Abstract：
:Neuronal nicotinic acetylcholine receptors (nAChR), recognized targets for drug development in cognitive and neuro-degenerative disorders, are allosteric proteins with dynamic interconversions between multiple functional states. Activation of the nAChR ion channel is primarily controlled by the binding of ligands (agonists, partial agonists, competitive antagonists) at conventional agonist binding sites, but is also regulated in either negative or positive ways by the binding of ligands to other modulatory sites. In this review, we discuss models for the activation and desensitization of nAChR, and the discovery of multiple types of ligands that influence those processes in both heteromeric nAChR, such as the high-affinity nicotine receptors of the brain, and homomeric α7-type receptors. In recent years, α7 nAChRs have been identified as a potential target for therapeutic indications leading to the development of α7-selective agonists and partial agonists. However, unique properties of α7 nAChR, including low probability of channel opening and rapid desensitization, may limit the therapeutic usefulness of ligands binding exclusively to conventional agonist binding sites. New enthusiasm for the therapeutic targeting of α7 has come from the identification of α7-selective positive allosteric modulators (PAMs) that work effectively on the intrinsic factors that limit α7 ion channel activation. While these new drugs appear promising for therapeutic development, we also consider potential caveats and possible limitations for their use, including PAM-insensitive forms of desensitization and cytotoxicity issues.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Williams DK,Wang J,Papke RLdoi
10.1016/j.bcp.2011.05.001subject
Has Abstractpub_date
2011-10-15 00:00:00pages
915-30issue
8eissn
0006-2952issn
1873-2968pii
S0006-2952(11)00291-7journal_volume
82pub_type
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(93)90069-9
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
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journal_title：Biochemical pharmacology
pub_type： 杂志文章,评审
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
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journal_title：Biochemical pharmacology
pub_type： 杂志文章,评审
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pub_type： 杂志文章
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pub_type： 杂志文章
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pub_type： 杂志文章
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
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pub_type： 杂志文章
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pub_type： 杂志文章,评审
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pub_type： 杂志文章
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更新日期：2002-06-15 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/s0006-2952(00)00303-8
更新日期：2000-07-01 00:00:00
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pub_type： 杂志文章
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更新日期：2012-12-15 00:00:00
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pub_type： 杂志文章
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pub_type： 杂志文章
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pub_type： 杂志文章
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pub_type： 杂志文章
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pub_type： 杂志文章,评审
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
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更新日期：2008-06-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
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更新日期：1987-05-01 00:00:00
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pub_type： 杂志文章
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
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更新日期：2012-01-15 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章,评审
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更新日期：2010-09-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
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更新日期：1989-01-01 00:00:00
