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Author (up) Amici, M.; Eusebi, F.; Miledi, R. file  url
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  Title Effects of the antibiotic gentamicin on nicotinic acetylcholine receptors Type Journal Article
  Year 2005 Publication Neuropharmacology Abbreviated Journal Neuropharmacology  
  Volume 49 Issue 5 Pages 627-637  
  Keywords Animals; Anti-Bacterial Agents--pharmacology; Cochlea--drug effects; DNA, Complementary--biosynthesis; Electrophysiology; Gentamicins--pharmacology; Humans; Membrane Potentials--drug effects, physiology; Mice; Nicotinic Antagonists; Oocytes--metabolism; Patch-Clamp Techniques; RNA, Complementary--biosynthesis; Receptors, Nicotinic--biosynthesis, drug effects, genetics; Torpedo; Vestibule, Labyrinth--drug effects; Xenopus; alpha7 Nicotinic Acetylcholine Receptor  
  Abstract Medical treatment with the aminoglycosidic antibiotic gentamicin may produce side effects that include neuromuscular blockage and ototoxicity; which are believed to result from a dysfunction of nicotinic acetylcholine receptors (AChRs). Gentamicin is known to reversibly block ACh-currents generated by the activation of muscle-type alphabetagammadelta-AChR and neuronal alpha9-AChR. We studied the effects of gentamicin on heteromeric alphabetagammadelta-AChR and homomeric alpha7-AChR expressed in Xenopus oocytes. Prolonged treatment with gentamicin, and other antibiotics, differentially altered alphabetagammadelta- and alpha7-AChR responses. Specifically, gentamicin accelerated desensitization and did not reduce ACh-currents in oocytes expressing alphabetagammadelta-AChRs, whereas ACh-currents were reduced and desensitization was unaltered in oocytes expressing alpha7-AChRs. Moreover, acutely applied gentamicin acted as a competitive antagonist on both types of receptors and increased the rate of desensitization in alphabetagammadelta-AChR while reducing the rate of desensitization in alpha7-AChR. This data helps to better understand the action of gentamicin on muscle and nervous tissues, providing mechanistic insights that could eventually lead to improving the medical use of aminoglycosides.  
  Call Number Serial 445  
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Author (up) Bertrand, D.; Gopalakrishnan, M. file  url
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  Title Allosteric modulation of nicotinic acetylcholine receptors Type Journal Article
  Year 2007 Publication Biochemical Pharmacology Abbreviated Journal Biochem Pharmacol  
  Volume 74 Issue 8 Pages 1155-1163  
  Keywords Allosteric Regulation; Animals; Binding Sites; Dose-Response Relationship, Drug; Humans; Receptors, Nicotinic/*chemistry/*drug effects; alpha7 Nicotinic Acetylcholine Receptor  
  Abstract Allosteric modulation refers to the concept that proteins could exist in multiple conformational states and that binding of allosteric ligands alters the energy barriers or “isomerization coefficients” between various states. In the context of ligand gated ion channels such as nicotinic acetylcholine receptors (nAChRs), it implies that endogenous ligand acetylcholine binds at the orthosteric site, and that molecules that bind elsewhere on the nAChR subunit(s) acts via allosteric interactions. For example, studies with the homomeric alpha7 nAChRs indicate that such ligand interactions can be well described by an allosteric model, and that positive allosteric effectors can affect energy transitions by (i) predominantly affecting the peak current response (Type I profile) or, (ii) both peak current responses and time course of agonist-evoked response (Type II profile). The recent discovery of chemically heterogeneous group of molecules capable of differentially modifying nAChR properties without interacting at the ligand binding site illustrates the adequacy of the allosteric model to predict functional consequences. In this review, we outline general principles of the allosteric concept and summarize the profiles of novel compounds that are emerging as allosteric modulators at the alpha7 and alpha4beta2 nAChR subtypes.  
  Call Number Serial 1877  
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Author (up) Bertrand, D.; Gopalakrishnan, M. file  url
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  Title Allosteric modulation of nicotinic acetylcholine receptors Type Journal Article
  Year 2007 Publication Biochemical Pharmacology Abbreviated Journal Biochem Pharmacol  
  Volume 74 Issue 8 Pages 1155-1163  
  Keywords Allosteric Regulation; Animals; Binding Sites; Dose-Response Relationship, Drug; Humans; Receptors, Nicotinic/*chemistry/*drug effects; alpha7 Nicotinic Acetylcholine Receptor  
  Abstract Allosteric modulation refers to the concept that proteins could exist in multiple conformational states and that binding of allosteric ligands alters the energy barriers or “isomerization coefficients” between various states. In the context of ligand gated ion channels such as nicotinic acetylcholine receptors (nAChRs), it implies that endogenous ligand acetylcholine binds at the orthosteric site, and that molecules that bind elsewhere on the nAChR subunit(s) acts via allosteric interactions. For example, studies with the homomeric alpha7 nAChRs indicate that such ligand interactions can be well described by an allosteric model, and that positive allosteric effectors can affect energy transitions by (i) predominantly affecting the peak current response (Type I profile) or, (ii) both peak current responses and time course of agonist-evoked response (Type II profile). The recent discovery of chemically heterogeneous group of molecules capable of differentially modifying nAChR properties without interacting at the ligand binding site illustrates the adequacy of the allosteric model to predict functional consequences. In this review, we outline general principles of the allosteric concept and summarize the profiles of novel compounds that are emerging as allosteric modulators at the alpha7 and alpha4beta2 nAChR subtypes.  
  Call Number Serial 1887  
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Author (up) Briggs, C.A.; Gronlien, J.H.; Curzon, P.; Timmermann, D.B.; Ween, H.; Thorin-Hagene, K.; Kerr, P.; Anderson, D.J.; Malysz, J.; Dyhring, T.; Olsen, G.M.; Peters, D.; Bunnelle, W.H.; Gopalakrishnan, M. file  url
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  Title Role of channel activation in cognitive enhancement mediated by alpha7 nicotinic acetylcholine receptors Type Journal Article
  Year 2009 Publication British Journal of Pharmacology Abbreviated Journal Br J Pharmacol  
  Volume 158 Issue 6 Pages 1486-1494  
  Keywords Allosteric Regulation; Animals; Avoidance Learning/drug effects; Azabicyclo Compounds/administration & dosage/*pharmacology; Behavior, Animal/drug effects; Cell Line; Cognition Disorders/drug therapy/physiopathology; Dose-Response Relationship, Drug; Furans/administration & dosage/*pharmacology; Humans; Male; Mice; Nicotinic Agonists/*pharmacology; Oocytes/drug effects/metabolism; Oxadiazoles/administration & dosage/*pharmacology; Pyridazines/pharmacology; Pyrroles/pharmacology; Rats; Receptors, Nicotinic/*drug effects/metabolism; Xenopus laevis; alpha7 Nicotinic Acetylcholine Receptor  
  Abstract BACKGROUND AND PURPOSE: Several agonists of the alpha7 nicotinic acetylcholine receptor (nAChR) have been developed for treatment of cognitive deficits. However, agonist efficacy in vivo is difficult to reconcile with rapid alpha7 nAChR desensitization in vitro; and furthermore, the correlation between in vitro receptor efficacy and in vivo behavioural efficacy is not well delineated. The possibility that agonists of this receptor actually function in vivo as inhibitors via desensitization has not been finally resolved. EXPERIMENTAL APPROACH: Two structurally related alpha7 nAChR agonists were characterized and used to assess the degree of efficacy required in a behavioural paradigm. KEY RESULTS: NS6784 activated human and rat alpha7 nAChR with EC(50)s of 0.72 and 0.88 microM, and apparent efficacies of 77 and 97% respectively. NS6740, in contrast, displayed little efficacy at alpha7 nAChR (<2% in oocytes, < or =8% in GH4C1 cells), although its agonist-like properties were revealed by adding a positive allosteric modulator of alpha7 nAChRs or using the slowly desensitizing alpha7V274T receptor. In mouse inhibitory avoidance (IA) memory retention, NS6784 enhanced performance as did the 60% partial agonist A-582941. In contrast, NS6740 did not enhance performance, but blocked effects of A-582941. CONCLUSIONS AND IMPLICATIONS: Collectively, these findings suggest that a degree of alpha7 nAChR agonist efficacy is required for behavioural effects in the IA paradigm, and that such behavioural efficacy is not due to alpha7 nAChR desensitization. Also, a partial agonist of very low efficacy for this receptor could be used as an inhibitor, in the absence of alpha7 nAChR antagonists with favourable CNS penetration.  
  Call Number Serial 1881  
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Author (up) Horti, A.G.; Ravert, H.T.; Gao, Y.; Holt, D.P.; Bunnelle, W.H.; Schrimpf, M.R.; Li, T.; Ji, J.; Valentine, H.; Scheffel, U.; Kuwabara, H.; Wong, D.F.; Dannals, R.F. file  url
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  Title Synthesis and evaluation of new radioligands [(11)C]A-833834 and [(11)C]A-752274 for positron-emission tomography of alpha7-nicotinic acetylcholine receptors Type Journal Article
  Year 2013 Publication Nuclear Medicine and Biology Abbreviated Journal Nucl Med Biol  
  Volume 40 Issue 3 Pages 395-402  
  Keywords Animals; Azabicyclo Compounds/*chemical synthesis/chemistry/metabolism; Bridged Bicyclo Compounds/*chemical synthesis/chemistry/metabolism; Chemistry Techniques, Synthetic; Fluorenes/*chemical synthesis/chemistry/metabolism; Indoles/*chemical synthesis/chemistry/metabolism; Ligands; Male; Mice; Papio; Positron-Emission Tomography/*methods; Pyrazines/*chemical synthesis/chemistry/metabolism; Radiochemistry; Receptors, Nicotinic/*metabolism; alpha7 Nicotinic Acetylcholine Receptor  
  Abstract INTRODUCTION: alpha7-nicotinic acetylcholine receptor (alpha7-nAChR) is one of the major neuronal nAChR subtypes. alpha7-nAChR is involved in variety of neuronal processes and disorders including schizophrenia and Alzheimer's disease. A number of alpha7-nAChR PET radioligands have been developed, but a quality radiotracer remains to be discovered. METHODS: High binding affinity alpha7-nAChR ligands A-833834 and A-752274 were radiolabeled with (11)C. Baseline and blockade biodistribution studies in the mouse brain of [(11)C]A-833834 (5-(6-(5-[(11)C]methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-1H-i ndole) and [(11)C]A-752274 (2-(6-[(11)C]methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-7-(6-methyl-3,6-diazabicy clo[3.2.0]heptan-3-yl)-9H-fluoren-9-one) were performed. [(11)C]A-752274 was evaluated in a baseline baboon PET study. RESULTS: [(11)C]A-833834 and [(11)C]A-752274 were synthesized by radiomethylation of corresponding des-methyl precursors. The radioligands were prepared with radiochemical yield of 12%-32%, high specific radioactivity (330-403GBq/mumol) and radiochemical purity>95%. Dissection studies with [(11)C]A-833834 demonstrated low specific alpha7-nAChR binding in the mouse brain. [(11)C]A-752274 specifically (~50%) labeled alpha7-nAChR in the mouse thalamus. However, [(11)CA-752274 exhibited low brain uptake in baboon (%SUV<100). CONCLUSION: Two novel alpha7-nAChR ligands radioligands were synthesized and studied in animals. Specific binding of [(11)C]A-833834 in the mouse brain is low due to the insufficient binding affinity of the radioligand. The very high binding affinity [(11)C]A-752274 exhibited good specific binding in the alpha7-nAChR-rich mouse brain regions. The low uptake of [(11)C]A-752274 in the baboon brain is due to its high hydrophilicity, rapid metabolism or other properties. Future development of alpha7-nAChR PET radioligands will be based on compounds with high binding affinities and good blood-brain barrier permeability.  
  Call Number Serial 1882  
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