MUSCARINIC RECEPTORS AND NOVEL STRATEGIES FOR THE TREATMENT OF AGE-RELATED BRAIN DISORDERS

The muscarinic class of acetylcholine receptors is widely distributed throughout the body and mediates numerous vital functions in both the brain and autonomic nervous system. Within the brain, muscarinic recep tors play an important role in learning, memory and the control of pos ture. There is a decrease in the synthesizing enzyme for acetylcholine in Alzheimer's disease, and damage to the ascending cholinergic syste m is thought to be an important determinant of the loss of memory and other functional deficits of this disease. Five subtypes of the muscar inic receptor (m(1)-m(5)) have been identified, and these receptors ha ve a differential distribution throughout the body. The differential d istribution of subtypes of the muscarinic receptor in the body suggest s that centrally acting mi and m(4) muscarinic agonists might be effic acious in the treatment of age-related memory disorders, without causi ng peripheral side effects. In addition to the primary ligand binding site, muscarinic receptors also possess a secondary allosteric site th at appears to be the target for some novel cardioselective muscarinic antagonists including the neuromuscular blocking agent gallamine. The existence of a secondary allosteric site on the muscarinic receptor su ggests that it might be possible to develop novel allosteric muscarini c agonists that potentiate the effects of endogenous acetylcholine muc h in the same way that benzodiazepines potentiate GABA. Although no su ch allosteric muscarinic agonists have been identified to date, they c ould be very efficacious in the treatment of Alzheimer's disease.