The discovery and characterization of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor potentiator N-{(3S,4S)-4-[4-(5-cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242).

A unique tetrahydrofuran ether class of highly potent α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiators has been identified using rational and structure-based drug design. An acyclic lead compound, containing an ether-linked isopropylsulfonamide and biphenyl group, was pharmacologically augmented by converting it to a conformationally constrained tetrahydrofuran to improve key interactions with the human GluA2 ligand-binding domain. Subsequent replacement of the distal phenyl motif with 2-cyanothiophene to enhance its potency, selectivity, and metabolic stability afforded N-{(3S,4S)-4-[4-(5-cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242, 3), whose preclinical characterization suggests an adequate therapeutic index, aided by low projected human oral pharmacokinetic variability, for clinical studies exploring its ability to attenuate cognitive deficits in patients with schizophrenia.

Activation of cannabinoid-1 receptors disrupts sensory gating and neuronal oscillation: relevance to schizophrenia.

BACKGROUND: Impaired auditory gating and abnormal neuronal synchrony are indicators of dysfunctional information processing in schizophrenia patients and possible underlying mechanisms of their impaired sensory and cognitive functions. Because cannabinoid receptors and endocannabinoids have been linked to psychiatric disorders, including schizophrenia, the aim of this study was to evaluate the effects of cannabinoid-1 (CB1) receptor activation on sensory gating and neuronal oscillations in rats. METHODS: Auditory sensory gating has been recorded from the hippocampus and entorhinal cortex (EC) in anesthetized rats. Neuronal network oscillations were recorded from the hippocampus, medial septum, EC, and medial prefrontal cortex in anesthetized and freely moving rats. Effects of systemic administration of CB1 receptor agonist CP-55940 were evaluated on these parameters. RESULTS: CP-55940 significantly disrupted auditory gating both in the hippocampus and EC in anesthetized rats. Theta field potential oscillations were disrupted in the hippocampus and EC, with simultaneous interruption of theta-band oscillations of septal neurons. Administration of the CB1 receptor antagonist AM-251 reversed both the agonist-induced gating deficit and the diminished oscillations. In freely moving rats, CP-55940 significantly reduced theta and gamma power in the hippocampus, whereas in the EC, only gamma power was attenuated. However, novelty-induced theta and gamma activities were significantly diminished by CP-55940 in both the hippocampus and EC. CONCLUSIONS: Our data indicate that activation of CB1 receptors interferes with neuronal network oscillations and impairs sensory gating function in the limbic circuitry, further supporting the connection between cannabis abuse and increased susceptibility of developing schizophrenia spectrum disorders.

Auditory sensory gating in hippocampus and reticular thalamic neurons in anesthetized rats.

BACKGROUND: Auditory gating is thought to reflect sensory information processing and is absent or diminished in schizophrenic patients. Although abnormal thalamic sensory processing has been proposed in schizophrenia, sensory gating of thalamic neurons has not been demonstrated experimentally. The aim of the present study was to establish whether auditory gating is present in the rat thalamus using a well-characterized animal model of auditory gating and schizophrenia. METHODS: Hippocampal electroencephalogram and single-unit activity in the thalamic reticular nucleus (nRT) were recorded in anaesthetized rats. Evoked potentials in the hippocampus and neuronal activity in the nRT were monitored in response to bilateral auditory stimuli. The effects of the psychostimulant D-amphetamine and the antipsychotic haloperidol on auditory gating were evaluated. RESULTS: Thalamic reticular nucleus neurons showed gated responses to paired-tone auditory stimuli, resembling hippocampal auditory gating. D-amphetamine disrupted auditory gating of nRT neurons and abolished their burst activity. D-amphetamine also disrupted hippocampal auditory gating and induced hippocampal theta activity. The amphetamine-induced gating deficit was reversed by haloperidol in both regions. CONCLUSIONS: Our findings provide the first experimental evidence for auditory gating of nRT neurons. We demonstrated that amphetamine disrupts sensory processing of nRT neurons, indicating similarities between hippocampal and thalamic sensory gating. These findings support the presumed connection between dopamine hyperfunction and abnormal thalamic filtering in schizophrenia.