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

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.

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

“…We have previously reported this method as part of our pre-clinical evaluation of SMM-189. 44 The method provided good correlation between the K i and EC 50 values; however, the K i deviated significantly from the previous determination 48 in part due to differences in K d and B max of the preparations. A second consideration stemmed from the identification that SMM-189 is a non-competitive antagonist against CP 55,940, thus indicating an overlapping binding site.…”

“…48 In the evaluation of the functional activity of the compounds it was discovered that SMM-189 exhibited selective inverse agonist activity at CB2. 44 Based on the potential of CB2 inverse agonist in treating CNS diseases, we demonstrated that SMM-189 beneficially down-regulates cytokine and chemokine production in LPS stimulated primary human microglia. 25,44 Subsequent testing of SMM-189 in the murine model of mild traumatic brain injury (mTBI), and pre-clinical evaluation of biopharmaceutical properties, demonstrated the protective effects of SMM-189 in mTBI and indicated that the 2,6-dihydroxy-biphenyl-aryl-methanone scaffold has acceptable drug-like properties to warrant further investigation.…”

“…44 Based on the potential of CB2 inverse agonist in treating CNS diseases, we demonstrated that SMM-189 beneficially down-regulates cytokine and chemokine production in LPS stimulated primary human microglia. 25,44 Subsequent testing of SMM-189 in the murine model of mild traumatic brain injury (mTBI), and pre-clinical evaluation of biopharmaceutical properties, demonstrated the protective effects of SMM-189 in mTBI and indicated that the 2,6-dihydroxy-biphenyl-aryl-methanone scaffold has acceptable drug-like properties to warrant further investigation. 25 The potential of the scaffold for developing selective CB2 inverse agonist prompted us to investigate the functional group requirements required for activity.…”

“…1 White solid (138 mg, 69%). 1 44 for membrane preparation methods], and 50 µL test ligand in binding buffer (final concentrations: 1 nM to 10 µM). Plates were incubated at 30°C for 90 minutes.…”

“…43 The triaryl bis-sulfones (Sch 414319), and our 2,6-dihydroxy-biphenyl-aryl-methanone analog (SMM-189), represent additional scaffolds that are being investigated as CB2 inverse agonists. 41,44 Raloxifen, himbacine and cannabidiol have also been reported to function as inverse agonist of CB2. [45][46][47] Undoubtedly the diversity of CB2 inverse agonist scaffolds will continue to expand owing to the as yet untapped potential in treating inflammation and immune system disorders.…”