XANOMELINE - A SELECTIVE MUSCARINIC AGONIST FOR THE TREATMENT OF ALZHEIMERS-DISEASE

Xanomeline is a novel muscarinic receptor agonist relatively devoid of parasympathomimetic side effects. Xanomeline had high affinity for mu scarinic receptors and much lower affinity for a variety of other neur onal receptors in radioligand binding assays. Functional studies in ce ll lines transfected with the muscarinic receptor subtypes demonstrate d that xanomeline had higher potency and efficacy for m1 and m4 recept ors than m2, m3, and m5 receptor subtypes. Similarly, in isolated tiss ue studies, xanomeline had higher potency and efficacy for M-1 recepto rs in rabbit vas deferens than at M-2 receptors in guinea pig atria or M-3 receptors in guinea pig bladder. Secretion of soluble amyloid pre cursor protein from m1 cell lines was potently stimulated by xanomelin e. In vivo, xanomeline robustly stimulated phosphoinositide hydrolysis in brain, consistent with m1 agonism. Xanomeline produced modest incr eases in brain acetylcholine levels and did not produce bradycardia, s uggesting little, if any, m2 agonist activity in vivo. Additionally, x anomeline did not induce nonselective cholinergic agonist side effects such as tremor, hypothermia and salivation. In animal behavior studie s, xanomeline reduced locomotion and blocked memory deficits that were induced by a muscarinic antagonist in a passive avoidance paradigm. X anomeline was found to be safe and reasonably well tolerated in safety studies in humans. In a placebo controlled double blind clinical tria l of 6 months duration, xanomeline halted cognitive decline in patient s with Alzheimer's disease. Furthermore, behavioral symptoms associate d with Alzheimer's disease such as hallucinations, delusions and vocal outbursts were significantly decreased by xanomeline treatment. Addit ional clinical trials are under way to assess the novel therapeutic ef fects of xanomeline. (C) 1997 Wiley-Liss, Inc.