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Beschreibung

A sulfonamide compound that prevents melanopsin/Opn4 photoactivation in a reversible and cis-Retinal-competitive manner (Kb = 6 and 0.16 µ,M in competitive binding studies using Opn4 pre-bound with cis-Retinal or not) without apparent affinity toward bovine retina rhodopsin or a panel of 74 other receptors, ion channels, and enzymes. Effectively inhibits cellular phototransduction mediated by human Opn4 in CHO transfectants (IC50 = 665 nM, drug added 30 min before 10 µ,M 9-cis-Retinal & photoactivation), by murine Opn4 in transfected Xenopus oocytes (IC50 = 190 nM, drug added 3 min before 50 µ,M 11-cis-Retinal and photoactivation), as well as by endogenous Opn4 in primary rat ipRGCs (intrinsically photosensitive retinal ganglion cells, 10 µ,M). Shown to be bioavailable in mice via i.p. injection (retina [AA92593] ~7.5 µ,M 30 min post 30 mg/kg i.p. dosing, >95% clearance within 2 h) and effectively suppress PLR (pupillary light reflex, pupil constriction) in a time- and Opn4-dependent manner in mice in vivo. Likewise, blue light insensitivity is observed in Opn4-/- and AA92593-treated wild-type, but not vehicle-treated wild-type, P14 neonatal mice., A sulfonamide compound that prevents melanopsin/Opn4 photoactivation in a reversible and cis-Retinal-competitive manner without apparent affinity toward bovine retina rhodopsin or a panel of 74 other receptors, ion channels, and enzymes. Effectively inhibits cellular phototransduction mediated by human Opn4 (IC50 = 665 nM, using CHO transfectants), murine Opn4 (IC50 = 190 nM, using transfected Xenopus oocytes), and rat Opn4 (10 µ,M, using primary rat ipRGCs). Shown to effectively suppress PLR (pupillary light reflex, pupil constriction) in a time- and Opn4-dependent manner in mice (30 mg/kg i.p.) in vivo. Likewise, blue light insensitivity is observed in Opn4-/- and AA92593-treated wild-type, but not vehicle-treated wild-type, P14 neonatal mice.