AA92593 is able to decrease IOP in rabbits living under normal light condition[2]. AA92593 produces an increment in melatonin levels resulting in a drop of IOP[2]. Animal Model: Wild type (WT) mice[4]. Dosage: 30 mg/kg. Administration: IP 20 min prior to PLR measurement. Result: Attenuated pupil constriction in response to light (1013 ph.cm−2.s−1) by ~50%.
In Vitro
AA92593 is a competitive melanopsin antagonist, its presence in the retinal-binding pocket of melanopsin leads to the displacement of retinal, which could trigger a downstream signaling that would ultimately result in Per1 increased expression[1]. AA92593 is shown to be specific because it competes with retinaldehyde for the melanopsin retinal binding site which is very distinct from other opsins[1]. Inhibition of melanopsin activity with AA92593 increases a-MSH expression and induces melanin dispersion in the melanophores, which darkens the embryo[3]. AA92593 exhibits an IC50 of 665 nM in CHOOpn4 cells[4]. Cell Viability Assay[1] Cell Line: Melan-a melanocytes and B16-F10 melanoma cells[1]. Concentration: 10 μM. Incubation Time: 1 hour (heat 39.5 °C). Result: Pharmacologically inhibited melanopsin.
Kinase Assay
Cell Assay
Animal Administration
References
[1]. Maria Nathália Moraes, et al. Melanopsin, a Canonical Light Receptor, Mediates Thermal Activation of Clock Genes. Sci Rep. 2017 Oct 25;7(1):13977.
[2]. Victoria Eugenia Lledó, et al. Yellow Filter Effect on Melatonin Secretion in the Eye: Role in IOP Regulation. Curr Eye Res. 2019 Jun;44(6):614-618.
[3]. Gabriel E Bertolesi, et al. Melanopsin photoreception in the eye regulates light-induced skin colour changes through the production of α-MSH in the pituitary gland. Pigment Cell Melanoma Res. 2015 Sep;28(5):559-71.
[4]. Kenneth A Jones, et al. Small-molecule antagonists of melanopsin-mediated phototransduction. Nat Chem Biol. 2013 Oct;9(10):630-5.
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