molecular Structure; Receptor, Cannabinoid, CB2; Skin Diseases; Structure-Activity Relationship; Thiophenes

Studies have shown that cannabinoid CB2 receptors are involved in wound repair, however, its physiological roles in fibrogenesis remain to be elucidated. In the present study, the capacity of cannabinoid CB2 receptors in the regulation of skin fibrogenesis during skin wound healing was investigated. To assess the function of cannabinoid CB2 receptors, skin excisional BALB/c mice were treated with either the cannabinoid CB2 receptor selective agonist, GP1a, or antagonist, AM630. Skin fibrosis was assessed by histological analysis and profibrotic cytokines were determined by immunohistochemistry, immunofluorescence staining, reverse transcription‑quantitative polymerase chain reaction and immunoblotting in these animals. GP1a decreased collagen deposition, reduced the levels of transforming growth factor (TGF)‑β1, TGF‑β receptor I (TβRI) and phosphorylated small mothers against decapentaplegic homolog 3 (P‑Smad3), but elevated the expression of its inhibitor, Smad7. By contrast, AM630 increased collagen deposition and the expression levels of TGF‑β1, TβRI and P‑Smad3. These results indicated that cannabinoid CB2 receptors modulate fibrogenesis and the TGF‑β/Smad profibrotic signaling pathway during skin wound repair in the mouse.

Topics: Actins; Animals; Blotting, Western; Collagen Type I; Collagen Type III; Cytokines; Disease Models, Animal; Fibrosis; Indoles; Male; Mice; Mice, Inbred BALB C; Microscopy, Fluorescence; Protein Serine-Threonine Kinases; Real-Time Polymerase Chain Reaction; Receptor, Cannabinoid, CB2; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Skin Diseases; Smad3 Protein; Transforming Growth Factor beta1; Wound Healing