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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

(A) In HEK-CNG+CB1 cells, SMM-189 has no effect on CP 55,940 activity. (B) In HEK-CNG+CB2 cells, SMM-189 increases maximum cAMP activity even in the presence of CP 55,940. N = 7, error bars ±SEM. Asterisks at the lowest tested concentration of CP 55,940 represent a significant SMM-189-driven increase in cAMP levels above basal levels, **P < 0.01 (t-test with basal). Asterisks at the highest tested concentration of CP 55,940 represent a significant increase in cAMP levels relative to CP 55,940 cAMP suppression, *P < 0.05, and **P < 0.01. Asterisks next to different tested concentrations of SMM-189 represent significant increases in the EC50 of CP 55,940 from base line levels, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. HEK-CNG+CB1, Human embryonic kidney cells transfected with a cyclic nucleotide-gated channel and cannabinoid receptor 1; SMM-189, 3′,5′-dichloro-2,6-dihydroxy-biphenyl-4-yl)-phenyl-methanone.
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fig03: (A) In HEK-CNG+CB1 cells, SMM-189 has no effect on CP 55,940 activity. (B) In HEK-CNG+CB2 cells, SMM-189 increases maximum cAMP activity even in the presence of CP 55,940. N = 7, error bars ±SEM. Asterisks at the lowest tested concentration of CP 55,940 represent a significant SMM-189-driven increase in cAMP levels above basal levels, **P < 0.01 (t-test with basal). Asterisks at the highest tested concentration of CP 55,940 represent a significant increase in cAMP levels relative to CP 55,940 cAMP suppression, *P < 0.05, and **P < 0.01. Asterisks next to different tested concentrations of SMM-189 represent significant increases in the EC50 of CP 55,940 from base line levels, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. HEK-CNG+CB1, Human embryonic kidney cells transfected with a cyclic nucleotide-gated channel and cannabinoid receptor 1; SMM-189, 3′,5′-dichloro-2,6-dihydroxy-biphenyl-4-yl)-phenyl-methanone.

Mentions: The functional activity of SMM-189 was further studied by assessing its antagonistic effects on agonist-driven decreases in cAMP fluorescence production. The nonselective CB1 and CB2 agonist CP 55,940 were selected as our control compound (Govaerts et al. 2004). In the HEK-CNG+CB1 and HEK-CNG+CB2, the control CP 55,940 demonstrated an average 90 percent reduction in cAMP response, whereas no response was observed using the parental HEK-CNG cells. Competition studies using SMM-189 against CP 55,940 in HEK-CNG+CB1 cells showed that SMM-189 has no significant effect in shifting cAMP response curves (Fig.3A), which is consistent with its very weak receptor binding and lack of CB1 receptor functional activity.


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)

(A) In HEK-CNG+CB1 cells, SMM-189 has no effect on CP 55,940 activity. (B) In HEK-CNG+CB2 cells, SMM-189 increases maximum cAMP activity even in the presence of CP 55,940. N = 7, error bars ±SEM. Asterisks at the lowest tested concentration of CP 55,940 represent a significant SMM-189-driven increase in cAMP levels above basal levels, **P < 0.01 (t-test with basal). Asterisks at the highest tested concentration of CP 55,940 represent a significant increase in cAMP levels relative to CP 55,940 cAMP suppression, *P < 0.05, and **P < 0.01. Asterisks next to different tested concentrations of SMM-189 represent significant increases in the EC50 of CP 55,940 from base line levels, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. HEK-CNG+CB1, Human embryonic kidney cells transfected with a cyclic nucleotide-gated channel and cannabinoid receptor 1; SMM-189, 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

fig03: (A) In HEK-CNG+CB1 cells, SMM-189 has no effect on CP 55,940 activity. (B) In HEK-CNG+CB2 cells, SMM-189 increases maximum cAMP activity even in the presence of CP 55,940. N = 7, error bars ±SEM. Asterisks at the lowest tested concentration of CP 55,940 represent a significant SMM-189-driven increase in cAMP levels above basal levels, **P < 0.01 (t-test with basal). Asterisks at the highest tested concentration of CP 55,940 represent a significant increase in cAMP levels relative to CP 55,940 cAMP suppression, *P < 0.05, and **P < 0.01. Asterisks next to different tested concentrations of SMM-189 represent significant increases in the EC50 of CP 55,940 from base line levels, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. HEK-CNG+CB1, Human embryonic kidney cells transfected with a cyclic nucleotide-gated channel and cannabinoid receptor 1; SMM-189, 3′,5′-dichloro-2,6-dihydroxy-biphenyl-4-yl)-phenyl-methanone.
Mentions: The functional activity of SMM-189 was further studied by assessing its antagonistic effects on agonist-driven decreases in cAMP fluorescence production. The nonselective CB1 and CB2 agonist CP 55,940 were selected as our control compound (Govaerts et al. 2004). In the HEK-CNG+CB1 and HEK-CNG+CB2, the control CP 55,940 demonstrated an average 90 percent reduction in cAMP response, whereas no response was observed using the parental HEK-CNG cells. Competition studies using SMM-189 against CP 55,940 in HEK-CNG+CB1 cells showed that SMM-189 has no significant effect in shifting cAMP response curves (Fig.3A), which is consistent with its very weak receptor binding and lack of CB1 receptor functional activity.

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