Exploitation of anti-amnesic drugs based on novel lead substance

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As the population of aged people increases, exploitation of new drugs preventing or improving amnesia is eagerly expected. We found that three types of peptides had anti-amnesic or memory-enhancing activity.Complement system has been recognized to have only immunological importance. We found that casoxin C, complement C3a agonist derived from casein digest, and complement C3a itself improved amnesia induced by scopolamine injection or brain ischemia after intracerebroventricular(icv.)administration in mice. These peptides were ineffective after oral administration. Orally active C3a agonist WPLPR was designed based on YPLPR, which corresponds to the pentapeptide at the carboxyl terminus of oryzatensin, a C3a agonist derived from rice albumin.δ-Opioid peptides have been reported to inhibit learning. However, gluten exorphin A(GYYPT), a δ-opioid which was isolated from enzymatic digest of wheat gluten, promoted learning after oral administration in mice. [D-Ala]ィイD11ィエD1-gluten exorphin A was about 60 fold more potent than the original peptide. The dose for promotion of learning by these peptides were lower than that for analgesia.Nociceptin is a hyperalgesic peptide isolated from brain. Previously, we found that methylester of retro-opioid peptides had opioid antagonist activity. We newly found that retronociceptin methylester had nociceptin antagonist activity in guinea-pig ileum assay. It also showed analgesic and memory-enhancing activities icv. administration. Retronociceptin methylester can be regarded as a lead sunstance for an ideal analgesic drugs because it did not induce torelance and memory impairment which are characteristic for morphin.We also found that endogenous peptides, enterostatin(VPDPR)and proadrenomedullin N-terminal 20 peptde(PAMP)had memory-enhancing and antiamnesic activities, respectively, after icv. administration.