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

Abstract

Selective muscarinic agonists might be useful in the treatment of Alzheimer's disease. To help characterize the activity and functional selectivity of two M 1 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 M 1 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 7 4.2% correct choices with saline, but 94 7 1.2% following CDD-0102 injection. In acute toxicity studies in mice, the LD 50 of CDD-0102 was greater than 1,000 mg/kg orally; 190 mg/kg i.p. The LD 50 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.

The Selective M1 Muscarinic Cholinergic Agonist CDD-0102A Enhances Working Memory and Cognitive Flexibility

“…Taken together with the in vivo mi- The finding that CDD-0102A enhanced delayed spontaneous alternation is consistent with other studies demonstrating that M 1 -preferring agonists enhance working memory in rodents and nonhuman primates (Wall et al, 2001;Terry et al, 2002). Moreover, CDD-0102A-enhanced delayed alternation is consistent with previous results indicating that CDD-0102A reverses a working memory deficit induced by a 192-IgG saporin lesion of basal forebrain cholinergic neurons (Messer et al, 2002). However, this is the first demonstration that CDD-0102A alone enhances working memory.…”

Muscarinic Receptor Agonists and Antagonists in the Treatment of Alzheimers Disease

“…CDD-102 produces fewer cholinergic effects such as salivation and diarrhea than Xanomeline and has a higher LD 50 than Xanomeline. These differences were attributed to lower overall affinity for muscarinic receptors [27].…”

Drugs that target muscarinic cholinergic receptors

“…Classical muscarinic antagonists such as scopolamine and atropine impair memory function in experimental animals and in humans. Lesions of basal forebrain cholinergic pathways with specific neurotoxins such as AF64A and 192 IgO-saporin also impair memory function [17][18][19][20][21][22]. The role of individual muscarinic receptor subtypes in memory and cognitive function has been limited by the availability of agonists and antagonists selective for muscarinic receptor subtypes.…”

“…Xanomeline shows functional selectivity for M I receptors [48], and enhances memory function on a paired-run alternation task in rats [22]. Xanomeline produced some cognitive benefits in Alzheimer's disease patients, particularly on the cognitive subscale of the Alzheimer's disease Assessment Scale (ADAS-Cog) [49,50], although unwanted side-effects greatly limited its therapeutic utility.…”