Papke Roger L, Quadri Marta, Gulsevin Alican
Department of Pharmacology and Therapeutics, University of Florida, PO Box 100267, Gainesville, 32610 FL, USA.
Olon S.p.A., Strada Rivoltana, Km 6/7 - 20053 Rodano (MI) - ITALY (MQ).
Pharmacol Res. 2023 Apr;190:106736. doi: 10.1016/j.phrs.2023.106736. Epub 2023 Mar 20.
We discuss models for the activation and desensitization of α7 nicotinic acetylcholine receptors (nAChRs) and the effects of efficacious type II positive allosteric modulators (PAMs) that destabilize α7 desensitized states. Type II PAMs such as PNU-120596 can be used to distinguish inactive compounds from silent agonists, compounds that produce little or no channel activation but stabilize the non-conducting conformations associated with desensitization. We discuss the effects of α7 nAChRs in cells of the immune system and their roles in modulating inflammation and pain through what has come to be known as the cholinergic anti-inflammatory system (CAS). Cells controlling CAS do not generate ion channel currents but rather respond to α7 drugs by modulating intracellular signaling pathways analogous to the effects of metabotropic receptors. Metabotropic signaling by α7 receptors appears to be mediated by receptors in nonconducting conformations and can be accomplished by silent agonists. We discuss electrophysiological structure-activity relationships for α7 silent agonists and their use in cell-based and in vivo assays for CAS regulation. We discuss the strongly desensitizing partial agonist GTS-21 and its effectiveness in modulation of CAS. We also review the properties of the silent agonist NS6740, which is remarkably effective at maintaining α7 receptors in PAM-sensitive desensitized states. Most silent agonists bind to sites overlapping those for orthosteric agonists, but some appear to bind to allosteric sites. Finally, we discuss α9* nAChRs and their potential role in CAS, and ligands that will be useful in defining and distinguishing the specific roles of α7 and α9 in CAS.
我们讨论了α7烟碱型乙酰胆碱受体（nAChRs）的激活和脱敏模型，以及有效II型正变构调节剂（PAMs）对α7脱敏状态的去稳定化作用。II型PAMs如PNU-120596可用于区分无活性化合物与沉默激动剂，沉默激动剂是指那些几乎不产生或不产生通道激活，但能稳定与脱敏相关的非传导构象的化合物。我们讨论了α7 nAChRs在免疫系统细胞中的作用，以及它们通过所谓的胆碱能抗炎系统（CAS）在调节炎症和疼痛方面的作用。控制CAS的细胞不会产生离子通道电流，而是通过调节细胞内信号通路来响应α7药物，这类似于代谢型受体的作用。α7受体的代谢型信号传导似乎是由非传导构象的受体介导的，并且可以由沉默激动剂完成。我们讨论了α7沉默激动剂的电生理构效关系，以及它们在基于细胞和体内的CAS调节测定中的应用。我们讨论了强脱敏部分激动剂GTS-21及其在调节CAS中的有效性。我们还综述了沉默激动剂NS6740的特性，它在将α7受体维持在PAM敏感的脱敏状态方面非常有效。大多数沉默激动剂与正构激动剂的结合位点重叠，但有些似乎与变构位点结合。最后，我们讨论了α9* nAChRs及其在CAS中的潜在作用，以及有助于定义和区分α7和α9在CAS中具体作用的配体。
