Discovery of Inhibitors of Insulin-Regulated Aminopeptidase as Cognitive Enhancers

被引:39
作者
Andersson, Hanna [1 ]
Hallberg, Mathias [2 ]
机构
[1] Uppsala Univ, BMC, Dept Med Chem, Div Organ Pharmaceut Chem, S-75123 Uppsala, Sweden
[2] Uppsala Univ, BMC, Dept Pharmaceut Biosci, Div Biol Res Drug Dependence, POB 591, S-75124 Uppsala, Sweden
基金
瑞典研究理事会;
关键词
D O I
10.1155/2012/789671
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The hexapeptide angiotensin IV (Ang IV) is a metabolite of angiotensin II (Ang II) and plays a central role in the brain. It was reported more than two decades ago that intracerebroventricular injection of Ang IV improved memory and learning in the rat. Several hypotheses have been put forward to explain the positive effects of Ang IV and related analogues on cognition. It has been proposed that the insulin-regulated aminopeptidase (IRAP) is the main target of Ang IV. This paper discusses progress in the discovery of inhibitors of IRAP as potential enhancers of cognitive functions. Very potent inhibitors of the protease have been synthesised, but pharmacokinetic issues (including problems associated with crossing the blood-brain barrier) remain to be solved. The paper also briefly presents an overview of the status in the discovery of inhibitors of ACE and renin, and of AT1R antagonists and AT2R agonists, in order to enable other discovery processes within the RAS system to be compared. The paper focuses on the relationship between binding affinities/inhibition capacity and the structures of the ligands that interact with the target proteins.
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页数:18
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