The Synthesis,activities And Brain Entry Of Neuropeptide S Analogues

Currently,the effective entry of drugs into brain is a major obstacle to the treatment of central nervous system(CNS)diseases,while the presence of the blood-brain barrier(BBB)restricts lots of promising therapeutic agents.Thus,the recent research was focus on avoiding or crossing the BBB.Certain drugs can be effectively delivered into brain tissue through nasal administration.The drugs can avoid BBB through olfactory/trigeminal nerve pathways and also can penetrate BBB via absorption by nasal-rich lymphatic vessels through systemic circulation which both following the nasal administration.Another method to cross BBB was through intravenous injection which agents can entry in CNS via receptor-mediated or direct penetration during systemic circulation.Previous studies of our group have found that Neuropeptide S(NPS)has the effect of anxiolytic-like and promoting learning and memory.However,the unique characteristics of neuropeptides limited its effective penetration into BBB.In this paper we considered whether drugs can be delivered by peptides such as cell penetrating peptides(CPPs)and blood-brain barrier shuttle peptides(BBB-shuttles)to avoid/cross BBB or not.Thus,we design and synthesis twelve NPS analogues through solid peptide synthesis,fragment condensation,analysis and purification methods according to the special characteristic of NPS.In vivo experiment results of elevated plus-maze test demonstrate that NPS 5,6 and 7 has similar anxiolytic-like effect compared with Nueropeptide S after nasal administration.In the meanwhile,NPS 5 and 7 have a better anxiolytic-like effect compared with NPS after intravenous administration.whereas the above results,we next conjugate NPS 5 covalent with cy7.5 and through Optical in vivo Imaging experiments to confirm that it can enter into the brain through nasal and intravenous administration.These results consistent with our supposition about NPS can be transported into brain successfully via small peptides.We look forward to our present works which small peptides act as transport vectors could avoid BBB and improve the bioavailability of drugs after nasal administration or cross BBB through general circulation after intravenous injection,this may beprovide a bright and clear direction for our subsequent research on drugs targeting for CNS.