Evaluation of synthetic novel ether aminophosphoglycerides for glucocorticoid-receptor complex modulator activity.
Modulator is an endogenous low-mol wt regulator of the glucocorticoid-receptor complex. Structural analysis of purified modulator suggested that it was a novel ether aminophosphoglyceride (Bodine and Litwack 1988b). Analogs of the putative modulator structure have now been synthesized. The synthetic compounds are 1-O-(6-carboxylhexyl)-glycero-3-phosphoserine and the sn-2-methoxy and sn-1-ethylester derivatives. Like modulator, these novel synthetic compounds are water soluble. However, thin-layer chromatography and spectroscopic analysis of these phosphoglycerides indicated significant structural differences between modulator and the synthetic analogs. In particular, the chromatographic behavior of the compounds suggests that modulator is more highly charged than the synthetic derivatives. The synthetic compounds, as well as lysophosphatidylserine, were also tested for in vitro modulator activity using the glucocorticoid-receptor complex activation inhibition and steroid-binding stabilization assays. None of the analogs exhibited modulator activity in these assays. However, the synthetic compounds were generally less detrimental to receptor steroid-binding than lysophosphatidylserine. From this work, we conclude that although modulator is not mimicked by one of these synthetic phosphoglycerides, a starting point for future structure-function studies has nonetheless been established.
Bodine
P V
PV
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140.
Garcia
M L
ML
Pascual
J
J
Bastida
E
E
Carganico
G
G
Litwack
G
G
D000588:Amines / Q000494:pharmacology*; D000818:Animals; D002482:Cellulose / Q000031:analogs & derivatives / Q000378:metabolism; D002855:Chromatography, Thin Layer; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004987:Ethers / Q000494:pharmacology*; D005994:Glycerophosphates / Q000494:pharmacology*; D006882:Hydroxyapatites / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000187:drug effects* / Q000378:metabolism; D013256:Steroids / Q000378:metabolism
D000588:Amines; C033190:DNA-cellulose; D004987:Ethers; D005994:Glycerophosphates; D006882:Hydroxyapatites; D008246:Lysophospholipids; D011965:Receptors, Glucocorticoid; D013256:Steroids; C079271:1-O-(6-carboxylhexyl)glycero-3-phosphoserine; D002482:Cellulose; D004247:DNA