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Short-acting T-type calcium channel antagonists significantly modify sleep architecture in rodents.

ABSTRACT: A novel phenyl acetamide series of short-acting T-type calcium channel antagonists has been identified and evaluated using in vitro and in vivo assays. Heterocycle substitutions of the 4-position of the phenyl acetamides afforded potent and selective antagonists that exhibited desired short plasma half-lives across preclinical species. Lead compound TTA-A8 emerged as a compound with excellent in vivo efficacy as indicated by its significant modulation of rat sleep architecture in an EEG telemetry model, favorable pharmacokinetic properties, and excellent preclinical safety. TTA-A8 recently progressed into human clinical trials, and in line with our predictions, preliminary studies (n = 12) with a 20 mg oral dose afforded a high C max of 1.82 ± 0.274 ?M with an apparent terminal half-life of 3.0 ± 1.1 h.

SUBMITTER: Yang ZQ

PROVIDER: S-EPMC4007914 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Short-acting T-type calcium channel antagonists significantly modify sleep architecture in rodents.

Yang Zhi-Qiang ZQ Schlegel Kelly-Ann S KA Shu Youheng Y Reger Thomas S TS Cube Rowena R Mattern Christa C Coleman Paul J PJ Small Jim J Hartman George D GD Ballard Jeanine J Tang Cuyue C Kuo Yuhsin Y Prueksaritanont Thomayant T Nuss Cindy E CE Doran Scott S Fox Steve V SV Garson Susan L SL Li Yuxing Y Kraus Richard L RL Uebele Victor N VN Taylor Adekemi B AB Zeng Wei W Fang Wei W Chavez-Eng Cynthia C Troyer Matthew D MD Luk Julie Ann JA Laethem Tine T Cook William O WO Renger John J JJ Barrow James C JC

ACS medicinal chemistry letters 20100824 9

A novel phenyl acetamide series of short-acting T-type calcium channel antagonists has been identified and evaluated using in vitro and in vivo assays. Heterocycle substitutions of the 4-position of the phenyl acetamides afforded potent and selective antagonists that exhibited desired short plasma half-lives across preclinical species. Lead compound TTA-A8 emerged as a compound with excellent in vivo efficacy as indicated by its significant modulation of rat sleep architecture in an EEG telemetr ...[more]

PMID: 24900239

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Project description:STUDY OBJECTIVES: Voltage-gated Ca(2+) channels (VGCCs) are key elements in mediating thalamocortical rhythmicity. Low-voltage activated (LVA) CaV 3 T-type Ca(2+) channels have been related to thalamic rebound burst firing and to generation of non-rapid eye movement (NREM) sleep. High-voltage activated (HVA) CaV 1 L-type Ca(2+) channels, on the opposite, favor the tonic mode of action associated with higher levels of vigilance. However, the role of the HVA Non-L-type CaV2.3 Ca(2+) channels, which are predominantly expressed in the reticular thalamic nucleus (RTN), still remains unclear. Recently, CaV2.3(-/-) mice were reported to exhibit altered spike-wave discharge (SWD)/absence seizure susceptibility supported by the observation that CaV2.3 mediated Ca(2+) influx into RTN neurons can trigger small-conductance Ca(2+)-activated K(+)-channel type 2 (SK2) currents capable of maintaining thalamic burst activity. Based on these studies we investigated the role of CaV2.3 R-type Ca(2+) channels in rodent sleep. METHODS: The role of CaV2.3 Ca(2+) channels was analyzed in CaV2.3(-/-) mice and controls in both spontaneous and artificial urethane-induced sleep, using implantable video-EEG radiotelemetry. Data were analyzed for alterations in sleep architecture using sleep staging software and time-frequency analysis. RESULTS: CaV2.3 deficient mice exhibited reduced wake duration and increased slow-wave sleep (SWS). Whereas mean sleep stage durations remained unchanged, the total number of SWS epochs was increased in CaV2.3(-/-) mice. Additional changes were observed for sleep stage transitions and EEG amplitudes. Furthermore, urethane-induced SWS mimicked spontaneous sleep results obtained from CaV2.3 deficient mice. Quantitative Real-time PCR did not reveal changes in thalamic CaV3 T-type Ca(2+) channel expression. The detailed mechanisms of SWS increase in CaV2.3(-/-) mice remain to be determined. CONCLUSIONS: Low-voltage activated CaV2.3 R-type Ca(2+) channels in the thalamocortical loop and extra-thalamocortical circuitries substantially regulate rodent sleep architecture thus representing a novel potential target for pharmacological treatment of sleep disorders in the future.

Dataset Information

Short-acting T-type calcium channel antagonists significantly modify sleep architecture in rodents.

Publications

Short-acting T-type calcium channel antagonists significantly modify sleep architecture in rodents.

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