Design And Synthesis Of PDZ Domain Inhibitors With NNOS-Capon Uncoupling Activity And Their Biological Activities

Anxiety disorder is one of the most common psychological disorders.It has attracted great attention in recent years worldwide because of its increasing morbidity.Its symptoms include inner nervousness,fear,anxiety and hyperfunction of autonomic nervous system.Althought its pathogenesis is not clear,but in terms of biochemical mechanisms,it has neurotransmitter hypothesis and neuroendocrime dysfunction hypothesis.However,the present clinical anxiolytic drugs have various side effect and/or slow efficacy.Therefore,development of drugs acting at new target with new mechanism is very important and is of great significance.Studies have shoen that,NO molecule can induce anxiety,bur NO is an important signal molecule,which is associated with a variety of important physiological functions.Thus,directly or indirectly inhibit the synthesis of NO is also inappropriate.The ideal drug can block the contact of target poteins associated with NO and nNOS,which can suppress the signal in anxiety without affecting Other physiological functions of NO passed down.We found and verified a new target for anxiety,that is uncoupling the interaction of nNOS-Capon showing significantly anxiolytic effect.In addition,uncoupling the interaction of nNOS-Capon showes neuroprotective effect.We designed,synthesized,and evaluated the bioactivity of peptidomimetics based on the C-terminal four peptide EIAV of Capon and the G-D/E-X-V ligand motif of nNOS PDZ domain to explore new series of compounds with anxiolytic or neuroprotective effect.We have synthesized 33 target compounds,and the structures of target compounds were charaterized by 1H NMR and MS.Preliminary biological evaluation indicates that CJ-3(H-Tyr-Leu-OH)at a concentration of 10-7 mol/L,10-6 mol/L,10-5 mol/L showed protective effect on glutamate-induced neuronal cell damage.