John W. Clader

One of the consistent findings in the brains of Alzheimers Disease (AD) patients is loss of cholinergic function. The cholinergic approach to treatment of AD involves counteracting this loss in cholinergic activity by pharmacological intervention to increase cholinergic transmission. The cognitive effects of acetylcholine are mediated via the muscarinic M1 receptor. Direct stimulation of this receptor using muscarinic M1 agonists improves cognition in animal models and improves performance in cognitive tests in Alzheimers patients. Alternatively, antagonists of central presynaptic M2 receptors improves cognition by increasing the central release of acetylcholine. Both approaches require high selectivity for one muscarinic receptor sub-type both for efficacy and to avoid cholinergic side effects. In this review summarizes recent progress in the identification and characterization of selective muscarinic receptor ligands for the treatment of Alzheimers disease.

Abstract: Atherosclerotic coronary artery disease remains a major healthcare concern especially in developed countries. While lowering plasma cholesterol levels via diet, exercise, and pharmacoptherapy can reduce this risk of developing coronary artery disease, there remains a need for more effective drug therapies. The azetidinone cholesterol absorption inhibitors typified by ezetimibe represent the first new approach to lipid lowering therapy in more than a decade. This review summarizes the medicinal chemistry of the azetidinone cholesterol absorption inhibitors as a class, with emphasis on factors that contributed both to the discovery of ezetimibe as well as to our overall understanding of S.A.R. trends in this area.

Characterized by loss of cholinergic neurons in regions of the brain that are known to be involved in learning and memory. Cholinergic therapy seeks to compensate for this loss by pharmacological enhancement of cholinergic transmission. The use of acetylcholinesterase inhibitors, M2 antagonists, nicotinic agonists and M1 agonists has been under investigation for more than a decade. Only the acetylcholinesterase inhibitors have yielded compounds in wide clinical use, although efficacy has been modest and all suffer from dose limiting side effects. No M1 agonists or nicotinic agonists have been approved, but efforts to discover more selective compounds are continuing. Selective M2 antagonists which enhance cognition in animal models have recently been described and may provide a safer and more effective treatment for AD.