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

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 MT1/MT2 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.