Anti-inflammatory and cytoprotective polypharmacology of Canephron N reveals targeting of the IKK-NF-κB and p38-MK2-RIPK1 axes.

Urinary tract infections are among the most frequently occurring forms of infection, and inflammation and tissue damage contribute significantly to symptoms, e.g., dysuria and urge.

An oil-in-water emulsion containing a combination of ginger extract and synthetic cannabidiol with potent in vitro anti-inflammatory effects alleviates symptoms of atopic dermatitis in a clinical trial.

Atopic dermatitis (AD) is a highly prevalent chronic skin disease. Anti-inflammatory and antipruritic emollients (emollients plus) with excellent cosmetic properties may alleviate AD-related symptoms and reduce the number of exacerbations. To screen for herbal extracts with potent anti-inflammatory and antioxidative potential in human skin cell cultures.

Fluoxetine exerts anti-inflammatory effects on human epidermal keratinocytes and suppresses their endothelin release.

Fluoxetine is a safe antidepressant with remarkable anti-inflammatory actions; therefore, we aimed to investigate its effects on immortalized (HaCaT) as well as primary human epidermal keratinocytes in a polyinosinic-polycytidylic acid (p(I:C))-induced inflammatory model. We found that a non-cytotoxic concentration (MTT-assay, CyQUANT-assay) of fluoxetine significantly suppressed p(I:C)-induced expression and release of several pro-inflammatory cytokines (Q-PCR, cytokine array, ELISA), and it decreased the release of the itch mediator endothelins (ELISA). These effects were not mediated by the inhibition of the NF-κB or p38 MAPK pathways (western blot), or by the suppression of the p(I:C)-induced elevation of mitochondrial ROS production (MitoSOX Red labeling).

Topical κ-opioid receptor agonist asimadoline improves dermatitis in a canine model of atopic dermatitis.

This prospective, 4-week, placebo-controlled, cross-over study aimed to investigate the efficacy of 1% topical κ-opioid agonist, asimadoline, in a model of canine atopic dermatitis (AD). Fourteen beagles were challenged with house dust mites every 3-4 days for a total of 9 challenges. Severity of dermatitis was assessed, and pruritus was monitored using GoPro HERO cameras.

Current and emerging treatments targeting the neuroendocrine system for disorders of the skin and its appendages.

The skin as a neuroendocrine organ and the role of neuroendocrine signalling in the development of disorders affecting the skin and its appendages has received increasing attention in the last years. Different neuroendocrine systems have been described in the barrier organ skin, including the thyroid system, the hypothalamic-pituitary-adrenal axis, the opioid, the endocannabinoid, the cholinergic, the secosteroidogenic and the serotonergic systems. All of these systems have been implicated in the development of skin diseases, which often have an inflammatory origin.

Non-neuronal kappa-opioid receptor activation enhances epidermal keratinocyte proliferation, and modulates mast cell functions in human skin ex vivo.

Kappa-opioid receptor (KOR) activation reportedly elicits anti-inflammatory responses and can downregulate neuropeptide release from sensory nerve fibers. While this renders KOR agonists (KORAs) potentially interesting therapeutics in skin diseases associated with neurogenic inflammation, it remains poorly understood how KOR agonists impact on human skin and dermal mast cells (MCs) ex vivo, in the absence of functional innervation. The KORA 5a was administrated to the culture medium (200 nmol/L and 1 µmol/L) in human skin organ culture, thus mimicking a "systemic" mode of application.

Small molecule drugs for the treatment of pruritus in patients with atopic dermatitis.

Chronic pruritus is a cardinal symptom of the inflammatory skin disease atopic dermatitis (AD). Pathogenic mechanisms in the periphery, spinal cord and the brain have been implicated in AD-related pruritus. Therefore, both systemic and topical administration of drugs could potentially provide relief.

Influence of Buffers of Different pH and Composition on the Murine Skin Barrier, Epidermal Proliferation, Differentiation, and Inflammation.

The pH of the skin is tightly regulated by endogenous buffering systems. We examined the influence of buffers of different pH and composition on skin barrier repair, pH, inflammation, and epidermal thickness/proliferation/differentiation. After tape-stripping in hairless mice buffers with pH 4-7 were applied in patch test chambers.

Modulators of the endocannabinoid system influence skin barrier repair, epidermal proliferation, differentiation and inflammation in a mouse model.

Endocannabinoids (ECs) are important regulators of cell signalling. Cannabinoid receptors are involved in keratinocyte proliferation/differentiation. Elevation of the endogenous cannabinoid tone leads to strong anti-inflammatory effects.

Can we teach old drugs new tricks?-Repurposing of neuropharmacological drugs for inflammatory skin diseases.

Despite the "hype" for monoclonal antibodies, the so-called biologics, which added significant value to the therapeutic armamentarium of dermatologists and improved the life of many patients, but may exhibit significant adverse effects, the vast majority of dermatological patients suffering from atopic dermatitis or psoriasis is still treated topically. Thus, there is a huge need for locally applied, locally acting drugs for inflammatory skin diseases with better risk-benefit profiles compared to topical corticosteroids or calcineurin inhibitors. Drug repositioning is a complex process, but offers advantages, in particular for indications with lower revenues.

Pharmacology, toxicology and clinical safety of glycopyrrolate.

The clinical use of the anticholinergic glycopyrrolate dates back to the early 1960s when it was first approved in the U.S. Since then, oral and inhalation formulations have been developed as therapeutic agents inhibiting the muscarinic acetylcholine receptor in various indications including chronic obstructive pulmonary disease (COPD), excessive salivation, and peptic ulcers.

Stereoselective synthesis of conformationally restricted KOR agonists based on the 2,5-diazabicyclo[2.2.2]octane scaffold.

It has been postulated that the KOR affinity depends on the dihedral angle of the ethylenediamine pharmacophore. Herein, 2,5-diazabicyclooctanes bearing a pyrrolidino moiety in the 7-position were envisaged to study KOR agonists with a conformationally rigid ethylenediamine pharmacophore and thus a defined N(pyrrolidine)-C7-C1-N2 dihedral angle. The first approach with an intramolecular addition at the chiral sulfinylimines 9 failed to give bicyclic products.

Echinacea purpurea-derived alkylamides exhibit potent anti-inflammatory effects and alleviate clinical symptoms of atopic eczema.

Background: Atopic eczema (AE) is a chronic inflammatory and pruritic skin disease. There is still an unmet need for topical anti-inflammatory and anti-pruritic substances exhibiting an excellent safety profile. The endocannabinoid system is known to regulate various aspects of cutaneous barrier and immune functions, thus targeting it may be a valid approach for alleviating the symptoms of AE.

Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake.

The extracellular effects of the endocannabinoids anandamide and 2-arachidonoyl glycerol are terminated by enzymatic hydrolysis after crossing cellular membranes by facilitated diffusion. The lack of potent and selective inhibitors for endocannabinoid transport has prevented the molecular characterization of this process, thus hindering its biochemical investigation and pharmacological exploitation. Here, we report the design, chemical synthesis, and biological profiling of natural product-derived -substituted 2,4-dodecadienamides as a selective endocannabinoid uptake inhibitor.

Design and Synthesis of Enantiomerically Pure Decahydroquinoxalines as Potent and Selective κ-Opioid Receptor Agonists with Anti-Inflammatory Activity in Vivo.

In order to develop novel κ agonists restricted to the periphery, a diastereo- and enantioselective synthesis of (4aR,5S,8aS)-configured decahydroquinoxalines 5-8 was developed. Physicochemical and pharmacological properties were fine-tuned by structural modifications in the arylacetamide and amine part of the pharmacophore as well as in the amine part outside the pharmacophore. The decahydroquinoxalines 5-8 show single-digit nanomolar to subnanomolar κ-opioid receptor affinity, full κ agonistic activity in the [S]GTPγS assay, and high selectivity over μ, δ, σ, and σ receptors as well as the PCP binding site of the NMDA receptor.

The tripeptide KdPT ameliorates ongoing psoriasis-like skin inflammation in murine and human skin.

Psoriasis is a chronic inflammatory disease appearing as scaly erythematous cutaneous lesions, which are characterized by parakeratosis and acanthosis as well as the infiltration of immune cells, such as T helper-1 and T helper-17 cells. Here, we demonstrated that KdPT, a tripeptide structurally related to the C-terminal amino acids of alpha-melanocyte-stimulating hormone, which was previously shown to exhibit anti-inflammatory effects in intestinal inflammation, ameliorated ongoing disease in the mouse model of imiquimod-induced psoriasis-like skin inflammation and in the small xenotransplant mouse model of psoriasis. We could show that systemic KdPT treatment significantly reduced hyperkeratosis and acanthosis in murine as well as human skin.

Conformationally restricted κ-opioid receptor agonists: Synthesis and pharmacological evaluation of diastereoisomeric and enantiomeric decahydroquinoxalines.

All diastereoisomeric decahydroquinoxalines representing conformationally restricted analogs of κ agonists U-50,488 and GR-89,696 have been prepared. Cis/trans configured compound 7 is by far the highest binding diastereoisomer with a Ki of 0.35 nM.

Correlating FAAH and anandamide cellular uptake inhibition using N-alkylcarbamate inhibitors: from ultrapotent to hyperpotent.

Besides the suggested role of a putative endocannabinoid membrane transporter mediating the cellular uptake of the endocannabinoid anandamide (AEA), this process is intrinsically coupled to AEA degradation by the fatty acid amide hydrolase (FAAH). Differential blockage of each mechanism is possible using specific small-molecule inhibitors. Starting from the natural product-derived 2E,4E-dodecadiene scaffold previously shown to interact with the endocannabinoid system (ECS), a series of diverse N-alkylcarbamates were prepared with the aim of generating novel ECS modulators.

Synthesis and pharmacological evaluation of 5-pyrrolidinylquinoxalines as a novel class of peripherally restricted κ-opioid receptor agonists.

5-Pyrrolidinyl substituted perhydroquinoxalines were designed as conformationally restricted κ-opioid receptor agonists restricted to the periphery. The additional N atom of the quinoxaline system located outside the ethylenediamine κ pharmacophore allows the fine-tuning of the pharmacodynamic and pharmacokinetic properties. The perhydroquinoxalines were synthesized stereoselectively using the concept of late stage diversification of the central building blocks 14.

Features of idebenone and related short-chain quinones that rescue ATP levels under conditions of impaired mitochondrial complex I.

Short-chain quinones have been investigated as therapeutic molecules due to their ability to modulate cellular redox reactions, mitochondrial electron transfer and oxidative stress, which are pathologically altered in many mitochondrial and neuromuscular disorders. Recently, we and others described that certain short-chain quinones are able to bypass a deficiency in complex I by shuttling electrons directly from the cytoplasm to complex III of the mitochondrial respiratory chain to produce ATP. Although this energy rescue activity is highly interesting for the therapy of disorders associated with complex I dysfunction, no structure-activity-relationship has been reported for short-chain quinones so far.