Synthesis and evaluation of potent and selective MGL inhibitors as a glaucoma treatment |
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Authors: | Shakiru O Alapafuja Michael S Malamas Vidyanand Shukla Alexander Zvonok Sally Miller Laura Daily Girija Rajarshi Christina Yume Miyabe Honrao Chandrashekhar JodiAnne Wood Sergiy Tyukhtenko Alex Straiker Alexandros Makriyannis |
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Institution: | 1. Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA;2. MAK Scientific LLC, 151 South Bedford Street, Burlington, MA 01803 USA;3. Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, USA |
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Abstract: | Monoacylglycerol lipase (MGL) inhibition provides a potential treatment approach to glaucoma through the regulation of ocular 2-arachidonoylglycerol (2-AG) levels and the activation of CB1 receptors. Herein, we report the discovery of new series of carbamates as highly potent and selective MGL inhibitors. The new inhibitors showed potent nanomolar inhibitory activity against recombinant human and purified rat MGL, were selective (>1000-fold) against serine hydrolases FAAH and ABHD6 and lacked any affinity for the cannabinoid receptors CB1 and CB2. Protein-based 1H NMR experiments indicated that inhibitor 2 rapidly formed a covalent adduct with MGL with a residence time of about 6?h. This interconversion process “intrinsic reversibility” was exploited by modifications of the ligand’s size (length and bulkiness) to generate analogs with “tunable’ adduct residence time (τ). Inhibitor 2 was evaluated in a normotensive murine model for assessing intraocular pressure (IOP), which could lead to glaucoma, a major cause of blindness. Inhibitor 2 was found to decrease ocular pressure by ~4.5?mmHg in a sustained manner for at least 12?h after a single ocular application, underscoring the potential for topically-administered MGL inhibitors as a novel therapeutic target for the treatment of glaucoma. |
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Keywords: | Glaucoma Monoacylglycerol lipase (MGL) Fatty acid amide hydrolase (FAAH) CB1 CB2 cannabinoid receptors Anandamide (AEA) Corresponding authors |
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