Characterization of 2-[[4-Fluoro-3-(trifluoromethyl)phenyl]amino]-4-(4-pyridinyl)-5-thiazolemethanol (JNJ-1930942), a Novel Positive Allosteric Modulator of the α₇ Nicotinic Acetylcholine Receptor

Abstract

The ␣ 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 ␣ 7 nAChRs improved sensory gating and cognitive function in animal models and in early clinical trials. Here we describe the novel highly selective 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 ␣ 7 channel-dependent, because it is blocked by the ␣ 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 ␣ 7 nAChR potentiation in central nervous system disorders in which a deficit in ␣ 7 nAChR neurotransmission is hypothesized to be involved.

Nicotinic ACh receptors as therapeutic targets in CNS disorders

“…In support of a mechanistic role for α7 * nAChRs in schizophrenia, studies on auditory gating (investigated using the P50 auditory-evoked response), in which deficits are known to be associated with schizophrenia, have been done. The systemic administration of the type II α7 nAChR PAMs (PNU-120596 or JNJ-1930942) improved auditory gating deficits caused by amphetamine or MK-801 in rodent models that reflect circuit level disturbances associated with schizophrenia [141–143]. Furthermore several clinical trials support the use of α7 nAChR agonists to treat cognitive deficits in schizophrenia.…”

Nicotinic ligands as multifunctional agents for the treatment of neuropsychiatric disorders

“…Similarly, JNJ-1930942 (described as an intermediate type α7 PAM with characteristics falling between the profiles of Type I and Type II modulators) has beneficial effects on the auditory-evoked sensory inhibition deficits in DBA/2 mice [147]. Interestingly, Stevens and colleagues [146] recently reported that while PNU 120596 was efficacious in reversing the sensory gating deficits in DBA/2 mice, the modulator was inactive in C3H Chrna7 heterozygote mice which display greater decreases in hippocampal α7 nAChRs (50–60%) than DBA/2 mice (~30%) and therefore, more closely matches the α7 nAChR deficits (~50) found in post-mortem brains of schizophrenics.…”

Differential Immediate and Sustained Memory Enhancing Effects of Alpha7 Nicotinic Receptor Agonists and Allosteric Modulators in Rats

“…Compared to agonists, there is much less data regarding the cognitive effects of α7 nAChR PAMs in animals, and no published clinical data. However, documented effects include improvements of pre-pulse inhibition and auditory gating as well as short- and long-term memory [21]–[25], resembling the behavioral effects of the agonists. Since PAMs do not activate the receptor per se , but modulate the effects of endogenous transmitters, they may enable more subtle regulation of α7 nAChR responses compared to agonists [2], but on the other hand, a lack of activation by the PAMs alone may hamper their effectiveness in patients with decreased levels of endogenous activation.…”