Design, Synthesis And Biological Activity Study Of NNOS-Capon Coupling Inhibitor Based On Capon Terminal Tetrapeptide

Anxiety disorders is a serious mental disorders which endanger people's health.Especially,with a booming economy and growing competition in the society,patients with anxiety have significantly increased in the present.According to statistics from the WHO,the prevalence rate of urban population in China has amounted to 2%³%,near 10%in developed countries,and is still increasing.Anxiety is a complex psychological and behavioral responses,which associated with a variety of behavioral response,but the specific pathogenesis is not clear.The current anxiety pathogenesis are mainly related by three aspects of endocrine system,immune system and neurotransmitters.Studies have shown that NO molecule can induce anxiety.What Knock nNOS genes out or use nNOS inhibitors to inhibit the activity for reducing the generation of NO have both anxiolytic effect,and the discovery provides the material basis for the further anxiolytic studies.But NO is an important signal molecule,which is associated with a variety of important physiological functions.It is inappropriate that if the synthesis of NO is directly or indirectly inhibited.Thus,the ideal drug can block the contact of target proteins 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,that is uncoupling the interaction of nNOS-Capon shows significantly anxiolytic effect.In addition,uncoupling the interaction of nNOS-Capon shows neuroprotective effect.We designed and synthesized Che-EIAV targeted compounds based on the C-terminal four peptide EIAV of Capon and the peptide library-best results G-D/E-A-V.We use manual solid phase method of 2-chlorotrityl chloride resin to synthesize polypeptide.We have synthesized 11 targeted compounds based on 9-fluorenyl-methoxycarbonyl?Fmoc?synthesis mechanism,and the structures of targeted compounds were characterized by¹H NMR?¹³C NMR and MS.Preliminary biological evaluation indicates that LG-11 have showed protective effect on glutamate-induced neuronal cell damage.