Synthesis and characterization of a novel retinylamine analog inhibitor of constitutively active rhodopsin mutants found in patients with autosomal dominant retinitis pigmentosa.
Two different mutations of the active-site Lys-296 in rhodopsin, K296E and K296M, have been found to cause autosomal dominant retinitis pigmentosa (ADRP). In vitro studies have shown that both mutations result in constitutive activation of the protein, suggesting that the activated state of the receptor may be responsible for retinal degeneration in patients with these mutations. Previous work has highlighted the potential of retinylamine analogs as active-site directed inactivators of constitutively active mutants of rhodopsin with the idea that these or related compounds might be used therapeutically for cases of ADRP involving mutations of the active-site Lys. Unfortunately, however, amine derivatives of 11-cis-retinal, although highly effective against a K296G mutant of rhodopsin, were without affect on the two naturally occurring ADRP mutants, presumably because of the greater steric bulk of Glu and Met side chains in comparison to Gly. For this reason we synthesized a retinylamine analog one carbon shorter than the parent 11-cis-retinal and show that this compound is indeed an effective inhibitor of both the K296E and K296M mutants. The 11-cis C19 retinylamine analog 1 inhibits constitutive activation of transducin by these mutants and their constitutive phosphorylation by rhodopsin kinase, and it does so in the presence of continuous illumination from room lights.
Yang
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Graduate Department of Biochemistry and Volen Center for Complex Systems, Brandeis University, Waltham, MA 02254, USA.
Snider
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BB
Oprian
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D000818:Animals; D001665:Binding Sites / Q000235:genetics; D019556:COS Cells; D004224:Diterpenes / Q000138:chemical synthesis* / Q000494:pharmacology*; D005799:Genes, Dominant; D006801:Humans; D066298:In Vitro Techniques; D010766:Phosphorylation; D017354:Point Mutation; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D012172:Retinaldehyde / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D012174:Retinitis Pigmentosa / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D012243:Rhodopsin / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism
C109617:15-nor-13,14-dihydroretinyl-14-amine; D004224:Diterpenes; D011994:Recombinant Proteins; D012243:Rhodopsin; D012172:Retinaldehyde