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

Presley C, Abidi A, Suryawanshi S, Mustafa S, Meibohm B, Moore BM - Pharmacol Res Perspect (2015)

Bottom Line: 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.Herein, we report the further characterization of SMM-189 as a potent and selective CB2 inverse agonist, which acts as a noncompetitive inhibitor of CP 55,940.The ability of SMM-189 to regulate microglial activation, in terms of chemokine expression and cell morphology, has been determined.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center Memphis, Tennessee.

ABSTRACT
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. Herein, we report the further characterization of SMM-189 as a potent and selective CB2 inverse agonist, which acts as a noncompetitive inhibitor of CP 55,940. The ability of SMM-189 to regulate microglial activation, in terms of chemokine expression and cell morphology, has been determined. Finally, we have determined that SMM-189 possesses acceptable biopharmaceutical properties indicating that the triaryl class of CB2 inverse agonists are viable compounds for continued preclinical development for the treatment of neurodegenerative disorders and traumatic brain injury.

No MeSH data available.


Related in: MedlinePlus

Structure of 3′,5′-dichloro-2,6-dihydroxy-biphenyl-4-yl)-phenyl-methanone.
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fig01: Structure of 3′,5′-dichloro-2,6-dihydroxy-biphenyl-4-yl)-phenyl-methanone.

Mentions: The Ki for SMM-189 (Fig.1) was lower at the CB2 receptor with a value of 121.3 nmol/L compared to that found at the CB1 receptor 4778 nmol/L––a CB1/CB2 ratio of 39.4, demonstrating a modest selectivity of SMM-189 for the CB2 receptor (Table1). The functional activity of SMM-189 was evaluated using the ACTOne cell-based cAMP assay in HEK-CNG+CB1, HEK-CNG+CB2, and parental HEK-CNG cells. In the HEK-CNG+CB2 cell system, SMM-189 caused a dose-dependent increase in cAMP-driven fluorescence (∼55% over baseline) thus demonstrating the inverse agonist functional activity at CB2 (Fig.2A). Overnight treatment of the HEK-CNG+CB2 cells with pertussis toxin abolished the aforementioned inverse agonist activity (Fig.2C). This indicates that, in the ACTOne cell-based assay, CB2 manifests significant constitutive activity and the inactive state of CB2 bound by SMM-189 may sequester Gi/o resulting in increased adenylate cyclase activity. Treatment of the HEK-CNG+CB1 with increasing concentrations of SMM-189 resulted in an elevation in cAMP-driven fluorescence that was not significantly different from parental HEK-CNG cells (Fig.2B). In parental HEK-CNG cells, there was no change in cAMP-driven fluorescence (Fig.2D) thus SMM-189 selectively increases cAMP via CB2.


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

Presley C, Abidi A, Suryawanshi S, Mustafa S, Meibohm B, Moore BM - Pharmacol Res Perspect (2015)

Structure of 3′,5′-dichloro-2,6-dihydroxy-biphenyl-4-yl)-phenyl-methanone.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4506688&req=5

fig01: Structure of 3′,5′-dichloro-2,6-dihydroxy-biphenyl-4-yl)-phenyl-methanone.
Mentions: The Ki for SMM-189 (Fig.1) was lower at the CB2 receptor with a value of 121.3 nmol/L compared to that found at the CB1 receptor 4778 nmol/L––a CB1/CB2 ratio of 39.4, demonstrating a modest selectivity of SMM-189 for the CB2 receptor (Table1). The functional activity of SMM-189 was evaluated using the ACTOne cell-based cAMP assay in HEK-CNG+CB1, HEK-CNG+CB2, and parental HEK-CNG cells. In the HEK-CNG+CB2 cell system, SMM-189 caused a dose-dependent increase in cAMP-driven fluorescence (∼55% over baseline) thus demonstrating the inverse agonist functional activity at CB2 (Fig.2A). Overnight treatment of the HEK-CNG+CB2 cells with pertussis toxin abolished the aforementioned inverse agonist activity (Fig.2C). This indicates that, in the ACTOne cell-based assay, CB2 manifests significant constitutive activity and the inactive state of CB2 bound by SMM-189 may sequester Gi/o resulting in increased adenylate cyclase activity. Treatment of the HEK-CNG+CB1 with increasing concentrations of SMM-189 resulted in an elevation in cAMP-driven fluorescence that was not significantly different from parental HEK-CNG cells (Fig.2B). In parental HEK-CNG cells, there was no change in cAMP-driven fluorescence (Fig.2D) thus SMM-189 selectively increases cAMP via CB2.

Bottom Line: 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.Herein, we report the further characterization of SMM-189 as a potent and selective CB2 inverse agonist, which acts as a noncompetitive inhibitor of CP 55,940.The ability of SMM-189 to regulate microglial activation, in terms of chemokine expression and cell morphology, has been determined.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center Memphis, Tennessee.

ABSTRACT
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. Herein, we report the further characterization of SMM-189 as a potent and selective CB2 inverse agonist, which acts as a noncompetitive inhibitor of CP 55,940. The ability of SMM-189 to regulate microglial activation, in terms of chemokine expression and cell morphology, has been determined. Finally, we have determined that SMM-189 possesses acceptable biopharmaceutical properties indicating that the triaryl class of CB2 inverse agonists are viable compounds for continued preclinical development for the treatment of neurodegenerative disorders and traumatic brain injury.

No MeSH data available.


Related in: MedlinePlus