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 receptors play an important role in learning, memory and the control of posture. There is a decrease in the synthesizing enzyme for acetylcholine in Alzheimer's disease, and damage to the ascending cholinergic system is thought to be an important determinant of the loss of memory and other functional deficits of this disease. Five subtypes of the muscarinic receptor (m1-m5) have been identified, and these receptors have a differential distribution throughout the body. The differential distribution of subtypes of the muscarinic receptor in the body suggests that centrally acting m1 and m4 muscarinic agonists might be efficacious in the treatment of age-related memory disorders, without causing peripheral side effects. In addition to the primary ligand binding site, muscarinic receptors also possess a secondary allosteric site that 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 suggests that it might be possible to develop novel allosteric muscarinic agonists that potentiate the effects of endogenous acetylcholine much in the same way that benzodiazepines potentiate GABA. Although no such allosteric muscarinic agonists have been identified to date, they could be very efficacious in the treatment of Alzheimer's disease.