Abstract
The α7 nicotinic acetylcholine receptor (nAChR) is a potential therapeutic target for the treatment of cognitive deficits associated with schizophrenia, Alzheimer's disease, Parkinson's disease, and attention-deficit/hyperactivity disorder. Activation of α7 nAChRs improved sensory gating and cognitive function in animal models and in early clinical trials. Here we describe the novel highly selective α7 nAChR positive allosteric modulator, 2-[[4-fluoro-3-(trifluoromethyl)phenyl]amino]-4-(4-pyridinyl)-5-thiazolemethanol (JNJ-1930942). This compound enhances the choline-evoked rise in intracellular Ca2+ levels in the GH4C1 cell line expressing the cloned human α7 nAChR. JNJ-1930942 does not act on α4β2, α3β4 nAChRs or on the related 5-HT3A channel. Electrophysiological assessment in the GH4C1 cell line shows that JNJ-1930942 increases the peak and net charge response to choline, acetylcholine, and N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide (PNU-282987). The potentiation is obtained mainly by affecting the receptor desensitization characteristics, leaving activation and deactivation kinetics as well as recovery from desensitization relatively unchanged. Choline efficacy is increased over its full concentration response range, and choline potency is increased more than 10-fold. The potentiating effect is α7 channel-dependent, because it is blocked by the α7 antagonist methyllycaconitine. Moreover, in hippocampal slices, JNJ-1930942 enhances neurotransmission at hippocampal dentate gyrus synapses and facilitates the induction of long-term potentiation of electrically evoked synaptic responses in the dentate gyrus. In vivo, JNJ-1930942 reverses a genetically based auditory gating deficit in DBA/2 mice. JNJ-1930942 will be a useful tool to study the therapeutic potential of α7 nAChR potentiation in central nervous system disorders in which a deficit in α7 nAChR neurotransmission is hypothesized to be involved.
Footnotes
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.173245.
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The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- nAChR
- nicotinic acetylcholine receptor
- PAM
- positive allosteric modulator
- XY-4083
- N-(4-chlorophenyl)-[[(4-chlorophenyl)amino]methylene]-3-methyl-5-isoxazoleacetamide
- LY2087101
- [2-(4-fluoro-phenylamino)-4-methyl-thiazol-5-yl]-thiopen-3-yl-methanone
- NS-1738
- N-(5-chloro-2-hydroxyphenyl)-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea
- PNU-120596
- 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea
- TQS
- 4-naphthalen-1-yl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonic acid amide
- A-867744
- 4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide
- JNJ-1930942
- 2-[[4-fluoro-3-(trifluoromethyl) phenyl]amino]-4-(4-pyridinyl)-5-thiazolemethanol
- LTP
- long-term potentiation
- GH4C1α7
- GH4C1 cells stably transfected with the human α7 nAChR
- FCS
- fetal calf serum
- A-585539
- (1S,4S)-2,2-dimethyl-5-(6-phenylpyridazin-3-yl)-5-aza-2-azoniabicyclo[2.2.1]heptane
- MLA
- methyllycaconitine
- DMSO
- dimethyl sulfoxide
- PBS
- phosphate-buffered saline
- ECS
- extracellular solution
- ACSF
- artificial cerebrospinal fluid
- fEPSP
- field excitatory postsynaptic potential
- MEA
- microelectrode array
- MPP
- medial perforant path
- DG
- dentate gyrus
- TBS
- θ-burst stimulation
- PVP
- polyvinylpyrrolidone
- α-BTX
- α-bungarotoxin
- PPR
- paired-pulse ratio
- CAMP
- the response amplitudes to the first (conditioning) stimulus S1
- TAMP
- the response amplitudes to the second (test) stimulus S2
- TC ratio
- TAMP/CAMP ratio
- GTS-21
- 3-[(3E)-3-[(2,4-dimethoxyphenyl)methylidene]-5,6-dihydro-4H-pyridin-2-yl]pyridine.
- Received August 20, 2010.
- Accepted November 15, 2010.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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