Design, Synthesis, And Anti-itch Activity Evaluation Of Indole Derivatives As Gastrin-Releasing Peptide Receptor Inhibitors

Gastrin-releasing peptide receptor (GRPR) is a G protein-coupledreceptor. Recent studies show that activation and overexpression of GRPR cancause many diseases including cacer, anxiety and so on. Meanwhile, activationof GRPR may also cause itch. Itch is a very common symptom that almosteveryone has experienced in his or her lifetime, and millions of peopleworldwide suffer from itch. In addition, pruritus is a major and distressingsymptom of many skin and systemic diseases. However, the traditionalanti–itch medicines can not cure this type of itch, such as antihistamine drug.Based on this, GRPR has been used in drug design as drug targets in thisarticle.Firstly,1U19protein was used as template protein. Then, the tertiarystructure of GRPR was predicted by homology modeling protein. According tothe method of structure-based drug design of computer-aided drug design andcombining with the flattening drug design principles, we selected a wide rangeof biological activity of the indole ring and cinnamic acid derivatives fromnature which were put together. Accoding to this, we design17indole GRPRinhibitors. Antidepressant mirtazapine is the role of anti-histamine,anti-serotonin and sedative, and it can be as anti-itch drug. Therefore, wechoose5-methoxytryptamine as the nucleus, which is a necessary intermediateof the synthesis of sedative and hypnotic effects of melatonin. Then, weselected cinnamic acid derivatives or structural analogues as another fragment,which has a variety of pharmacological activity including antibacterial,antiviral, antitumor and antioxidant, such as: caffeic acid, ferulic acid.Meanwhile, these compounds were synthesized with5-methoxytryptamine as the basic skeleton by amidation with phenylacrylicacid or phenylacetic acid derivatives, and5-methoxytryptamine wasprepared by Gabriel reaction as previously reported, and their chemicalstructures were corroboration by FT-IR and1H NMR.Herein, their anti-itch activites were evaluated. Among them, compoundSEM09IS007exhibited the most potent anti-itch activity in vivo (The number of scratches is128), whose anti-itch activity is higher than anti-itch activity ofPD176252(The number of scratches is360). Then we learned from theanalysis of structure-activity relationship with these compounds:①5-methoxytryptamine cinnamic acid amide derivatives of cinnamic acid ringR1and R4were replaced by chlorine and trifluoromethyl and increasing theiranti-itch activity;②When,5-methoxytryptamine phenylacetic acid amidederivatives contain chlorine, methoxy, fluorine and methyl in phenylacetatering, their anti-itch activity were significantly enhanced. Finally, mouse’s GRPlevels were determined to verify itching signaling pathway, and the pathway isthat the chloroquine phosphate activated MrgprA3, and MrgprA3expressedGRP, which caused itch.