Synthesis, biochemical activity and behavioral effects of a series of 1,4,5,6-tetrahydropyrimidines as novel ligands for M1 receptors

Messer, William S.; Dunbar, Philip G.; Rho, Taikyun; Periyasamy, Sumudra; Ngur, Dan O.; Ellerbrock, Brenda R.; Bohnett, Mark; Ryan, Kevin; Durant, G. J.; Hoss, Wayne

doi:10.1016/s0960-894x(00)80531-4

Cited by 11 publications

(16 citation statements)

References 28 publications

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“…Dispositional memory function is not impaired by manipulation of the septohippocampal cholinergic system [Messer et al, 1991]. Similar procedures have also documented improvement of representational memory function following injections of muscarinic agonists [Hoss et al, 1990;Messer et al, 1992Messer et al, , 1997a.…”

Section: Representational Memory Taskmentioning

confidence: 88%

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: Representational Memory Taskmentioning

confidence: 88%

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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“…The activity of 1,4,5,6-tetrahydropyrimidine derivatives in A9 L cells expressing m1 receptors was consistent with responses observed previously at muscarinic receptors coupled to PI metabolism in the rat central nervous system. 29,30 Moreover, the agonist activity of compounds 1a, 1f, and 2a at m1 receptors suggests that they should be considered fully efficacious muscarinic agonists (class A compounds according to the classification proposed by Fisher). 20,43 In rat hippocampal slices, however, the maximal level of PI metabolism produced by 1a is only a fraction of that produced by the corresponding oxadiazole derivative (2a).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Biological Characterization of 1,4,5,6-Tetrahydropyrimidine and 2-Amino-3,4,5,6-tetrahydropyridine Derivatives as Selective m1 Agonists

et al. 1997

J. Med. Chem.

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Previous studies identified several novel tetrahydropyrimidine derivatives exhibiting muscarinic agonist activity in rat brain. Such compounds might be useful in treating cognitive and memory deficits associated with low acetylcholine levels, as found in Alzheimer's disease. To determine the molecular features of ligands important for binding and activity at muscarinic receptor subtypes, the series of tetrahydropyrimidines was extended. Several active compounds were examined further for functional selectivity through biochemical studies of muscarinic receptor activity using receptor subtypes expressed in cell lines. Several amidine derivatives displayed high efficacy at m1 receptors and lower activity at m3 receptors coupled to phosphoinositide (PI) metabolism in A9 L cells. Four ligands, including 1b, 1f, 2b, and 7b, exhibited marked functional selectivity for m1 vs m3 receptors. Compound 1f also exhibited low activity at m2 receptors coupled to the inhibition of adenylyl cyclase in A9 L cells. Molecular modeling studies also were initiated to help understand the nature of the interaction of muscarinic agonists with the m1 receptor using a nine amino model of the m1 receptor. Several important interactions were identified, including interactions between the ester moiety and Thr192. Additional interactions were found for oxadiazoles and alkynyl derivatives with Asn382, suggesting that enhanced potency and selectivity may be achieved by maximizing interactions with Asp105, Thr192, and Asn382. Taken together, the data indicate that several amidine derivatives display functional selectivity for m1 muscarinic receptors, warranting further evaluation as therapeutic agents for the treatment of Alzheimer's disease. In addition, several amino acid residues were identified as potential binding sites for m1 agonists. These data may be useful in directing efforts to develop even more selective m1 agonists.

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“…Muscarinic agonists, including CDD-0034, CDD-0078, CDD-0097, CDD-0098, and CDD-0102, were synthesized using established methods [Messer et al, 1992;Dunbar et al, 1993;. Pirenzepine, AF-DX 116, and p-F-hexahydrosiladifenidol (p-F-HHSiD) were purchased from Research Biochemical International (Natick, MA).…”

Section: Materials and Methods Materialsmentioning

confidence: 99%

“…In previous studies, a variety of novel amidine derivatives were synthesized and tested for muscarinic agonist activity in rat brain [Messer et al, 1992;Dunbar et al, 1993Dunbar et al, , 1994Ojo et al, 1997]. Of these compounds, several tetrahydropyrimidine derivatives, including CDD-0078, CDD-0097, and CDD-0102 (Scheme 1), displayed muscarinic agonist activity at, and selectivity for, m1 receptors expressed in cultured cell lines [Messer and Dunbar, 1996;Messer et al, 1997].…”

Section: Introductionmentioning

confidence: 99%

Tetrahydropyrimidine derivatives display functional selectivity for M1 muscarinic receptors in brain

et al. 1997

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Selective muscarinic agonists might be useful in the treatment of Alzheimer's disease. Previous studies identified several amidine derivatives as selective and efficacious m1 agonists, using muscarinic receptor subtypes expressed in cell lines. In the present studies, the functional selectivities, side effect profiles and memory‐enhancing properties of these ligands were examined through a series of in vitro and in vivo experiments. CDD‐0078, CDD‐0097, and CDD‐0102 behaved as partial agonists by stimulating PI turnover in rat cortical slices to roughly 100% above basal levels. Pirenzepine was more potent than either AF‐DX 116 or p‐F‐hexahydrosiladifenidol (p‐F‐HHSiD) in blocking the PI responses of each ligand, suggesting that the responses were due to activation of M1 receptors. The time course of pharmacological responses was examined following i.p. injections of muscarinic agonists. Low does (0.1 and 1.0 mg/kg) of CDD‐0078, CDD‐0097, and CDD‐0102 did not elicit signs of cholinergic activity during the 2‐hr testing period. The highest dose tested (10 mg/kg) produced a modest degree of salivation and lacrimation during the first 30‐min period. Core body temperature remained unaffected. Central nervous system (CNS) penetration was evaluated through ex vivo binding studies. CDD‐0097 inhibited 1.0 nM [3H]pirenzepine binding in a dose‐dependent manner 30 min following i.p. injections. In behavioral studies, CDD‐0097 (1.0 mg/kg) completely reversed the memory deficits induced by hemicholinium‐3 or by IgG‐192 saporin in two types of memory tasks. It did not impair the performance of control animals in either task. In summary, CDD‐0097 displayed a limited side‐effect profile and the ability to penetrate into the central nervous system and stimulate M1 receptors. The amidine derivatives should be useful in further exploring the functional consequences of activating M1 muscarinic receptors in the CNS. The beneficial effects of CDD‐0097 on memory function warrant further examination of the compound as a selective M1 agonist for the treatment of Alzheimer's disease. Drug Dev. Res. 40:171–184, 1997. © 1997 Wiley‐Liss, Inc.

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Synthesis, biochemical activity and behavioral effects of a series of 1,4,5,6-tetrahydropyrimidines as novel ligands for M1 receptors

Cited by 11 publications

References 28 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

Synthesis and Biological Characterization of 1,4,5,6-Tetrahydropyrimidine and 2-Amino-3,4,5,6-tetrahydropyridine Derivatives as Selective m1 Agonists

Tetrahydropyrimidine derivatives display functional selectivity for M1 muscarinic receptors in brain

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Synthesis, biochemical activity and behavioral effects of a series of 1,4,5,6-tetrahydropyrimidines as novel ligands for M1 receptors

Cited by 11 publications

References 28 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

Synthesis and Biological Characterization of 1,4,5,6-Tetrahydropyrimidine and 2-Amino-3,4,5,6-tetrahydropyridine Derivatives as Selective m1 Agonists

Tetrahydropyrimidine derivatives display functional selectivity for M1 muscarinic receptors in brain

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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