Abstract
A series of arylidene anabaseines were synthesized to probe the functional impact of hydrogen bonding on human α7 nicotinic acetylcholine receptor (nAChR) activation and desensitization. The aryl groups were either hydrogen bond acceptors (furans), donors (pyrroles), or neither (thiophenes). These compounds were tested against a series of point mutants of the ligand-binding domain residue Gln-57, a residue hypothesized to be proximate to the aryl group of the bound agonist and a putative hydrogen bonding partner. Q57K, Q57D, Q57E, and Q57L were chosen to remove the dual hydrogen bonding donor/acceptor ability of Gln-57 and replace it with hydrogen bond donating, hydrogen bond accepting, or nonhydrogen bonding ability. Activation of the receptor was compromised with hydrogen bonding mismatches, for example, pairing a pyrrole with Q57K or Q57L, or a furan anabaseine with Q57D or Q57E. Ligand co-applications with the positive allosteric modulator PNU-120596 produced significantly enhanced currents whose degree of enhancement was greater for 2-furans or -pyrroles than for their 3-substituted isomers, whereas the nonhydrogen bonding thiophenes failed to show this correlation. Interestingly, the PNU-120596 agonist co-application data...Continue Reading
References
Aug 9, 1996·Neuroscience Letters·R L PapkeP Lippiello
May 26, 1998·Psychopharmacology·K E StevensR Freedman
Apr 20, 2000·European Journal of Pharmacology·J A DaniV I Pidoplichko
Aug 15, 2000·Behavioural Brain Research·W R Kem
Aug 17, 2002·British Journal of Pharmacology·Roger L Papke, Julia K Porter Papke
Nov 19, 2002·Journal of Neurobiology·Nicolas Le NovèreJean-Pierre Changeux
Nov 19, 2002·Journal of Neurobiology·Michael W Quick, Robin A J Lester
May 3, 2003·The EMBO Journal·Thomas GrutterJean-Pierre Changeux
Mar 30, 2004·Proteins·Matthew P JacobsonRichard A Friesner
Feb 14, 2006·Current Pharmaceutical Design·Michael R D'Andrea, Robert G Nagele
Mar 14, 2007·International Review of Neurobiology·Laura F Martin, Robert Freedman
Jun 15, 2007·Molecular Pharmacology·Jens Halvard GrønlienJohn Malysz
Aug 30, 2008·Neuropharmacology·Neil S Millar, Cecilia Gotti
Sep 5, 2008·Molecular Pharmacology·Nicole A HorensteinRoger L Papke
Sep 16, 2008·Proceedings of the National Academy of Sciences of the United States of America·Gareth T YoungNeil S Millar
Dec 17, 2008·Bioorganic & Medicinal Chemistry Letters·Jingyi WangNicole A Horenstein
Feb 19, 2009·The Journal of Pharmacology and Experimental Therapeutics·Roger L PapkeNicole A Horenstein
Feb 19, 2009·The Journal of Pharmacology and Experimental Therapeutics·Renza RoncaratiGeorg C Terstappen
Mar 3, 2009·Nature·Xinan XiuDennis A Dougherty
Apr 9, 2009·Pharmacology & Therapeutics·Steven C LeiserJohn Dunlop
Jun 10, 2009·Current Neuropharmacology·Alvin V Terry
Aug 22, 2009·The EMBO Journal·Ryan E HibbsYves Bourne
Jan 9, 2010·Acta Crystallographica. Section D, Biological Crystallography·Vincent B ChenDavid C Richardson
Sep 9, 2010·Molecular Pharmacology·Jingyi WangRoger L Papke
Feb 3, 2011·The Journal of Pharmacology and Experimental Therapeutics·Roger L PapkeStephen A Bloom
Feb 24, 2011·The Journal of Biological Chemistry·Nyssa L PuskarDennis A Dougherty
Mar 30, 2011·The Journal of General Physiology·Dustin K WilliamsRoger L Papke
Jul 7, 2011·Proceedings of the National Academy of Sciences of the United States of America·Simon GravelCarlos D Bustamante
Sep 3, 2011·Molecular Pharmacology·Dustin K WilliamsRoger L Papke
Citations
Feb 4, 2014·Neuropharmacology·Krisztina PestiE Sylvester Vizi
Feb 4, 2014·Neuropharmacology·Anett K SzaboE Sylvester Vizi
Sep 1, 2012·Cellular and Molecular Life Sciences : CMLS·Angelo Keramidas, Joseph W Lynch
May 10, 2017·British Journal of Pharmacology·Roger L PapkeNicole A Horenstein
Jun 22, 2019·The Journal of Biological Chemistry·Jack NorleansJon Lindstrom
Jul 16, 2019·Psychopharmacology·Asti JacksonM I Damaj
Apr 13, 2019·Journal of Biological Engineering·Jianan NingZonghui Yuan
Jan 29, 2013·Biochemical Pharmacology·Matthew D IsaacsonRoger L Papke