The α(7) 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 α(7) nAChRs improved sensory gating and cognitive function in animal models and in early clinical trials. Here we describe the novel highly selective α(7) 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 Ca(2+) levels in the GH4C1 cell line expressing the cloned human α(7) 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 α(7) channel-dependent, because it is blocked by the α(7) 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 α(7) nAChR potentiation in central nervous system disorders in which a deficit in α(7) nAChR neurotransmission is hypothesized to be involved.