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Synthesis and evaluation of potent and selective MGL inhibitors as a glaucoma treatment.

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.

SUBMITTER: Alapafuja SO

PROVIDER: S-EPMC8344409 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Synthesis and evaluation of potent and selective MGL inhibitors as a glaucoma treatment.

Alapafuja Shakiru O SO Malamas Michael S MS Shukla Vidyanand V Zvonok Alexander A Miller Sally S Daily Laura L Rajarshi Girija G Miyabe Christina Yume CY Chandrashekhar Honrao H Wood JodiAnne J Tyukhtenko Sergiy S Straiker Alex A Makriyannis Alexandros A

Bioorganic & medicinal chemistry 20181103 1

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 an ...[more]

PMID: 30446439

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Synthesis and evaluation of potent and selective MGL inhibitors as a glaucoma treatment.

Publications

Synthesis and evaluation of potent and selective MGL inhibitors as a glaucoma treatment.

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