Identification of Darmstoff analogs as selective agonists and antagonists of lysophosphatidic acid receptors.
Darmstoff describes a family of gut smooth muscle-stimulating acetal phosphatidic acids initially isolated and characterized from the bath fluid of stimulated gut over 50 years ago. Despite similar structural and biological profiles, Darmstoff analogs have not previously been examined as potential LPA mimetics. Here, we report a facile method for the synthesis of potassium salts of Darmstoff analogs. To understand the effect of stereochemistry on lysophosphatidic acid mimetic activity, synthesis of optically pure stereoisomers of selected Darmstoff analogs was achieved starting with chiral methyl glycerates. Each Darmstoff analog was evaluated for subtype-specific LPA receptor agonist/antagonist activity, PPARgamma activation, and autotaxin inhibition. From this study we identified compound 12 as a pan-antagonist and several pan-agonists for the LPA(1-3) receptors. Introduction of an aromatic ring in the lipid chain such as analog 22 produced a subtype-specific LPA(3) agonist with an EC(50) of 692 nM. Interestingly, regardless of their LPA(1/2/3) ligand properties all of the Darmstoff analogs tested activated PPARgamma. However, these compounds are weak inhibitors of autotaxin. The results indicate that Darmstoff analogs constitute a novel class of lysophosphatidic acid mimetics.
Gududuru
Veeresa
V
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Zeng
Kui
K
Tsukahara
Ryoko
R
Makarova
Natalia
N
Fujiwara
Yuko
Y
Pigg
Kathryn R
KR
Baker
Daniel L
DL
Tigyi
Gabor
G
Miller
Duane D
DD
D000818:Animals; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D066298:In Vitro Techniques; D008024:Ligands; D008968:Molecular Conformation; D047495:PPAR gamma / Q000187:drug effects; D010712:Phosphatidic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049368:Receptors, Lysophosphatidic Acid / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D008024:Ligands; D047495:PPAR gamma; D010712:Phosphatidic Acids; D049368:Receptors, Lysophosphatidic Acid; C015775:darmstoff