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

Presley, Chaela S.; Mustafa, Suni M.; Abidi, Ammaar H.; Moore, Bob M.

doi:10.1016/j.bmc.2015.07.057

Cited by 12 publications

(8 citation statements)

References 57 publications

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“…Membrane proteins were isolated using binding buffer, as previously described (Presley et al, 2015b). Prior to starting the assay, filter plates were prepared by incubation with 0.05% (w/v) polyethyleneamine mixed in deionized water for 60 minutes at room temperature.…”

Section: Receptor Binding and Activitymentioning

confidence: 99%

“…Human embryonic kidney (HEK)-cyclic nucleotide gated (CNG), HEK-CNG1CB1, and HEK-CNG1CB2 cells were obtained from Codex BioSolutions. The ACTOne functional assay was performed as described by Presley et al (2015b). In brief, 5 Â 10 4 cells were plated (B and C) C57BL/6J mice were administered 6 mg/kg into the intraperitoneal space and blood and kidneys were harvested at the appropriate time points shown in the graph.…”

Section: Actone Functional Assaymentioning

confidence: 99%

See 1 more Smart Citation

Selective Cannabinoid 2 Receptor Stimulation Reduces Tubular Epithelial Cell Damage after Renal Ischemia-Reperfusion Injury

Pressly

Mustafa

Adibi

et al. 2017

J Pharmacol Exp Ther

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Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI), which is an increasing problem in the clinic and has been associated with elevated rates of mortality. Therapies to treat AKI are currently not available, so identification of new targets that can be modulated to ameliorate renal damage upon diagnosis of AKI is essential. In this study, a novel cannabinoid receptor 2 (CB2) agonist, SMM-295 [3'-methyl-4-(2-(thiophen-2-yl)propan-2-yl)biphenyl-2,6-diol], was designed, synthesized, and tested in vitro and in silico. Molecular docking of SMM-295 into a CB2 active-state homology model showed that SMM-295 interacts well with key amino acids to stabilize the active state. In human embryonic kidney 293 cells, SMM-295 was capable of reducing cAMP production with 66-fold selectivity for CB2 versus cannabinoid receptor 1 and dose-dependently increased mitogen-activated protein kinase and Akt phosphorylation. In vivo testing of the CB2 agonist was performed using a mouse model of bilateral IRI, which is a common model to mimic human AKI, where SMM-295 was immediately administered upon reperfusion of the kidneys after the ischemia episode. Histologic damage assessment 48 hours after reperfusion demonstrated reduced tubular damage in the presence of SMM-295. This was consistent with reduced plasma markers of renal dysfunction (i.e., creatinine and neutrophil gelatinase-associated lipocalin) in SMM-295-treated mice. Mechanistically, kidneys treated with SMM-295 were shown to have elevated activation of Akt with reduced terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling (TUNEL)-positive cells compared with vehicle-treated kidneys after IRI. These data suggest that selective CB2 receptor activation could be a potential therapeutic target in the treatment of AKI.

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Section: Receptor Binding and Activitymentioning

confidence: 99%

Section: Actone Functional Assaymentioning

confidence: 99%

Selective Cannabinoid 2 Receptor Stimulation Reduces Tubular Epithelial Cell Damage after Renal Ischemia-Reperfusion Injury

Pressly

Mustafa

Adibi

et al. 2017

J Pharmacol Exp Ther

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“…Among them, the novel CB 2 R inverse agonist SMM-189 (Figure 1 ) ( K i (CB 2 ) = 121 nM; K i (CB 1 ) = 4780 nM; EC 50 = 153 nM) showed in a murine model of mild traumatic brain injury efficacy in reducing the motor, visual, and emotional deficits; such neuroprotection was seemingly achieved by modulating microglial activation (Reiner et al, 2015 ) and chemokine expression. Reduction of the proinflammatory markers, oetaxin, MCP-1, and IP-10 by SMM-189 suggests that SMM-189 would decrease infiltration of peripheral macrophage and other cells of the immune system implicated in neurodegeneration events (Presley et al, 2015 ). The chromenoisoxazole PM226 (Figure 1 ) has been described as a selective CB 2 R agonist ( K i (CB 2 ) = 13 nM; K i (CB 1 R) > 40 μM; EC 50 = 39 nM) with neuroprotective properties in vitro and in vivo evaluations (Gómez-Cañas et al, 2016 ).…”

Section: Cb 2 R Ligands As Therapeutic Agents In Cmentioning

confidence: 99%

Targeting Cannabinoid CB2 Receptors in the Central Nervous System. Medicinal Chemistry Approaches with Focus on Neurodegenerative Disorders

et al. 2016

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Endocannabinoids activate two types of specific G-protein-coupled receptors (GPCRs), namely cannabinoid CB1 and CB2. Contrary to the psychotropic actions of agonists of CB1 receptors, and serious side effects of the selective antagonists of this receptor, drugs acting on CB2 receptors appear as promising drugs to combat CNS diseases (Parkinson's disease, Huntington's chorea, cerebellar ataxia, amyotrohic lateral sclerosis). Differential localization of CB2 receptors in neural cell types and upregulation in neuroinflammation are keys to understand the therapeutic potential in inter alia diseases that imply progressive neurodegeneration. Medicinal chemistry approaches are now engaged to develop imaging tools to map receptors in the living human brain, to develop more efficacious agonists, and to investigate the possibility to develop allosteric modulators.

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“…Extensive pharmacology studies on SMM-189 in CBR-transfected human embryonic kidney cells have shown intracellular cAMP levels to be definitively linked to the drug's action at CB2 receptors 218 . These studies have also confirmed that SMM-189 exerts no functional activity at CB1 receptors 218,337 . Assays used in previous studies of SMM-189 could only account for CB1-or CB2-mediated changes in cAMP, so there is a possibility that the drug may act on other receptors giving rise to off-target effects.…”

Section: The Complicated Issue Of Microglial Polarizationsupporting

confidence: 53%

Mild Traumatic Brain Injury with Associated Visual System Dysfunction: Investigating Histopathology, Functional Correlates, and a Novel Therapeutic Immune Modulator

Guley¹

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Arguably the most important recognitions are due to my parents Michael and Sally, and my siblings Jessica, Lara, and Michael. You helped mold me into the person I am, and have provided unwavering support and assistance through my entire journey. No words can convey my gratitude. Also to my beautiful and intelligent daughter Elowyn, you are too young to read this now but you have brought me joy and grounded me through some of the toughest days. You have also frustrated me to tears, a feat your grandfather would be proud of. To my best friends, Erin Gooch, Jordan Toler, and Dr. Brienne Petcher. You women are beautiful and amazing, and I am honored that you are a part of my life. All of these people have graced my life with so many blessings, it is truly unbelievable to reflect on. Lastly, to my husband, Dr. Patrick Guley, the most analytical and thoroughly skeptical scientist I have ever met. Your incessant love of debate has often challenged my patience, while simultaneously expanding my mind to explore possibilities and topics I would never have previously considered. I cannot thank you enough for the countless hours you've spent discussing my research, giving opinions and suggestions, and critiquing conclusions at every step of the way. When we joined our hands in marriage, we vowed to always pursue the truth, and I could not have asked for a better partner in exploring every inch of this wondrous cosmos. I love you with all of my being. vi ABSTRACT Background. Traumatic brain injury (TBI) is a significant source of morbidity and mortality worldwide. Injuries associated with moderate to severe TBI can be profound, and have historically overshadowed the significant impact mild TBI (mTBI) can have on the lives of affected individuals. Mild TBI can manifest in a number of different ways, but one of the most significant and often debilitating is its impact on the visual system. In order to further investigate the underlying pathology of mTBI and test potential therapeutics, we developed a mouse model of mTBI induced by blast overpressure. In this model, a 50-60 psi blast wave from a highly pressurized bolus of air is directed at a focal region of the left lateral cranium of a mouse, and produces replicable motor, emotional, and visual system deficits with concomitant histopathology. Importantly, this model closely simulates functional visual system damage seen in human cases of mTBI. A major component of the brain's reaction to trauma is an immune response that can cause additional long-term damage above and beyond that of the initial injury. This response was observed in our model as regions of microglial cell activation throughout areas of the brain important for visual processing. A novel therapeutic drug acting at cannabinoid type 2 receptors (CB2), known as SMM-189, had previously shown promise in improving visual outcome after mTBI in our model, but no studies were done to elucidate the cause of this improvement. The purpose of this dissertation was to further characterize visual system dysfunction and histopa...

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

Cited by 12 publications

References 57 publications

Selective Cannabinoid 2 Receptor Stimulation Reduces Tubular Epithelial Cell Damage after Renal Ischemia-Reperfusion Injury

Selective Cannabinoid 2 Receptor Stimulation Reduces Tubular Epithelial Cell Damage after Renal Ischemia-Reperfusion Injury

Targeting Cannabinoid CB2 Receptors in the Central Nervous System. Medicinal Chemistry Approaches with Focus on Neurodegenerative Disorders

Mild Traumatic Brain Injury with Associated Visual System Dysfunction: Investigating Histopathology, Functional Correlates, and a Novel Therapeutic Immune Modulator

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