A new synthetic ether aminophosphoglyceride exhibits partial modulator activity towards the glucocorticoid receptor.
Modulator is an endogenous low-molecular weight regulator of both glucocorticoid and mineralocorticoid receptors, as well as protein kinase C. Analogs of the putative modulator structure have been synthesized. These compounds include 1-O-(3'-carboxypropyl) or (5'-carboxypentyl)-L-glycero-3-phospho-L-serine or L-threonine, and the D-glycerol stereoisomers. These compounds were tested for in vitro modulator activity using the glucocorticoid-receptor complex activation inhibition and steroid-binding stabilization assays. One of the ether phosphoglycerides, 1-O-(5'-carboxypentyl)-L-glycero-3-phospho-L-threonine (H-GPT-1), partially inhibited steroid-receptor complex activation in a dose-dependent manner. However, none of the other compounds exhibited any modulator activity towards the glucocorticoid-receptor complex. Like modulator, H-GPT-1 did not inhibit activated glucocorticoid-receptor complex binding to DNA-cellulose. Surprisingly, in contrast to modulator, H-GPT-1 partially inhibited unoccupied receptor steroid-binding in a dose-dependent manner. These results suggest that although modulator is not exactly mimicked by this compound, H-GPT-1 is the first synthetic organic molecule to exhibit some modulator activity towards the glucocorticoid receptor.
Bodine
P V
PV
Department of Pharmacology, College of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Hajdu
J
J
Litwack
G
G
D000315:Adrenalectomy; D000818:Animals; D002846:Chromatography, Affinity; D003600:Cytosol / Q000378:metabolism; D005994:Glycerophosphates / Q000138:chemical synthesis / Q000494:pharmacology*; D007202:Indicators and Reagents; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D010769:Phosphothreonine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000302:isolation & purification / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid / Q000187:drug effects / Q000302:isolation & purification / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014222:Triamcinolone Acetonide / Q000378:metabolism
D005994:Glycerophosphates; D007202:Indicators and Reagents; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D010769:Phosphothreonine; C089110:1-O-(5'-carboxypentyl)glycero-3-phosphothreonine; D014222:Triamcinolone Acetonide