Allosteric modulators of class B G-protein-coupled receptors.
Allosteric modulators of class B G-protein-coupled receptors.
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B 类 G 蛋白偶联受体的变构调节剂。
DOI：
10.2174/157015907781695928
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发表时间：
2007-09
影响因子：
5.3
通讯作者：
Hoare SR
中科院分区：
文献类型：
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作者：
Hoare SR
B类GPCR由肽配体激活，通常是30-40个氨基酸残基，参与主要的生理功能，如葡萄糖稳态（胰高血糖素和胰高血糖素样肽1）、钙稳态和骨转换（甲状旁腺激素和降钙素），以及应激轴的控制（促肾上腺皮质激素释放因子）。针对这些受体的多肽疗法已经开发出来，但是能够口服给药的非多肽配体的开发一直具有挑战性。这些受体的变构调节为开发抑制、激活或增强这些受体激活的非肽配体提供了一条潜在途径。本文综述了针对B类GPCR的变构调节剂的已知机制，特别是促肾上腺皮质激素释放因子1受体的非肽拮抗剂和胰高血糖素样肽-1受体的变构增强剂。还讨论了拮抗剂配体通过竞争性抑制肽结合位点之一来发挥作用的可能性，类似于Charniere机制。这些机制随后被用于讨论B类GPCR变构调节剂未来发展的潜在策略和药理学复杂性管理。
Class B GPCR’s are activated by peptide ligands, typically 30-40 amino acid residues, that are involved in major physiological functions such as glucose homeostasis (glucagon and glucagon-like peptide 1), calcium homeostasis and bone turnover (parathyroid hormone and calcitonin), and control of the stress axis (corticotropin-releasing factor). Peptide therapeutics have been developed targeting these receptors but development of nonpeptide ligands, enabling oral administration, has proved challenging. Allosteric modulation of these receptors provides a potential route to developing nonpeptide ligands that inhibit, activate, or potentiate activation of these receptors. Here the known mechanisms of allosteric modulators targeting Class B GPCR’s are reviewed, particularly nonpeptide antagonists of the corticotropin-releasing factor 1 receptor and allosteric enhancers of the glucagon-like peptide-1 receptor. Also discussed is the potential for antagonist ligands to operate by competitive inhibition of one of the peptide binding sites, analogous to the Charniere mechanism. These mechanisms are then used to discuss potential strategies and management of pharmacological complexity in the future development of allosteric modulators for Class B GPCR’s.