Design, synthesis, and neurochemical evaluation of 5-(3-alkyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidines as M1 muscarinic receptor agonists

Dunbar, Philip G.; Durant, G. J.; Fang, Zhenghuan; Abuh, Yahaya F.; El-Assadi, Afif A.; Ngur, Dan O.; Periyasamy, Sumudra; Hoss, Wayne; Messer, William S.

doi:10.1021/jm00059a008

Cited by 45 publications

(45 citation statements)

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“…[Sauerberg et al, 1992] and CDD-0102 [Dunbar et al, 1993] were synthesized according to published procedures. Both NMR and microanalytical data were obtained to verify chemical structure and purity (499%).…”

Section: Methodsmentioning

confidence: 99%

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

Messer

Bachmann

Dockery

et al. 2002

Drug Development Research

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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.

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Section: Methodsmentioning

confidence: 99%

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

Messer

Bachmann

Dockery

et al. 2002

Drug Development Research

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“…Overall, however, there is strong evidence that activation of M 1 receptors results in enhanced memory function, leading to drug development efforts focused on M 1 agonists for the treatment of memory and cognitive deficits associated with neurological disorders including Alzheimer's disease and schizophrenia. 5-(3-Ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine hydrochloride (CDD-0102A) was synthesized and characterized as a selective muscarinic agonist in a variety of binding and functional assays (Dunbar et al, 1993;Messer et al, 1997a, b). CDD-0102A is a functionally selective agonist with partial agonist activity at M 1 muscarinic receptors, weak activity at M 3 receptors, and no activity at other muscarinic receptor subtypes (Fig.…”

Section: Introductionmentioning

confidence: 99%

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

Ragozzino¹,

Artis²,

Singh³

et al. 2011

J Pharmacol Exp Ther

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Various neurodegenerative diseases and psychiatric disorders are marked by alterations in brain cholinergic function and cognitive deficits. Efforts to alleviate such deficits have been limited by a lack of selective M 1 muscarinic agonists. 5-(3-Ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine hydrochloride (CDD-0102A) is a partial agonist at M 1 muscarinic receptors with limited activity at other muscarinic receptor subtypes. The present studies investigated the effects of CDD-0102A on working memory and strategy shifting in rats. CDD-0102A administered intraperitoneally 30 min before testing at 0.1, 0.3, and 1 mg/kg significantly enhanced delayed spontaneous alternation performance in a four-arm cross maze, suggesting improvement in working memory. In separate experiments, CDD-0102A had potent enhancing effects on learning and switching between a place and visual cue discrimination.Treatment with CDD-0102A did not affect acquisition of either a place or visual cue discrimination. In contrast, CDD-0102A at 0.03 and 0.1 mg/kg significantly enhanced a shift between a place and visual cue discrimination. Analysis of the errors in the shift to the place or shift to the visual cue strategy revealed that in both cases CDD-0102A significantly increased the ability to initially inhibit a previously relevant strategy and maintain a new, relevant strategy once selected. In anesthetized rats, the minimum dose required to induce salivation was approximately 0.3 mg/kg i.p. Salivation increased with dose, and the estimated ED 50 was 2.0 mg/kg. The data suggest that CDD-0102A has unique memory and cognitive enhancing properties that might be useful in the treatment of neurological disorders at doses that do not produce adverse effects such as salivation.

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“…APE had been shown to exert the negative chronotropic and inotropic effects [11][12][13] and has been considered as a potential candidate for the treatment of Alzheimer's disease [6,7]. However, the ionic mechanisms that might underlie the cardiovascular effects of APE are unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, several postsynaptic M 1 muscarinic receptor agonists were evaluated for clinical treatment of Alzheimer's disease [5][6][7]. However, they were found to be limited in their therapeutic use against this disease.…”

Section: Introductionmentioning

confidence: 99%

Activation of muscarinic K+ channels by arecaidine propargyl ester in isolated guinea-pig atrial myocytes

Chen

2005

J Biomed Sci

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Arecaidine propargyl ester (APE) was developed as a potential candidate compound for the treatment of Alzheimer's disease. APE has been shown to have cardiovascular effects. APE produces negative chronotropic and inotropic effects in isolated atria. However, the ionic mechanisms underlying the cardiovascular effects of APE in guinea-pig atria are unclear. The aims of this study were: (1) to examine the shortening effect of APE on action potential duration (APD) and to compare the difference in potency between APE and muscarine in isolated single guinea-pig atrial myocytes by using the current clamp method, (2) to examine by using patch clamp techniques the ionic mechanisms underlying the cardiac effects of APE, and (3) to determine whether the cardiac effects caused by APE affect the usefulness of APE as a potential candidate for the treatment of Alzheimer's disease. The APE significantly reduced the APD in guinea-pig atria and produced no direct effect on ventricular myocytes. APE is approximately 20 times as potent as muscarine in shortening the APD. Attenuation of the APD was consistently accompanied by a hyperpolarization of the resting membrane potential in a concentration-dependent manner. The APE activated muscarinic K+ channels and increased potassium conductance in guinea-pig atrial myocytes. In the cell-attached configuration, the APE contained in the pipette increased the channel-opening probability and decreased the closed-state time interval. The proposal that APE can be used as a potential remedy for the treatment of Alzheimer's disease should be taken into consideration the undesirable cardiovascular side effects that APE causes at lower concentrations.

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Design, synthesis, and neurochemical evaluation of 5-(3-alkyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidines as M1 muscarinic receptor agonists

Cited by 45 publications

References 13 publications

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

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

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

Activation of muscarinic K+ channels by arecaidine propargyl ester in isolated guinea-pig atrial myocytes

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Design, synthesis, and neurochemical evaluation of 5-(3-alkyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidines as M1 muscarinic receptor agonists

Cited by 45 publications

References 13 publications

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

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

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

Activation of muscarinic K+ channels by arecaidine propargyl ester in isolated guinea-pig atrial myocytes

Contact Info

Product

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

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

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