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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.

Through exposure of rabbits (V=10) to barometric pressures equivalent to that encountered at 18,000 ft for 6-8 hr, we found no increase in water content of various parts of the brain (temporal, parietal, frontal cortices; dien cephalon, mid-brain, hindbrain, cerebellum). Repeated exposure of rabbits (N=57) to hypoxia equivalent to 8,000 to 16,000 ft generally lead to an increase in CSF pressure. However, we found no influence of hypoxia upon CSF arginine vasopressin contents. When injected into the lateral ventricles of rabbits, arginine vasopressin, norepinephrine, prostaglandin E2 and prostaglandin F 1 alpha did not influence CSF pressures. Angiotensin II generally caused an increase in CSF pressure while saralasin, an AII blocker generally caused a decrease in CSF pressure when given by itself and prevented a rise in CSF pressure if given before AII. Injection of acetazolamide ito the lateral ventricles did not consistently alter CSF pressures but when given systematically, acetazolamide caused a decreae in CSF pressure in two thirds of the treated animals.