Identification of Bivalent Ligands with Melatonin Receptor Agonist and Fatty Acid Amide Hydrolase (FAAH) Inhibitory Activity That Exhibit Ocular Hypotensive Effect in the Rabbit

Abstract

Activation of melatonin receptors and inhibition of fatty acid amide hydrolase (FAAH) have both shown potential benefits for the treatment of glaucoma. To exploit the combination of these biological activities in single therapeutic agents, we designed dual-acting compounds sharing the pharmacophore elements required for the two targets, in search for balanced potencies as MT/MT agonists and FAAH inhibitors. In particular, the N-anilinoethylamide scaffold, previously developed for melatonergic ligands, was decorated at meta position with a polymethylene linker bound to an O-arylcarbamate group, substituted according to known structure-activity relationships for FAAH inhibition. For the most active series, the N-anilinoethylamide portion was also replaced with the indole scaffold of melatonin. O-Biphenyl-3-ylcarbamate derivatives were characterized by remarkable and balanced activity at both targets, in the nanomolar range for compound 29. Topical administration reduced elevated intraocular pressure in rabbits, with a longer action and improved efficacy compared to the reference compounds melatonin and URB597.

Phenotype Screening of an Azole-bisindole Chemical Library Identifies URB1483 as a New Antileishmanial Agent Devoid of Toxicity on Human Cells

“…Docking studies were performed with Glide included in the Schrodinger software package ( 34 ) starting from LdTOP1LS-DNA-topotecan ternary model described above, following a protocol successfully applied to predict the docking pose of indole-containing compounds. 35 The docking grid was centered on the position of topotecan ligand. Dimensions of enclosing and bounding boxes were set to 20 and 10 Å on each side, respectively, and van der Waals radii of protein atoms were not scaled during grid generation.…”

How to Modulate the Immunoinflammatory Biological Response in Cancer, Autoimmunity and Viral Infections by a Psychoneuroimmune Approach

“…MLT, as well as 5-methoxytryptamine, at high pharmacological doses have also appeared to protect against DNA damage-and lymphocyte death-induced by x-ray irradiation [57]. MLT is also essential for the maintenance of cannabinoid system function by counteracting an excessive activity of FAAH [58], which could determine an endocannabinoid deficiency, and a consequent predisposition to most human systemic diseases. In fact, abnormally high blood levels of FAAH, and a consequent endocannabinoid system failure, may predispose to cancer and cardiovascular disorders, as well as to more severe complications during viral infections [45].…”

Melatonin receptor ligands: A pharmaco‐chemical perspective

“…Due to the claimed antioxidant property of melatonin, several groups have been attracted by the idea of synthesizing mixed compounds, for example, melatonin linked to the “multi‐active” molecule curcumin 145,146 or melatonin linked to the selective estrogen receptor modulator, tamoxifen 147 . Other examples of dually acting ligands are hybrids composed of MT 1 /MT 2 agonists and fatty acid amide hydrolase inhibitor 148 and of melatonin linked to p‐benzoquinone methide 149 . Of note, some natural derivatives, such as magnolol, 150 have been described and could represent a pharmacophore out of the already explored structures; however, because of their low affinities (100 µmol/L), their “usefulness” as novel melatoninergic ligands awaits further testing in vivo.…”