PMID- 19556356
OWN - NLM
STAT- MEDLINE
DCOM- 20090909
LR  - 20211020
IS  - 1521-0111 (Electronic)
IS  - 0026-895X (Print)
IS  - 0026-895X (Linking)
VI  - 76
IP  - 3
DP  - 2009 Sep
TI  - Selective inhibition of acetylcholine-evoked responses of alpha7 neuronal 
      nicotinic acetylcholine receptors by novel tris- and tetrakis-azaaromatic 
      quaternary ammonium antagonists.
PG  - 652-66
LID - 10.1124/mol.109.056176 [doi]
AB  - A family of 20 tris-azaaromatic quaternary ammonium (AQA) compounds were tested 
      for their inhibition of alpha7 nicotinic acetylcholine receptors (nAChRs) 
      expressed in Xenopus laevis oocytes. The potency of inhibitory activity was 
      related to the hydrophobic character of the tris head groups. Two tris-AQA 
      compounds were studied in detail: the highly effective inhibitor 
      1,3,5-tri-[5-(1-quinolinum)-pent-1-yn-1-yl]-benzene tribromide (tPyQB) and the 
      less potent antagonist 1,3,5,-tri-5-[1-(2-picolinium)]-pent-1-yn-1-ylbenzene 
      tribromide (tPy2PiB). In addition, we evaluated 
      1,2,4,5-tetra-5-[1-(3-benzyl)pyridinium]pent-1-ylbenzene tetrabromide 
      (tkP3BzPB), a tetrakis-AQA with very hydrophobic headgroups. We compared the 
      activity of the AQA compounds to the frequently used alpha7-antagonist 
      methyllycaconitine (MLA). Both tPyQB and tkP3BzPB were selective antagonists of 
      alpha7. However, although inhibition by tPyQB was reversible within 5 min, the 
      recovery time constant for tkP3BzPB inhibition was 26.6 +/- 0.8 min, so that the 
      equilibrium inhibition in the prolonged presence of nanomolar concentrations of 
      tkP3BzPB was nearly 100%. The potency, selectivity, and slow reversibility of 
      tkP3BzPB were comparable with or greater than that of MLA. The inhibitory actions 
      of tPyQB, tPy2PiB, and tkP3BzPB were evaluated on the acetylcholine (ACh)-evoked 
      responses of native nAChRs in rat brain slices. The alpha7-mediated responses of 
      hippocampal interneurons were effectively reduced by 1 microM tPyQB and tkP3BzPB 
      but not tPy2PiB. In rat medial septum, tkP3BzPB produced a greater inhibition of 
      ACh-evoked responses of cells with fast inward currents (type I) than of cells 
      with predominantly slow kinetics (type II), suggesting that tkP3BzPB can block 
      alpha7 yet preserve the responsiveness of non-alpha7 receptors. These agents 
      might be helpful in elucidating complex receptor responses in brain regions with 
      mixed populations of nAChRs.
FAU - Lopez-Hernandez, Gretchen Y
AU  - Lopez-Hernandez GY
AD  - Department of Pharmacology and Therapeutics, University of Florida, P.O. Box 
      100267, Gainesville, FL 32610-0267, USA.
FAU - Thinschmidt, Jeffrey S
AU  - Thinschmidt JS
FAU - Zheng, Guangrong
AU  - Zheng G
FAU - Zhang, Zhenfa
AU  - Zhang Z
FAU - Crooks, Peter A
AU  - Crooks PA
FAU - Dwoskin, Linda P
AU  - Dwoskin LP
FAU - Papke, Roger L
AU  - Papke RL
LA  - eng
GR  - R01 GM057481-08/GM/NIGMS NIH HHS/United States
GR  - T32-AG000196/AG/NIA NIH HHS/United States
GR  - R01 GM057481-07/GM/NIGMS NIH HHS/United States
GR  - R01 GM057481/GM/NIGMS NIH HHS/United States
GR  - U19-DA017548/DA/NIDA NIH HHS/United States
GR  - R01 GM057481-06/GM/NIGMS NIH HHS/United States
GR  - P01-AG010485/AG/NIA NIH HHS/United States
GR  - R01 GM057481-05A2/GM/NIGMS NIH HHS/United States
GR  - R01-GM057481/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20090625
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (Chrna7 protein, rat)
RN  - 0 (Quaternary Ammonium Compounds)
RN  - 0 (Receptors, Nicotinic)
RN  - 0 (alpha7 Nicotinic Acetylcholine Receptor)
RN  - N9YNS0M02X (Acetylcholine)
SB  - IM
MH  - Acetylcholine/metabolism/pharmacology
MH  - Animals
MH  - Neurons/drug effects/metabolism
MH  - Oocytes
MH  - Quaternary Ammonium Compounds/*pharmacology
MH  - Rats
MH  - Receptors, Nicotinic/biosynthesis/*drug effects
MH  - Xenopus laevis
MH  - alpha7 Nicotinic Acetylcholine Receptor
PMC - PMC2730394
EDAT- 2009/06/27 09:00
MHDA- 2009/09/10 06:00
PMCR- 2010/09/01
CRDT- 2009/06/27 09:00
PHST- 2009/06/27 09:00 [entrez]
PHST- 2009/06/27 09:00 [pubmed]
PHST- 2009/09/10 06:00 [medline]
PHST- 2010/09/01 00:00 [pmc-release]
AID - mol.109.056176 [pii]
AID - 0652 [pii]
AID - 10.1124/mol.109.056176 [doi]
PST - ppublish
SO  - Mol Pharmacol. 2009 Sep;76(3):652-66. doi: 10.1124/mol.109.056176. Epub 2009 Jun 
      25.