Small-molecule antagonists of melanopsin-mediated phototransduction

Abstract

Melanopsin, expressed in a subset of retinal ganglion cells, mediates behavioral adaptation to ambient light and other non-image forming photic responses. This has raised the possibility that pharmacological manipulation of melanopsin can modulate several CNS responses including photophobia, sleep, circadian rhythms and neuroendocrine function. Here we describe the identification of a potent synthetic melanopsin antagonist with in vivo activity. Novel sulfonamide compounds inhibiting melanopsin (opsinamides) compete with retinal binding to melanopsin and inhibit its function without affecting rod/cone mediated responses. In vivo administration of opsinamides to mice specifically and reversibly modified melanopsin-dependent light responses including the pupillary light reflex and light aversion. The discovery of opsinamides raises the prospect of therapeutic control of the melanopsin phototransduction system to regulate light-dependent behavior and remediate pathological conditions.

Development of a Chromatic Pupillography Protocol for the First Gene Therapy Trial in Patients With CNGA3-Linked Achromatopsia

“…The involvement of ipRGCs in photophobia has been described in mice. [24][25][26] It has been confirmed that the pupil diameter increases when ipRGC and rod excitation is at a minimum. 27 Furthermore, there is strong evidence of an inhibiting influence of S-cones on ipRGCs.…”

Retinal Attachment Instability Is Diversified among Mammalian Melanopsins

“…Previous studies have found the absorption maxima of purified melanopsins and the maximal spectral sensitivity of melanopsin-expressing cultured cells are both around 480 nm (13, 14, 16 -21). Although some G q -independent signaling by melanopsin has been suggested (22), a variety of melanopsins are reported to show light-dependent G q activation in vivo and in vitro (14,17,18,(23)(24)(25)(26), consistent with their high sequence similarity with the invertebrate visual pigments, which also use G q -dependent signaling (7,9) (Fig. 1A).…”

“…Because melanopsins are coupled with G q -type G proteins, light-dependent G q activation by melanopsin can be detected as an increase in the Ca 2ϩ -activated Cl Ϫ current (14, 39,40). To detect the difference in the retinal release rate from melanopsin, melanopsin-expressing oocytes were treated with retinal and subsequently incubated at 37°C in the dark for 90 min in the presence or absence of a melanopsin-specific antagonist AA92593 (24). A previous study has shown that the antagonist can bind to the retinal-free form of melanopsin and block retinal binding to the protein, leading to reduction of light-dependent current by melanopsin (24).…”

Circadian Clock and Stress Interactions in the Molecular Biology of Psychiatric Disorders

“…Indeed, it has been suggested that the mood stabilizer lithium may have a circadian mechanism of action [97], and casein kinase 1δ/ε inhibitors have shown promise in pre-clinical animal models of AUD [121] and BD [122]. Additional compounds have been developed to target the ROR/REV-ERB nuclear receptors [123], CRYs [124], melanopsin-containing photoreceptors [125] and other complex mechanisms [123] that strongly affect circadian rhythms, but remain poorly characterized with respect to brain effects and potential as treatments for psychiatric conditions. Suppression of GC synthesis with metyrapone counteracts the elevations in GC levels associated with environmental changes, and accelerates the clock's adaptation, potentially offering the means to better adjust the circadian system to stressful environments [23].…”