Development of CDD‐0102 as a selective M1 agonist for the treatment of Alzheimer's disease

Abstract

AbstractSelective muscarinic agonists might be useful in the treatment of Alzheimer's disease. To help characterize the activity and functional selectivity of two M1 muscarinic agonists, secretion of amyloid precursor protein, brain penetration, side effect profiles, cognition‐enhancing properties, oral bioavailability, and acute toxicity were evaluated. CDD‐0102 stimulated the secretion of APP from CHO‐K1 cells expressing M1 receptors and penetrated into the brain following i.p. administration in rodents. CDD‐0102 produced relatively few cholinergic side effects (e.g., diarrhea, salivation) following i.p. administration in mice. The effects of muscarinic agonists on memory function were examined following bilateral injections of 192 IgG‐saporin into the diagonal band of rats to lesion basal forebrain cholinergic pathways. 192 IgG‐saporin produced decreases in cortical and hippocampal choline acetyltransferase activity and impaired performance of a paired‐run, delayed‐alternation task in a T‐maze relative to vehicle‐injected controls. Toxin‐treated rats performed significantly better following i.p. injections (1 mg/kg) of either xanomeline or CDD‐0102 as compared with saline. Prominent cholinergic side effects (e.g., diarrhea) were apparent only following xanomeline treatments. In separate studies, oral administration of CDD‐0102 (10 mg/kg) reversed the memory deficits induced by 192 IgG‐saporin in the T‐maze task. Rats achieved 54 ± 4.2% correct choices with saline, but 94 ± 1.2% following CDD‐0102 injection. In acute toxicity studies in mice, the LD50 of CDD‐0102 was greater than 1,000 mg/kg orally; 190 mg/kg i.p. The LD50 of xanomeline was 100 mg/kg p.o. and 75 mg/kg i.p. In summary, both xanomeline and CDD‐0102 displayed beneficial effects on memory function, while CDD‐0102 also exhibited a low side effect profile and low toxicity. CDD‐0102 warrants further evaluation as a therapeutic agent for the treatment of Alzheimer's disease. Drug Dev. Res. 57:200–213, 2002. © 2003 Wiley‐Liss, Inc.