Molecular basis for lysophosphatidic acid receptor antagonist selectivity.
Recent characterization of lysophosphatidic acid (LPA) receptors has made possible studies elucidating the structure-activity relationships (SAR) for agonist activity at individual receptors. Additionally, the availability of these receptors has allowed the identification of antagonists of LPA-induced effects. Two receptor-subtype selective LPA receptor antagonists, one selective for the LPA1/EDG2 receptor (a benzyl-4-oxybenzyl N-acyl ethanolamide phosphate, NAEPA, derivative) and the other selective for the LPA3/EDG7 receptor (diacylglycerol pyrophosphate, DGPP, 8:0), have recently been reported. The receptor SAR for both agonists and antagonists are reviewed, and the molecular basis for the difference between agonism and antagonism as well as for receptor-subtype antagonist selectivity identified by molecular modeling is described. The implications of the newly available receptor-subtype selective antagonists are also discussed.
Sardar
Vineet M
VM
Department of Chemistry and Computational Research on Materials Institute, The University of Memphis, Memphis, TN 38152-6060, USA.
Bautista
Debra L
DL
Fischer
David J
DJ
Yokoyama
Kazuaki
K
Nusser
Nora
N
Virag
Tamas
T
Wang
De-an
DA
Baker
Daniel L
DL
Tigyi
Gabor
G
Parrill
Abby L
AL
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010743:Phospholipids / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D008024:Ligands; D010743:Phospholipids; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid