Anti-inflammatory activity of cannabinoid receptor 2 ligands in primary hPDL fibroblasts.

Objectives: Approximately 65 million adults in the US have periodontitis, causing tooth loss and decreased quality of life. Cannabinoids modulate immune responses, and endocannabinoids are prevalent during oral cavity inflammation. Targets for intervention in periodontal inflammation are cannabinoid type 1 and 2 receptors (CB1R, CB2R), particularly CB2R because its levels increase during inflammation.

Optimization of cAMP fluorescence dataset from ACTOne cannabinoid receptor 1 cell line.

The ACTOne cannabinoid receptor 1 functional system is comprised of transfected HEK cells with the parental cyclic nucleotide gated channel (CNG) co-transfected with cannabinoid receptor 1 (CB1). The ACTOne CB1 cell line was evaluated for cAMP driven fluorescence by optimizing experimental conditions for sensitivity to forskolin and CP 55,940, reading time point, reliability of cell passage number, and pertussis inactivation of Gi/o.

Cannabinoid receptor 1 ligands revisited: Pharmacological assessment in the ACTOne system.

In vitro cannabinoid pharmacology has evolved over time from simple receptor binding to include [(35)S]GTPγ, β-arrestin, and cAMP assays. Each assay has benefits and drawbacks; however, no single functional system has been used for high-throughput evaluation of compounds from binding to pharmacological functionality and antagonist assessment in a well-characterized human cell line. In this study, we evaluated and validated one system-ACTOne human embryonic kidney cells transfected with a cyclic nucleotide gated channel and cannabinoid receptor 1 (CB1)-and compared human CB1 affinity, functional, and antagonistic effects on cAMP with previously published results.

Synthesis and biological evaluation of (3',5'-dichloro-2,6-dihydroxy-biphenyl-4-yl)-aryl/alkyl-methanone selective CB2 inverse agonist.

Cannabinoid receptor 2 (CB2) selective agonists and inverse agonists possess significant potential as therapeutic agents for regulating inflammation and immune function. Although CB2 agonists have received the greatest attention, it is emerging that inverse agonists also manifest anti-inflammatory activity. In process of designing new cannabinoid ligands we discovered that the 2,6-dihydroxy-biphenyl-aryl methanone scaffold imparts inverse agonist activity at CB2 receptor without functional activity at CB1.

Preclinical evaluation of SMM-189, a cannabinoid receptor 2-specific inverse agonist.

Cannabinoid receptor 2 agonists and inverse agonists are emerging as new therapeutic options for a spectrum of autoimmune-related disease. Of particular interest, is the ability of CB2 ligands to regulate microglia function in neurodegenerative diseases and traumatic brain injury. We have previously reported the receptor affinity of 3',5'-dichloro-2,6-dihydroxy-biphenyl-4-yl)-phenyl-methanone (SMM-189) and the characterization of the beneficial effects of SMM-189 in the mouse model of mild traumatic brain injury.

Motor, visual and emotional deficits in mice after closed-head mild traumatic brain injury are alleviated by the novel CB2 inverse agonist SMM-189.

We have developed a focal blast model of closed-head mild traumatic brain injury (TBI) in mice. As true for individuals that have experienced mild TBI, mice subjected to 50-60 psi blast show motor, visual and emotional deficits, diffuse axonal injury and microglial activation, but no overt neuron loss. Because microglial activation can worsen brain damage after a concussive event and because microglia can be modulated by their cannabinoid type 2 receptors (CB2), we evaluated the effectiveness of the novel CB2 receptor inverse agonist SMM-189 in altering microglial activation and mitigating deficits after mild TBI.

A sensitive and fast LC-MS/MS method for determination of β-receptor agonist JP-49b: application to a pharmacokinetic study in rats.

Ocular administration of the beta (β)-adrenergic receptor agonist JP-49b prevents retinopathy-like damage in a preclinical rat model of diabetes. Importantly, JP-49b did not induce characteristic β-adrenergic agonist-related side effects (e.g.

Preclinical pharmacokinetics of the radiomitigator KZ-41 in rats.

KZ-41, a quinic acid derivative, significantly reduces mortality in a murine model of hematopoietic acute radiation syndrome. The purpose of this study was to evaluate the systemic pharmacokinetics, elimination, and oral bioavailability of KZ-41 in rats. Male Sprague-Dawley rats (n = 6 per group) received a single dose (10 mg/kg) of KZ-41 administered either intravenously via the jugular vein or orally via gavage.