Use of kCNQ-openers for treating or reducing the symptoms of schizophrenia
A technology for schizophrenia and symptoms, applied in the direction of organic active ingredients, nervous system diseases, active ingredients of heterocyclic compounds, etc.
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Embodiment 1
[0757] Example 1. Electrophysiology, Rat.
[0758] Reports have suggested that inhibition of the number of spontaneously active dopaminergic neurons in the rat ventral tegmental area, i.e., the mesolimbic system, may account for the antipsychotic potential of the compound (Chiodo and Bunney, 1983, J. Neurosci., 5, 2539 -2544). In the mesolimbic system, all clinically used neuroleptics initially increase the firing rate of dopaminergic neurons (Tung et al., 1991, J. Neural Transm. Gen Sect., 84(1-2), 53- 64). After chronic administration, this neuroleptic eventually (after 3-4 weeks of treatment) reduces the firing rate below the preconditioning level (Skarsfeldt, 1992, Synapse, 10, 2533; White and Wang, 1983, Science, 221, 1054 -1057). This inhibitory effect on dopaminergic neurons is thought to be mediated by depolarization blockade and is thought to have therapeutic implications for the antipsychotic effects of neuroleptics (Grace and Bunney, 1986, J. Pharmacol. Exp. The...
Embodiment 2
[0767] Example 2. Amphetamine challenge, rat.
[0768] Administration of D-amphetamine to rodents stimulates increased locomotor activity via mesolimbic dopamine receptors in the nucleus accumbens. Although psychostimulant psychosis may not serve as a model for all forms of schizophrenia, it may have applicability to delusional schizophrenia and non-schizophrenic disorders (Krystal et al., pp. 214-224 in Neurobiology of Mental Illness ISBN 0-19-511265-2). Inhibition of amphetamine-induced increases in locomotor activity is believed to be a reliable method for evaluating compounds with antipsychotic potential ( et al., European J. Pharmacol. 1984, 102, 459-464). In the following experiment it will be tested if the inhibition of spontaneous DA neurons in the mesolimbic circuit evaluated above can be converted to a behavioral antipsychotic endpoint ).
[0769] subject. Male Wistar rats (Taconic, Denmark) weighing 170-240 g were used. Animals were housed on a 12-hr light / da...
Embodiment 3
[0774] Example 3. Microdialysis, Rat.
[0775] Psychostimulants are well known to increase voluntary activity by elevating extracellular DA levels in the nucleus accumbens, the terminal region of mesolimbic DA projections (Guix et al., 1992, Neurosci. Lett., 138( 1), 137-140; Moghaddam et al., 1989, Synapse, 4(2), 156-161). It is also known that the antagonistic effect of antipsychotics on stimulus-induced hyperkinesia is related to the effect of antipsychotics on suppressing stimulated DA levels in the nucleus accumbens. (Broderick et al., 2004, Prog. Neuropsychopharmacology and Biol. Psych., 28, 157-171). Thus, the nucleus accumbens is a well-established neuroanatomical site for testing for reversal of positive psychotic symptoms. Therefore, the following experiments were carried out to investigate ethyl N-(2-amino-4-(4-fluorobenzylamino)-phenyl)carbamate, 2-cyclopentyl-N-(2,6-dimethyl Base-4-morpholin-4-yl-phenyl)-acetamide, N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-d...
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