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Mechanistic studies of novel sodium ...

University of Virginia.

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Mechanistic studies of novel sodium channel blockers for the treatment of epilepsy.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Mechanistic studies of novel sodium channel blockers for the treatment of epilepsy./
作者:	Jones, Paulianda Jaimin.
面頁冊數:	207 p.
附註:	Adviser: Milton L. Brown.
Contained By:	Dissertation Abstracts International67-11B.
標題:	Biology, Neuroscience. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3239955
ISBN:	9780542947322

Mechanistic studies of novel sodium channel blockers for the treatment of epilepsy.
Jones, Paulianda Jaimin.

Mechanistic studies of novel sodium channel blockers for the treatment of epilepsy. - 207 p.

Adviser: Milton L. Brown.

Thesis (Ph.D.)--University of Virginia, 2007.

Epilepsy is a common neurological disorder that affects approximately 1-2% of the population. Treatment of epilepsy focuses on the suppression of seizures via the use of antiepileptic drugs (AEDs). Recent advances in the treatment of epilepsy have produced several new AEDs. However, despite the availability of newer AEDs, one-third of epilepsy patients continue to suffer from uncontrolled seizures. In addition, substantial problems exist with toxicity, resistance, and idiosyncratic reactions for several AEDs, all of which likely contribute to their failure rate. Subsequently, a significant achievement would be to not only identify effective and safer AEDs, but also elucidate the mechanism by which these aims are accomplished. Voltage-gated sodium (Na) channels play a critical role in determining neuronal excitability and constitute a proven target for the suppression of seizures.

ISBN: 9780542947322Subjects--Topical Terms:

1017680
Biology, Neuroscience.

Mechanistic studies of novel sodium channel blockers for the treatment of epilepsy.
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100 1 $a Jones, Paulianda Jaimin. $3 1017679
245 1 0 $a Mechanistic studies of novel sodium channel blockers for the treatment of epilepsy.
300 $a 207 p.
500 $a Adviser: Milton L. Brown.
500 $a Source: Dissertation Abstracts International, Volume: 67-11, Section: B, page: 6222.
502 $a Thesis (Ph.D.)--University of Virginia, 2007.
520 $a Epilepsy is a common neurological disorder that affects approximately 1-2% of the population. Treatment of epilepsy focuses on the suppression of seizures via the use of antiepileptic drugs (AEDs). Recent advances in the treatment of epilepsy have produced several new AEDs. However, despite the availability of newer AEDs, one-third of epilepsy patients continue to suffer from uncontrolled seizures. In addition, substantial problems exist with toxicity, resistance, and idiosyncratic reactions for several AEDs, all of which likely contribute to their failure rate. Subsequently, a significant achievement would be to not only identify effective and safer AEDs, but also elucidate the mechanism by which these aims are accomplished. Voltage-gated sodium (Na) channels play a critical role in determining neuronal excitability and constitute a proven target for the suppression of seizures.
520 $a This thesis examines the biophysical and behavioral properties of a set of rationally designed small molecule inhibitors of neuronal voltage-gated Na channels. The central hypothesis of this dissertation proposes that using traditional medicinal chemistry modifications of the alpha-hydroxyamide scaffold, novel Na channel blockers can be designed, and their mechanisms of inhibition evaluated using patch-clamp electrophysiology. Furthermore, the biophysical properties of these novel compounds could be predictive of their in vivo AED activity. In this thesis, we have designed and synthesized novel Na channel blockers, and determined their biophysical effects on recorded neuronal Na currents. Each lead compound, JDA3135, HS357, and YWI92 exhibited a greater affinity for the inactivated state of the Na channel over the resting state of the channel. In addition, each of these compounds demonstrated greater use-dependent block and delayed recovery from inactivation, in comparison to their respective parent compounds. These state-dependent properties were corroborated with a selective reduction of neuronal excitability in hyperexcited CA1 hippocampal neurons. Consistent with these electrophysiology studies, each lead compound protected from seizure activity induced in acute and/or chronic models of epilepsy. Efficacious doses of JDA3135, HS357, and YW192 were without effect on motor coordination, as assessed in the rotorod toxicity assay. Thus, the a-hydroxyamide scaffold represents an important structural motif from which effective and safer anticonvulsants may be developed.
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