Lysophosphatidic acid (LPA), a bioactive lipid, functions via at least six G protein-coupled receptors, LPA receptors 1-6 (LPA1-6), for various physiological functions. Importantly, LPA5 is important for pain signal transmission in the spinal cord. A study from Nobuhito Murai discovered and identified a novel LPA5 antagonist AS2717638.

AS2717638 is an Oral Active LPA5 Antagonist

Mechanically, AS2717638 bound to the LPA-binding site and selectively inhibited LPA-induced cyclic adenosine monophosphate accumulation in human LPA5- but not LPA1-, 2-, or 3-expressing cells.

In vitro, AS2717638 inhibited LPA-induced cAMP accumulation in CHO cells expressing human LPA5 at IC50 values (95% confidence interval) of 0.038 (0.033-0.043) μM. Additionally, AS2717638 inhibited the binding to three rat receptors (adenosine A1 receptor, non-selective opioid receptor, and μ-opioid receptor) by more than 50%.

Furthermore, in vivo, oral administration of AS2717638 inhibited LPA5 agonist-induced allodynia in mice. AS2717638 significantly inhibited LPA-induced allodynia at oral doses of 3, 10, and 30 mg/kg and GGPP-induced allodynia at 1, 3, 10, and 30 mg/kg. AS2717638 also significantly improved PGE2-, PGF2α-, and AMPA-induced allodynia. Besides, both pregabalin and duloxetine alleviated only PGE2-induced allodynia in mice. Likewise, AS2717638 significantly ameliorated static mechanical allodynia and thermal hyperalgesia in rat models of chronic constriction injury (CCI)-induced neuropathic pain. AS2717638 also showed analgesic effects in a rat model of inflammatory pain. These results suggest that LPA5 antagonists elicit broad analgesic effects against both neuropathic and inflammatory pain.

To sum up, AS2717638 is an oral active and selective lysophosphatidic acid receptor 5 (LPA5) antagonist. And it also significantly improves PGE2-, PGF2α-, and AMPA-induced allodynia.

Murai N, et al. Analgesic effects of novel lysophosphatidic acid receptor 5 antagonist AS2717638 in rodents. Neuropharmacology. 2017 Nov;126:97-107.