Mechanism of action of aromatic amines that short-circuit the visual cycle

DAPP [1,5-bis(p-aminophenoxy)pentane] is an antischistosomal drug that can inhibit dark adaptation in vertebrates by impairing formation of 11-cis-retinoids in the eye and by depleting preformed stores of them [Bernstein, P. S., & Rando, R. R. (1985) Vis. Res. 25, 741-748]. It has recently been shown that p-phenetidine and other monofunctional analogues of DAPP (a symmetric bifunctional molecule) can duplicate DAPP's effects, and it was proposed that these retinotoxic compounds exert their effects in vivo by "short-circuiting" the visual cycle, catalyzing the thermodynamically downhill isomerization of 11-cis-retinal to all-trans-retinal [Bernstein, P. S., Lichtman, J. R., & Rando, R. R. (1986) Proc. Natl. Acad. Sci. U.S.A. 83, 1632-1635]. In this paper, the "short-circuit" hypothesis is investigated more fully. Numerous phenetidine-like molecules are assayed for their ability to inhibit rhodopsin formation and 11-cis-retinyl palmitate formation in the living frog eye. It is found that virtually any aromatic amine with a moderately hydrophobic alkyl chain "tail" is an active inhibitor in vivo. The tail can be in either the para or the meta position and can be attached to the aromatic ring either by direct linkage or by an ether linkage. Compounds that can be metabolized in vivo to such active compounds are also inhibitory. Amino group modification studies demonstrate an absolute requirement for structures that can form a Schiff base with retinal.(ABSTRACT TRUNCATED AT 250 WORDS)