Renal drug targeting using a vector "alkylglycoside"

A specific sugar-modified peptide has previously been shown to have renal t argeting potential in vivo and to have a specific binding site which has be en identified in the kidney membrane fraction. in this report, we studied t he inhibitory effects of glycosylated derivatives on the binding of [H-3]Gl c-O-C8-AVP la glucosylated derivative of Arg(8)-vasopressin (AVP), K-d = 55 nM] to clarify the structural requirements necessary for renal recognition . Glc-S-C7-Me (octyl-beta-D-thioglucoside) markedly inhibited the binding, to a much greater extent than Glc-O-C7-Me (octyl beta-D-glucoside) and Ga[- S-C7-Me (octyl beta-D-thiogalactoside). Also, [H-3]Glc-S-C7-Me was shown to have a specific binding site on the kidney membrane (K-d = 17 nM, B-max = 24 pmol/mg protein) rather than the liver membrane and, in addition, Glc-S- C7-Me exhibited effective and selective renal uptake in vivo. To examine th e possibility that Glc-S-C7-Me might be of practical use as a renal targeti ng vector, AVP, tryptamine and 4-nitrobenz-2-oxa-1,3-diazole were modified with Glc-S-C8- and the tissue uptake of the resulting derivatives was evalu ated. Ail of these derivatives showed clear renal targeting potential becau se the apparent uptake clearance by the kidney was greater than 3 ml/min/g kidney in each case. As far as the AVP derivatives were concerned, derivati ves having different numbers of methylene groups were compared with Glc-S-C 8-AVP. Glc-S-C11-AVP exhibited increased kidney targeting potential, wherea s that of Glc-S-C5-AVP was reduced. These differences suggest that the "alk ylglycoside" moiety is important for renal uptake. in addition, these renal ly targeted derivatives inhibited the binding of [H-3]Glc-S-C7-Me to the ki dney membrane fraction. Our findings allow us to conclude that the alkylgly coside is a suitable candidate vector for renal targeting.