posted on 2023-12-11, 18:12authored byMazin
A. S. Abdelwahid, Kosuke Ohsawa, Akiharu Uwamizu, Kuniyuki Kano, Junken Aoki, Takayuki Doi
Lysophosphatidic
acid (LPA) is a key player in many physiological
and pathophysiological processes. The biological activities of LPA
are mediated through interactions withat leastsix
subtypes of G-protein-coupled receptors (GPCRs) named LPA1–6. Developing a pharmacological tool molecule that activates LPA subtype
receptors selectively will allow a better understanding of their specific
physiological roles. Here, we designed and synthesized conformationally
restricted 25 1-oleoyl LPA analogues MZN-001 to MZN-025 by incorporating its glycerol linker into dihydropyran,
tetrahydropyran, and pyrrolidine rings and variating the lipophilic
chain. The agonistic activities of these compounds were evaluated
using the TGFα shedding assay. Overall, the synthesized analogues
exhibited significantly reduced agonistic activities toward LPA1, LPA2, and LPA6, while demonstrating
potent activities toward LPA3, LPA4, and LPA5 compared to the parent LPA. Specifically, MZN-010 showed more than 10 times greater potency (EC50 = 4.9
nM) than the standard 1-oleoyl LPA (EC50 = 78 nM) toward
LPA5 while exhibiting significantly lower activity on LPA1, LPA2, and LPA6 and comparable potency
toward LPA3 and LPA4. Based on the MZN-010 scaffold, we synthesized additional analogues with improved selectivity
and potency toward LPA5. Compound MZN-021,
which contains a saturated lipophilic chain, exhibited 50 times more
potent activity (EC50 = 1.2 nM) than the natural LPA against
LPA5 with over a 45-fold higher selectivity when compared
to those of other LPA receptors. Thus, MZN-021 was found
to be a potent and selective LPA5 agonist. The findings
of this study could contribute to broadening the current knowledge
about the stereochemical and three-dimensional arrangement of LPA
pharmacophore components inside LPA receptors and paving the way toward
synthesizing other subtype-selective pharmacological probes.