5‐HT<sub>6</sub> antagonists as potential treatment for cognitive dysfunction

Liu, Kevin G.; Robichaud, Albert J.

doi:10.1002/ddr.20293

Cited by 79 publications

(55 citation statements)

References 115 publications

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“…On the other hand, 5-HT 6 was excluded from the short list after further analysis because a comprehensive literature search revealed no direct evidence for APD-associated metabolic side effects. In fact, it has been suggested that blockade of the 5-HT 6 receptor leads to a cognitive enhancement in schizophrenia (Liu and Robichaud, 2009). In the interpretation of S2, it must be kept in mind that statistical association is not equivalent to causation.…”

Section: Statistical Methods For Multireceptorial Binding Profiles 155mentioning

confidence: 99%

A Novel Multilevel Statistical Method for the Study of the Relationships between Multireceptorial Binding Affinity Profiles and In Vivo Endpoints

Selent

Bauer-Mehren²,

López³

et al. 2009

Mol Pharmacol

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The present work introduces a novel method for drug research based on the sequential building of linked multivariate statistical models, each one introducing a different level of drug description. The use of multivariate methods allows us to overcome the traditional one-target assumption and to link in vivo endpoints with drug binding profiles, involving multiple receptors. The method starts with a set of drugs, for which in vivo or clinical observations and binding affinities for potentially relevant receptors are known, and allows obtaining predictions of the in vivo endpoints highlighting the most influential receptors. Moreover, provided that the structure of the receptor binding sites is known (experimentally or by homology modeling), the proposed method also highlights receptor regions and ligandreceptor interactions that are more likely to be linked to the in vivo endpoints, which is information of high interest for the design of novel compounds. The method is illustrated by a practical application dealing with the study of the metabolic side effects of antipsychotic drugs. Herein, the method detects related receptors confirmed by experimental results. Moreover, the use of structural models of the receptor binding sites allows identifying regions and ligand-receptor interactions that are involved in the discrimination between antipsychotic drugs that show metabolic side effects and those that do not. The structural results suggest that the topology of a hydrophobic sandwich involving residues in transmembrane helices (TM) 3, 5, and 6, as well as the assembling of polar residues in TM5, are important discriminators between target/antitarget receptors. Ultimately, this will provide useful information for the design of safer compounds inducing fewer side effects.The classic formulation in which a disease is associated to a single biological receptor is clearly an oversimplification, valid only for exceptional situations. Recent advances in genomics, proteomics, and systems biology depict a far more complex scenario, much less comfortable to work with, in which the biochemical mechanisms of diseases and therapies involve many different biological receptors linked in complex interaction pathways, which are usually poorly understood. The best possible therapies for many complex diseases will probably require a deep and detailed understanding of those relationships. However, because of the extreme complexity of the involved mechanisms, we will not achieve such detailed understanding in the immediate future. Hence, there is a need for new methodological approaches that are able to advance in this way. In this work, we propose a novel method for exploiting pharmacologic information obtained for sets of currently available drugs that are known to interact with multiple related receptors. This method is intended to improve our understanding of the biological mechanisms implicated in the pharmacological treatments but also to provide hints about how the chemical structure of the studied drugs could be improve...

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Section: Statistical Methods For Multireceptorial Binding Profiles 155mentioning

confidence: 99%

A Novel Multilevel Statistical Method for the Study of the Relationships between Multireceptorial Binding Affinity Profiles and In Vivo Endpoints

Selent

Bauer-Mehren²,

López³

et al. 2009

Mol Pharmacol

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“…Due to the high presence of 5-HT 6 R in brain, the 5-HT 6 R active ligands play an important role in CNS disorders such as schizophrenia, dementia, Alzheimer's disease, Parkinson's disease and other neurodegenerative disorders. Various structurally diverse small molecules containing the basic nitrogen (for primary binding) and the two other aromatic sites (for secondary binding) have been known to bind selectively at 5-HT 6 R [5][6][7][8] . In the past decade various molecules like SB-742457, SUVN-502, PRX-07034, SAM-531, SAM-315, LY-483518 and Lu AE58054 were reported as 5-HT 6 R ligands with positive clinical data [9][10][11][12][13] .…”

Section: -Htmentioning

confidence: 99%

Design, synthesis and pharmacological evaluation of conformationally restricted N-arylsulfonyl-3-aminoalkoxy indoles as a potential 5-HT₆ receptor ligands

Nirogia

Kambhampati

Daulatabad

et al. 2011

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Several 5-HT 6 antagonists have been evaluated in clinical trials for the treatment of cognitive deficits and dementia associated with Alzheimer's disease (Upton et al, 2008;Johnson et al, 2008;Geldenhuys and Van der Schyf, 2009). 5-HT 6 antagonists also have been proposed to have utility as an adjunctive treatment of cognitive dysfunction in schizophrenia (Roth et al, 2004;Schreiber et al, 2006) and other neurological diseases (Liu and Robichaud, 2009;Rosse and Schaffhauser, 2010;Codony et al, 2011). Recent clinical evidence further illustrates the potential utility of 5-HT 6 antagonists in the symptomatic treatment of Alzheimer's disease (Maher-Edwards et al, 2010, 2011.…”

Section: Introductionmentioning

confidence: 99%

Disposition and Metabolic Profiling of [¹⁴C]Cerlapirdine Using Accelerator Mass Spectrometry

et al. 2014

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Cerlapirdine (SAM-531, PF-05212365) is a selective, potent, full antagonist of the 5-hydroxytryptamine 6 (5-HT 6 ) receptor. Cerlapirdine and other 5-HT 6 receptor antagonists have been in clinical development for the symptomatic treatment of Alzheimer's disease. A human absorption, distribution, metabolism, and excretion study was conducted to gain further understanding of the metabolism and disposition of cerlapirdine. Because of the low amount of radioactivity administered, total 14 C content and metabolic profiles in plasma, urine, and feces were determined using accelerator mass spectrometry (AMS). After a single, oral 5-mg dose of [ C was almost complete, with feces being the major route of elimination of the administered dose, whereas urinary excretion played a lesser role. The extent of absorption was estimated to be at least 70%.Metabolite profiling in pooled plasma samples showed that unchanged cerlapirdine was the major drug-related component in circulation, representing 51% of total 14 C exposure in plasma. One metabolite (M1, desmethylcerlapirdine) was detected in plasma, and represented 9% of the total 14 C exposure. In vitro cytochrome P450 reaction phenotyping studies showed that M1 was formed primarily by CYP2C8 and CYP3A4. In pooled urine samples, three major drug-related peaks were detected, corresponding to cerlapirdine-N-oxide (M3), cerlapirdine, and desmethylcerlapirdine. In feces, cerlapirdine was the major 14 C component excreted, followed by desmethylcerlapirdine. The results of this study demonstrate that the use of the AMS technique enables comprehensive quantitative elucidation of the disposition and metabolic profiles of compounds administered at a low radioactive dose.

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5‐HT₆ antagonists as potential treatment for cognitive dysfunction

Cited by 79 publications

References 115 publications

A Novel Multilevel Statistical Method for the Study of the Relationships between Multireceptorial Binding Affinity Profiles and In Vivo Endpoints

A Novel Multilevel Statistical Method for the Study of the Relationships between Multireceptorial Binding Affinity Profiles and In Vivo Endpoints

Design, synthesis and pharmacological evaluation of conformationally restricted N-arylsulfonyl-3-aminoalkoxy indoles as a potential 5-HT₆ receptor ligands

Disposition and Metabolic Profiling of [¹⁴C]Cerlapirdine Using Accelerator Mass Spectrometry

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5‐HT6 antagonists as potential treatment for cognitive dysfunction

Cited by 79 publications

References 115 publications

A Novel Multilevel Statistical Method for the Study of the Relationships between Multireceptorial Binding Affinity Profiles and In Vivo Endpoints

A Novel Multilevel Statistical Method for the Study of the Relationships between Multireceptorial Binding Affinity Profiles and In Vivo Endpoints

Design, synthesis and pharmacological evaluation of conformationally restricted N-arylsulfonyl-3-aminoalkoxy indoles as a potential 5-HT6 receptor ligands

Disposition and Metabolic Profiling of [14C]Cerlapirdine Using Accelerator Mass Spectrometry

Contact Info

Product

Resources

About

5‐HT₆ antagonists as potential treatment for cognitive dysfunction

Design, synthesis and pharmacological evaluation of conformationally restricted N-arylsulfonyl-3-aminoalkoxy indoles as a potential 5-HT₆ receptor ligands

Disposition and Metabolic Profiling of [¹⁴C]Cerlapirdine Using Accelerator Mass Spectrometry