Point-to-point ligand-receptor interactions across the subunit interface modulate the induction and stabilization of conformational states of alpha7 nAChR by benzylidene anabaseines

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• 作者：Matthew D. Isaacson^a ; ¹ ; ^{misaacson01@gmail.com} ; Nicole A. Horenstein^b ; ^{horen@chem.ufl.edu} ; Clare Stokes^a ; ^{clear@ufl.edu} ; William R. Kem^a ; ^{wrkem@ufl.edu} ; Roger L. Papke^a ; ^{rlpapke@ufl.edu}
• 关键词：ACh ; acetylcholine ; nAChR ; nicotinic acetylcholine receptor ; BA ; benzylidene anabaseine ; RD ; residual desensitization ; Ds ; PAM-sensitive desensitization ; Di ; PAM-insensitive desensitization ; PAM ; positive allosteric modulator ; LBD ; ligand-binding domain
• 刊名：Biochemical Pharmacology
• 出版年：2013
• 出版时间：15 March, 2013
• 年：2013
• 卷：85
• 期：6
• 页码：817-828
• 全文大小：1734 K

文摘

The homomeric ¦Á7 nicotinic acetylcholine receptor is a well-studied therapeutic target, though its characteristically rapid desensitization complicates the development of drugs with specific agonist effects. Moreover, some experimental compounds such as GTS-21 (2,4diMeOBA), a derivative of the ¦Á7-selective partial agonist benzylidene anabaseine (BA), produce a prolonged residual desensitization (RD) in which the receptor remains non-activatable long after the drug has been removed from extracellular solution. In contrast, the desensitization caused by GTS-21's dihydroxy metabolite (2,4diOHBA) is relatively short-lived. RD is hypothetically due to stable binding of the ligand to the receptor in its desensitized state. We can attribute the reduction in RD to a single BA hydroxyl group on the 4¡ä benzylidene position. Computational prediction derived from homology modeling showed the serine36 (S36) residue of ¦Á7 as a reasonable candidate for point-to-point interaction between BA compounds and the receptor. Through evaluating the activity of BA and simple derivatives on wild-type and mutant ¦Á7 receptors, it was observed that the drug-receptor pairs which were capable of hydrogen bonding at residue 36 exhibited significantly less stable desensitization. Further experiments involving the type II positive allosteric modulator (PAM) PNU-120596 showed that the various BA compounds¡¯ preference to induce either a PAM-sensitive (D_s) or PAM-insensitive (D_i) desensitized state is concentration dependent and suggested that both states are destabilized by S36 H-bonding. These results indicate that the fine-tuning of agonists for specific interaction with S36 can facilitate the development of therapeutics with targeted effects on ion channel desensitization properties and conformational state stability.