It is now known that many neurotransmitter systems are responsible for diseases of the central nervous system (CNS). One of the most common CNS disease is depression. Considering that in the treatment and the genesis of depression, the most important are the serotonin receptors from 5-HT_1A, 5-HT_2A, 5-HT₆ and 5-HT₇ groups, and dopamine D₂R this article describes searching for group of new ligands for mentioned receptors. In the searching for potentially useful compound, we decided to start from the structure of well-known Fananserin. We tried to developed new derivatives, with changed profile of activity compared to Fananserin. Literature analysis and virtual screening emerged group of halogenated long-chain arylpiperazines derivatives of 1,8 naphthosultam/lactam with hexyl carbon chain to synthesis. The compounds obtaining method was developed with a microwave assisted synthesis. Reactions were carried out in acetonitrile, water or in solvent-free conditions. The obtained compounds were tested for their affinity for the serotonin receptors mentioned above. The work managed to obtain compounds acting on selected serotonin receptors, including multifunctional 5-HT_1A/5-HT₇/D₂ ligand 5k, dual 5-HT_1A/D₂ ligand 5j and selective 5-HT_1A ligands 5r and 5c. The SAR analysis showed a visible dependence of affinity for the 5-HT₆ receptors from structure of ligands. This relationship was discussed using molecular docking methods. A conformal analysis was also performed for selected ligands and the Fukui indexes were calculated using the DFT (B3LYP/6-311+G (d,p) level of theory) methods. The conducted research and analysis using molecular docking methods allows for selecting further pathways of structural modifications in the design of new ligands for serotonin receptors belonging to the group mentioned. What is more, conducted research show the potential using of Fukui indices to predict the biological activity of new molecules.

2012-07-01·Clinical Schizophrenia & Related Psychoses

Antipsychotic Dosing: Extended, and Transient

Review

作者: Remington, Gary ; Seeman, Philip

New Ways of Antipsychotic Dosing Considering the few new medications being developed for schizophrenia, it is recognized that novel avenues of research are needed for drug treatment of schizophrenia. While current antipsychotic drugs primarily block dopamine D2 receptors or interfere with dopamine neurotransmission (1, 2), many drugs for non-D2 pathways and receptors have been tested as possible antipsychotics, but not with much success. These include antagonists or agonists at receptors for D1 (SCH 23390), D3 (BP897; ABT925), D4 (fananserin/sonepiprazole), cannabinoids (rimonabant), neurokinins (SR142801; osanetant), neurotensin (SR48692), glycine transport inhibitors, ampakines (CX516), and serotonin (MDL100907; SR 46349B). The hypoglutamate hypothesis of schizophrenia suggests that low stimulation of glutamate receptors may be a basis for the illness. In fact, Patil et al. (3) reported that activation of the metabotropic glutamate-2/3 receptors (mGluR2/3) by LY404039 (or its precursor, LY2140023) was clinically equi-effective as olanzapine in alleviating psychotic signs and symptoms of patients with schizophrenia. Recently, however, Kinon et al. (4) reported that the clinical efficacy of LY404039 was “inconclusive.” At present, therefore, it appears that at least a D2-blocking component is needed for the treatment of schizophrenia. In addition, while there is preclinical information in animals that stimulation of mGluR2/3 receptors might be therapeutic, the clinical efficacy of this approach has not yet been clearly established (4). While interference with dopamine transmission at D2 is the minimum drug requirement for treating schizophrenia, there are new ways and new drugs that optimize the dosing of patients to minimize side effects and rehospitalization. These new ways are based on the fact that some antipsychotics, such as clozapine, quetiapine, amisulpride, remoxipride and amoxapine, attach to the D2 receptor in vitro for brief periods of time (half-times of 15 to 66 seconds) before dissociating from the D2 receptors (5-7). In fact, the transient attachment (a few hours in vivo) of quetiapine to D2 has been confirmed in patients (8).

2008-11-01·Journal of Pharmaceutical Sciences3区 · 医学

Ordering and disordering of molecular solids upon mechanical milling: The case of fananserine

3区 · 医学

Article

作者: A. Rameau ; J.F. Willart ; C. Neves ; M. Descamps ; A. De Gusseme

In this article, we study the physical transformations of the forms III and IV of fananserine upon mechanical milling. The investigations have been performed through X-Ray powder diffraction and differential scanning calorimetry experiments. The results indicate that both forms undergo a polymorphic transformation toward the metastable form I upon milling at room temperature (25 degrees C) while an amorphization is observed upon milling at 0 degrees C. It thus appears that the nature of the transformation induced by milling does not depend on the initial polymorphic state, but strongly depends on the milling temperature. Interestingly, the change in the nature of the transformation with the milling temperature occurs in a short temperature range around the glass transition temperature (T(g) = 19 degrees C). The implication of T(g) in the duality "amorphisation/polymorphic transformation" generally observed upon milling is thus discussed. The physical stability of the end products is also investigated and discussed with respect to the storage temperature of the material.

100 项与法南色林相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
D02656	法南色林	-	-

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
焦虑症	临床3期	-	Sanofi	-
焦虑症	临床3期	法国	-	-
精神分裂症	临床前	法国	-	-
精神分裂症	临床前	-	Sanofi	-
精神分裂症	药物发现	法国	-	-
精神分裂症	药物发现	-	Sanofi	-