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Biochem Pharmacol
2013 Mar 15;856:817-28. doi: 10.1016/j.bcp.2013.01.010.
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Point-to-point ligand-receptor interactions across the subunit interface modulate the induction and stabilization of conformational states of alpha7 nAChR by benzylidene anabaseines.
Isaacson MD
,
Horenstein NA
,
Stokes C
,
Kem WR
,
Papke RL
.
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The homomeric α7 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 α7-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' benzylidene position. Computational prediction derived from homology modeling showed the serine36 (S36) residue of α7 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 α7 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.
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Positive allosteric modulation of the alpha7 nicotinic acetylcholine receptor: ligand interactions with distinct binding sites and evidence for a prominent role of the M2-M3 segment.
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Bertrand,
Positive allosteric modulation of the alpha7 nicotinic acetylcholine receptor: ligand interactions with distinct binding sites and evidence for a prominent role of the M2-M3 segment.
2008,
Pubmed
,
Xenbase
Chen,
MolProbity: all-atom structure validation for macromolecular crystallography.
2010,
Pubmed
Dajas-Bailador,
The alpha7 nicotinic acetylcholine receptor subtype mediates nicotine protection against NMDA excitotoxicity in primary hippocampal cultures through a Ca(2+) dependent mechanism.
2000,
Pubmed
Dani,
Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system.
2007,
Pubmed
Freedman,
Initial phase 2 trial of a nicotinic agonist in schizophrenia.
2008,
Pubmed
Giebelen,
Local stimulation of alpha7 cholinergic receptors inhibits LPS-induced TNF-alpha release in the mouse lung.
2007,
Pubmed
Grønlien,
Distinct profiles of alpha7 nAChR positive allosteric modulation revealed by structurally diverse chemotypes.
2007,
Pubmed
,
Xenbase
Halevi,
Conservation within the RIC-3 gene family. Effectors of mammalian nicotinic acetylcholine receptor expression.
2003,
Pubmed
,
Xenbase
Hibbs,
Structural determinants for interaction of partial agonists with acetylcholine binding protein and neuronal alpha7 nicotinic acetylcholine receptor.
2009,
Pubmed
Horenstein,
Reversal of agonist selectivity by mutations of conserved amino acids in the binding site of nicotinic acetylcholine receptors.
2007,
Pubmed
,
Xenbase
Horenstein,
Multiple pharmacophores for the selective activation of nicotinic alpha7-type acetylcholine receptors.
2008,
Pubmed
,
Xenbase
Kem,
The brain alpha7 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer's disease: studies with DMXBA (GTS-21).
2000,
Pubmed
Kem,
Hydroxy metabolites of the Alzheimer's drug candidate 3-[(2,4-dimethoxy)benzylidene]-anabaseine dihydrochloride (GTS-21): their molecular properties, interactions with brain nicotinic receptors, and brain penetration.
2004,
Pubmed
,
Xenbase
Kox,
GTS-21 inhibits pro-inflammatory cytokine release independent of the Toll-like receptor stimulated via a transcriptional mechanism involving JAK2 activation.
2009,
Pubmed
Marrero,
Convergence of alpha 7 nicotinic acetylcholine receptor-activated pathways for anti-apoptosis and anti-inflammation: central role for JAK2 activation of STAT3 and NF-kappaB.
2009,
Pubmed
Millar,
Diversity of vertebrate nicotinic acetylcholine receptors.
2009,
Pubmed
Moustakas,
Development and validation of a modular, extensible docking program: DOCK 5.
2006,
Pubmed
Papke,
Effects at a distance in alpha 7 nAChR selective agonists: benzylidene substitutions that regulate potency and efficacy.
2004,
Pubmed
,
Xenbase
Papke,
Activation and desensitization of nicotinic alpha7-type acetylcholine receptors by benzylidene anabaseines and nicotine.
2009,
Pubmed
,
Xenbase
Papke,
Comparative pharmacology of rat and human alpha7 nAChR conducted with net charge analysis.
2002,
Pubmed
,
Xenbase
Paterson,
Neuronal nicotinic receptors in the human brain.
2000,
Pubmed
,
Xenbase
Pavlov,
Selective alpha7-nicotinic acetylcholine receptor agonist GTS-21 improves survival in murine endotoxemia and severe sepsis.
2007,
Pubmed
Ren,
Multiple calcium channels and kinases mediate alpha7 nicotinic receptor neuroprotection in PC12 cells.
2005,
Pubmed
Slavov,
A computational study of the binding of 3-(arylidene) anabaseines to two major brain nicotinic acetylcholine receptors and to the acetylcholine binding protein.
2010,
Pubmed
Svensson,
Beta-estradiol attenuate amyloid beta-peptide toxicity via nicotinic receptors.
1999,
Pubmed
Séguéla,
Molecular cloning, functional properties, and distribution of rat brain alpha 7: a nicotinic cation channel highly permeable to calcium.
1993,
Pubmed
,
Xenbase
Wang,
Potential state-selective hydrogen bond formation can modulate activation and desensitization of the α7 nicotinic acetylcholine receptor.
2012,
Pubmed
Wang,
Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation.
2003,
Pubmed
Williams,
Differential regulation of receptor activation and agonist selectivity by highly conserved tryptophans in the nicotinic acetylcholine receptor binding site.
2009,
Pubmed
,
Xenbase
Williams,
Investigation of the molecular mechanism of the α7 nicotinic acetylcholine receptor positive allosteric modulator PNU-120596 provides evidence for two distinct desensitized states.
2011,
Pubmed
,
Xenbase
Williams,
Intrinsically low open probability of α7 nicotinic acetylcholine receptors can be overcome by positive allosteric modulation and serum factors leading to the generation of excitotoxic currents at physiological temperatures.
2012,
Pubmed
,
Xenbase
Young,
Nicotine improves sustained attention in mice: evidence for involvement of the alpha7 nicotinic acetylcholine receptor.
2004,
Pubmed
