Phase I clinical trials with WAL 2014, a new muscarinic agonist for the treatment of Alzheimer's disease

Adamus, W.S.; Leonard, J. P.; Tröger, Wolfgang

doi:10.1016/0024-3205(95)00024-z

Cited by 25 publications

(16 citation statements)

References 10 publications

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“…Although some of these symptoms are likely to be triggered by binding to a variety of targets, including the M2 and M3 receptors, the pharmacodynamic properties of talsaclidine indicate that its inhibition of NET uptake is clinically relevant and might also occur in vivo (Table 1 and SI Text) (37). These results further support the hypothesis that talsaclidine effects can be explained by stimulation of both the adrenergic and cholinergic systems (36).…”

Section: Discussionsupporting

confidence: 86%

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Structure-based discovery of prescription drugs that interact with the norepinephrine transporter, NET

Schlessinger

Geier

Fan

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

118

136

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The norepinephrine transporter (NET) transports norepinephrine from the synapse into presynaptic neurons, where norepinephrine regulates signaling pathways associated with cardiovascular effects and behavioral traits via binding to various receptors (e.g., β2-adrenergic receptor). NET is a known target for a variety of prescription drugs, including antidepressants and psychostimulants, and may mediate off-target effects of other prescription drugs. Here, we identify prescription drugs that bind NET, using virtual ligand screening followed by experimental validation of predicted ligands. We began by constructing a comparative structural model of NET based on its alignment to the atomic structure of a prokaryotic NET homolog, the leucine transporter LeuT. The modeled binding site was validated by confirming that known NET ligands can be docked favorably compared to nonbinding molecules. We then computationally screened 6,436 drugs from the Kyoto Encyclopedia of Genes and Genomes (KEGG DRUG) against the NET model. Ten of the 18 high-scoring drugs tested experimentally were found to be NET inhibitors; five of these were chemically novel ligands of NET. These results may rationalize the efficacy of several sympathetic (tuaminoheptane) and antidepressant (tranylcypromine) drugs, as well as side effects of diabetes (phenformin) and Alzheimer's (talsaclidine) drugs. The observations highlight the utility of virtual screening against a comparative model, even when the target shares less than 30% sequence identity with its template structure and no known ligands in the primary binding site.

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Section: Discussionsupporting

confidence: 86%

“…Talsaclidine failed in clinical trials because it triggered dose-limiting side effects (36). For example, in some patients talsaclidine caused symptoms including tachycardia, high blood pressure, nausea, diarrhea, excessive sweating, and palpitation.…”

Section: Discussionmentioning

confidence: 99%

Structure-based discovery of prescription drugs that interact with the norepinephrine transporter, NET

Schlessinger

Geier

Fan

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

118

136

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“…Previous reports have shown that M1 agonists, such as xanomeline [12] , WAY-132983 [14] , CI979 [15] and WAL2014 [16] , could significantly ameliorate memory decline in aged mice and cognition-impaired mice. The usefulness of these drugs has been limited, however, by the significant side effects caused by hyper-activation of peripheral cholinergic pathways [12,[14][15][16] , including salivation, lacrimation, tremors and diarrhea [12] .…”

Section: Discussionmentioning

confidence: 99%

A novel derivative of xanomeline improved memory function in aged mice

et al. 2008

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Objective To characterize the function of a new xanomeline-derived M1 agonist, 3-[3-(3-florophenyl-2-propyn-1-ylthio)-1,2,5-thiadiazol-4-yl]-1,2,5,6-tetrahydro-1-methylpyridine Oxalate (EUK1001), the acute toxicity and the effects on synaptic plasticity and cognition of EUK1001 were evaluated. Methods To examine the median lethal dose (LD50) of EUK1001, a wide dose range of EUK1001 was administered by p.o. and i.p. in aged mice. Furthermore, novel object recognition task and in vitro electrophysiological technique were utilized to investigate the effects of EUK1001 on recognition memory and hippocampal synaptic plasticity in aged mice. Results EUK1001 exhibited lower toxicity than xanomeline, and improved the performance of aged mice in the novel object recognition test. In addition, bath application of 1 μmol/L EUK1001 directly induced long-term potentiation in the hippocampus slices. Conclusion We conclude that EUK1001 can improve the agerelated cognitive deficits.

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“…For instance, talsaclidine is a muscarinic M1 receptor ligand that failed in clinical trials for treating Alzheimer's disease, due to side effects related to adrenergic effects (e.g., high blood pressure) (Fig. 2.2d) (Adamus et al 1995). The pharmacodynamic Schlessinger et al 2011) and kinetic properties of talsaclidine suggest that inhibition of the NET uptake might occur in clinically relevant concentrations and contribute to the positive and negative pharmacological effects of the drug.…”

Section: The Norepinephrine Transporter (Net Slc6a2)mentioning

confidence: 98%

Characterizing the Structure, Function, and Evolution of Human Solute Carrier (SLC) Transporters Using Computational Approaches

Schlessinger¹

2014

Springer Series in Biophysics

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Solute Carrier (SLC) transporters are membrane proteins that transport a broad range of solutes including metabolites, ions, toxins, and prescription drugs. In humans, there are about 400 SLC members, many of which are of medical importance. They can be drug target themselves (e.g., the serotonin transporter, SERT) or regulate the absorption, distribution, metabolism, and excretion (ADME) of drugs (e.g., the organic cation transporter 1, OCT-1). An important step toward describing the mechanisms of solute transport by SLC transporters includes computational or experimental characterization of their ligand-bound or unbound structures in different conformations. Due to a variety of technical issues, human SLC transporters are challenging targets for both experimental and computational characterizations. However, recent advances in computational approaches such as molecular docking and comparative modeling, coupled with the atomic structure determination of several membrane transporters, expanded our ability to characterize the human SLC families using in silico structure-based approaches. In this chapter, we first provide an overview of the structure, function, and pharmacology of the human SLC transporters. Second, we describe different computational methods, including sequence analysis, structural modeling, and ligand docking, that are commonly used, in combination with experimental testing, to characterize the human SLC transporters. Third, we demonstrate the utility of these approaches to characterize SLC members with three examples-the norepinephrine transporter (NET), the γ-aminobutyric acid (GABA) transporter 2 (GAT-2), and the L-type amino acid transporter (LAT-1). Finally, future directions in the field of computational structural biology of human SLC transporters are discussed.

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Phase I clinical trials with WAL 2014, a new muscarinic agonist for the treatment of Alzheimer's disease

Cited by 25 publications

References 10 publications

Structure-based discovery of prescription drugs that interact with the norepinephrine transporter, NET

Structure-based discovery of prescription drugs that interact with the norepinephrine transporter, NET

A novel derivative of xanomeline improved memory function in aged mice

Characterizing the Structure, Function, and Evolution of Human Solute Carrier (SLC) Transporters Using Computational Approaches

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