Phosphorothioate analogues of alkyl lysophosphatidic acid as LPA3 receptor-selective agonists.
The metabolically stabilized LPA analogue 1-oleoyl-2-O-methyl-rac-glycerophosphorothioate (OMPT) was recently shown to be a potent subtype-selective agonist for LPA3, a G-protein-coupled receptor (GPCR) in the endothelial differentiation gene (EDG) family. Further stabilization was achieved by replacing the sn-1 O-acyl group with an O-alkyl ether. A new synthetic route for the enantiospecific synthesis of the resulting alkyl LPA phosphorothioate analogues is described. The pharmacological properties of the alkyl OMPT analogues were characterized for subtype-specific agonist activity using Ca2+-mobilization assays in RH7777 cells expressing the individual EDG family LPA receptors. Alkyl OMPT analogues induced cell migration in cancer cells mediated through LPA1. Alkyl OMPT analogues also activated Ca2+ release through LPA2 activation but with less potency than sn-1-oleoyl LPA. In contrast, alkyl OMPT analogues were potent LPA3 agonists. The alkyl OMPTs 1 and 3 induced cell proliferation at submicromolar concentrations in 10T 1/2 fibroblasts. Interestingly, the absolute configuration of the sn-2 methoxy group of the alkyl OMPT analogues was not recognized by any of the LPA receptors in the EDG family. By using a reporter gene assay for the LPA-activated nuclear transcription factor PPARgamma, we demonstrated that phosphorothioate diesters have agonist activity that is independent of their ligand properties at the LPA-activated GPCRs. The availability of new alkyl LPA analogues expands the scope of structure-activity studies and will further refine the molecular nature of ligand-receptor interactions for this class of GPCRs.
Qian
Lian
L
Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, Utah 84108-1257, USA.
Xu
Yong
Y
Simper
Ted
T
Jiang
Guowei
G
Aoki
Junken
J
Umezu-Goto
Makiko
M
Arai
Hiroyuki
H
Yu
Shuangxing
S
Mills
Gordon B
GB
Tsukahara
Ryoko
R
Makarova
Natalia
N
Fujiwara
Yuko
Y
Tigyi
Gabor
G
Prestwich
Glenn D
GD
D000818:Animals; D002460:Cell Line; D008246:Lysophospholipids / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D009943:Organophosphorus Compounds / Q000737:chemistry*; D049368:Receptors, Lysophosphatidic Acid / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D008246:Lysophospholipids; D009943:Organophosphorus Compounds; D049368:Receptors, Lysophosphatidic Acid; C032881:lysophosphatidic acid