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Exploitation of anti-amnesic drugs based on novel lead substance

基于新型先导物质的抗遗忘药物的开发

基本信息

批准号：
09559009
负责人：
YOSHIKAWA Masaaki
金额：
$ 8.7万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

项目摘要

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.

随着老年人口的增加，开发预防或改善健忘症的新药是人们热切期待的。我们发现三种类型的肽具有抗遗忘或增强记忆的活性。补体系统一直被认为只有免疫学的重要性。我们发现，酪蛋白消化体衍生的补体C3a激动剂和补体C3a本身可改善小鼠东莨菪碱注射或脑室内（icv）给药后脑缺血引起的健忘症。这些多肽口服后无效。口服活性C3a激动剂WPLPR是基于YPLPR设计的，它对应于水稻白蛋白衍生的C3a激动剂oryzatenin的羧基末端五肽。δ-阿片肽有抑制学习的报道。然而，谷蛋白外啡蛋白A（GYYPT）是一种从小麦谷蛋白酶解中分离出来的δ-阿片样物质，口服给药后对小鼠的学习有促进作用。[D-Ala] γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ。这些肽促进学习的剂量低于镇痛的剂量。痛觉肽是从脑中分离出来的一种致痛觉肽。先前，我们发现逆转录阿片肽的甲基lester具有阿片拮抗剂活性。我们在豚鼠回肠试验中新发现甲基退孕肽具有返孕肽拮抗活性。它还具有镇痛和增强记忆的作用。管理。甲基雷斯脱后痛觉肽不具有吗啡的耐受性和记忆障碍，可作为理想镇痛药物的先导物。我们还发现内源性肽，肠抑素（VPDPR）和肾上腺髓素前n端20肽（PAMP）分别在icv后具有增强记忆和抗遗忘活性。管理。