Discovery of Novel Pyrano[3,2-a]carbazole Alkaloid Derivatives against Ischemic Stroke by Targeting ADGRL3.

ADGRL3 is an important protein mediating neural activities, which is closely associated with various physiological processes including synaptic regulation, motor function, attention, and cognitive behaviors. However, its role in cerebral ischemia has not been investigated to date. In this work, we used CZ-7 which is a pyrano[3,2-a]carbazole alkaloid as hit compound and synthesized 25 nitrone/oxime-bearing derivatives. Pharmacological evaluations showed that 14a and its nano formulation (14a-NPs) mitigated multiple indices of cerebral ischemic injury, outperformed Edaravone-Dexborneol and dl-3-n-butylphthalide (dl-NBP), and displayed a favorable safety profile. Pharmacokinetic results showed that 14a-NPs was highly enriched in the brain compared with plasma. Meanwhile, transcriptomic analysis identified ADGRL3 as its therapeutic target, and the synaptic protective effect of 14a was verified. Collectively, we report for the first time that ADGRL3 is a novel therapeutic target for stroke, and that 14a exerts protective effects against cerebral ischemic injury by targeting ADGRL3 to preserve synaptic function.