Evaluation of ampyrone (4-aminoantipyrine), an activator of the intra-melanosomal domain of human tyrosinase, as a potential therapeutic agent for oculocutaneous albinism type 1B

Abstract

Purpose : To evaluate the role of 4-aminoantipyrine (ampyrone) in improving pigmentation in a mouse model of oculocutaneous albinism type 1B (OCA1B).

Methods : We used high-throughput screening (HTS) to identify potential activators and inhibitors of the intra-melanosomal domain of human tyrosinase (hTyr). Activators were investigated by in vitro enzymology. C57BL/6J-Tyr^c-h/c-h mice (a model of OCA1B) were intraperitoneally (i.p.) injected with three doses of ampyrone for thirty days and evaluated for increased melanin pigmentation in the fur and eyes using clinical/biochemical methods and light/electron microscopy.

Results : High-throughput screening of ~34,000 unique compounds identified 115 candidate inhibitors and 9 candidate activators of hTyr enzymatic activity. Among the activators, ampyrone increased the in vitro catalytic efficiency of the OCA1B-related hTyr variant P406L by ~40%, suggesting a partial recovery of function. Treating OCA1B mice with ampyrone up to 48 mg/kg/day i.p. for 30 days resulted in a mild improvement of melanin deposition in fur, as determined by spectrophotometric analysis. However, data on changes in pigmentation of iris and retinal pigment epithelium upon treatment were inconclusive.

Conclusions : Our data support the use of HTS for the identification of candidate compounds to modulate tyrosinase activity. The limited effect of ampyrone on pigmentation, especially in eye tissues, suggests the need to expand the pool of candidate activators through alternative screening strategies and to combine in vitro with in vivo testing for the identification of promising candidates.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.