Non-naturally Occurring Regio Isomer of Lysophosphatidylserine Exhibits Potent Agonistic Activity toward G Protein-Coupled Receptors

Lysophosphatidylserine
(LysoPS), an endogenous ligand of G protein-coupled
receptors, consists of l-serine, glycerol, and fatty acid
moieties connected by phosphodiester and ester linkages, respectively.
An ester linkage of phosphatidylserine can be hydrolyzed at the 1-position
or at the 2-position to give 2-acyl lysophospholipid or 1-acyl lysophospholipid,
respectively. 2-Acyl lysophospholipid is in nonenzymatic equilibrium
with 1-acyl lysophospholipid in vivo. On the other
hand, 3-acyl lysophospholipid is not found, at least in mammals, raising
the question of whether the reason for this might be that the 3-acyl
isomer lacks the biological activities of the other isomers. Here,
to test this idea, we designed and synthesized a series of new 3-acyl
lysophospholipids. Structure–activity relationship studies
of more than 100 “glycol surrogate” derivatives led
to the identification of potent and selective agonists for LysoPS
receptors GPR34 and P2Y10. Thus, the non-natural 3-acyl compounds
are indeed active and appear to be biologically orthogonal with respect
to the physiologically relevant 1- and 2-acyl lysophospholipids.