scholarly journals Design, Synthesis and Biological Investigation of Flavone Derivatives as Potential Multi-Receptor Atypical Antipsychotics

Molecules ◽  
2020 ◽  
Vol 25 (18) ◽  
pp. 4107
Author(s):  
Lanchang Gao ◽  
Zhengge Yang ◽  
Jiaying Xiong ◽  
Chao Hao ◽  
Ru Ma ◽  
...  
Keyword(s):  
Serotonin Receptors ◽  
Atypical Antipsychotics ◽  
Qt Prolongation ◽  
Biological Investigation ◽  
Design Synthesis ◽  
Receptor Affinity ◽  
High Affinity ◽  
Behavioral Studies ◽  
Flavone Derivatives

The design of a series of novel flavone derivatives was synthesized as potential broad-spectrum antipsychotics by using multi-receptor affinity strategy between dopamine receptors and serotonin receptors. Among them, 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl) piperidin- 1-yl) butoxy)-2,2-dimethylchroman-4-one (6j) exhibited a promising preclinical profile. Compound 6j not only showed high affinity for dopamine D2, D3, and serotonin 5-HT1A, 5-HT2A receptors, but was also endowed with low to moderate activities on 5-HT2C, α1, and H1 receptors, indicating a low liability to induce side effects such as weight gain, orthostatic hypotension and QT prolongation. In vivo behavioral studies suggested that 6j has favorable effects in alleviating the schizophrenia-like symptoms without causing catalepsy. Taken together, compound 6j has the potential to be further developed as a novel atypical antipsychotic.

scholarly journals The 1,3,5-Triazine Derivatives as Innovative Chemical Family of 5-HT6 Serotonin Receptor Agents with Therapeutic Perspectives for Cognitive Impairment

2019 ◽  
Vol 20 (14) ◽  
pp. 3420 ◽  
Author(s):  
Gniewomir Latacz ◽  
Annamaria Lubelska ◽  
Magdalena Jastrzębska-Więsek ◽  
Anna Partyka ◽  
Małgorzata Anna Marć ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Serotonin Receptors ◽  
Serotonin Receptor ◽  
Molecular Mechanisms ◽  
Binding Properties ◽  
Piperazine Derivatives ◽  
Behavioral Studies ◽  
Triazine Derivatives

Among serotonin receptors, the 5-HT6 subtype is the most controversial and the least known in the field of molecular mechanisms. The 5-HT6R ligands can be pivotal for innovative treatment of cognitive impairment, but none has reached pharmacological market, predominantly, due to insufficient “druglikeness” properties. Recently, 1,3,5-triazine-piperazine derivatives were identified as a new chemical family of potent 5-HT6R ligands. For the most active triazine 5-HT6R agents found (1–4), a wider binding profile and comprehensive in vitro evaluation of their drug-like parameters as well as behavioral studies and an influence on body mass in vivo were investigated within this work. Results indicated the most promising pharmacological/druglikeness profiles for 4-((1H-indol-3-yl)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (3) and 4-((2-isopropyl-5-methylphenoxy)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (4), which displayed a significant procognitive action and specific anxiolytic-like effects in the behavioral tests in vivo together with satisfied pharmaceutical and safety profiles in vitro. The thymol derivative (4) seems to be of higher importance as a new lead candidate, due to the innovative, non-indole and non-sulfone structure with the best 5-HT6R binding properties.

The Importance of Serotonin-Dopamine Interactions in the Action of Clozapine

1992 ◽  
Vol 160 (S17) ◽  
pp. 22-29 ◽  
Author(s):  
Herbert Y. Meltzer
Keyword(s):  
Atypical Antipsychotic ◽  
Atypical Antipsychotics ◽  
Antipsychotic Drugs ◽  
Typical Antipsychotic ◽  
Atypical Antipsychotic Drugs ◽  
Clinical Dose ◽  
High Affinity ◽  
The Relationship

Clozapine has an affinity for the dopamine (DA) D2 receptor which is relatively weak but is in line with its average clinical dose when compared with typical neuroleptic drugs. A few atypical antipsychotic drugs may have high absolute affinities for the D2 receptor, but most are weak D2 blockers. The atypical antipsychotic drugs also differ from the typical antipsychotic drugs by a relatively high affinity for the serotonin (5-HT2) receptor. This is evident on both in vitro and in vivo binding to cortical 5-HT2 receptors. The atypical antipsychotics are best distinguished from the typical antipsychotics on the basis of the relationship between strong 5-HT2 and weak D2 affinities. High D1 receptor binding is not characteristic of the group of atypical drugs. A new group of putative atypical antipsychotic drugs with high affinities for 5-HT2 compared to D2 receptors is under study.

Neurochemical alterations in schizophrenia affecting the putative receptor targets of atypical antipsychotics

1999 ◽  
Vol 174 (S38) ◽  
pp. 12-22 ◽  
Author(s):  
P. J. Harrison
Keyword(s):  
Side Effect ◽  
Serotonin Receptors ◽  
Adrenergic Receptors ◽  
Atypical Antipsychotics ◽  
Side Effect Profile ◽  
Common View ◽  
High Affinity ◽  
Putative Receptor ◽  
Receptor Targets ◽  
Typical Antipsychotics

What mechanisms make an antipsychotic atypical? A common view is that the different therapeutic and side-effect profile of atypical compared to typical antipsychotics is due to their high affinity for specific dopamine and/or 5-HT (serotonin) receptors. Dopamine D4 and 5-HT2a receptors are particularly implicated, though many others have been proposed as well, including dopamine D1 and D3, 5-HT1a, 5-HT2c, 5-HT6, 5-HT7 and α2 adrenergic receptors (for review, see Deutch et al, 1991; Ashby & Wang, 1996; Kinon & Lieberman, 1996).

scholarly journals In vitro opioid receptor affinity and in vivo behavioral studies of Nelumbo nucifera flower

2015 ◽  
Vol 174 ◽  
pp. 57-65 ◽  
Author(s):  
Mallika Kumarihamy ◽  
Francisco León ◽  
Sara Pettaway ◽  
Lisa Wilson ◽  
Janet A. Lambert ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Nelumbo Nucifera ◽  
Receptor Affinity ◽  
Behavioral Studies

Effects of Heparin Oligosaccharides with High Affinity for Antithrombin III in Experimental Venous Thrombosis

1982 ◽  
Vol 47 (03) ◽  
pp. 244-248 ◽  
Author(s):  
D P Thomas ◽  
Rosemary E Merton ◽  
T W Barrowcliffe ◽  
L Thunberg ◽  
U Lindahl
Keyword(s):  
Antithrombin Iii ◽  
Specific Activity ◽  
High Specific Activity ◽  
Factor Xa ◽  
Blood Levels ◽  
Thrombin Time ◽  
High Affinity ◽  
Very High

SummaryThe in vitro and in vivo characteristics of two oligosaccharide heparin fragments have been compared to those of unfractionated mucosal heparin. A decasaccharide fragment had essentially no activity by APTT or calcium thrombin time assays in vitro, but possessed very high specific activity by anti-Factor Xa assays. When injected into rabbits at doses of up to 80 ¼g/kg, this fragment was relatively ineffective in impairing stasis thrombosis despite producing high blood levels by anti-Xa assays. A 16-18 monosaccharide fragment had even higher specific activity (almost 2000 iu/mg) by chromogenic substrate anti-Xa assay, with minimal activity by APTT. When injected in vivo, this fragment gave low blood levels by APTT, very high anti-Xa levels, and was more effective in preventing thrombosis than the decasaccharide fragment. However, in comparison with unfractionated heparin, the 16-18 monosaccharide fragment was only partially effective in preventing thrombosis, despite producing much higher blood levels by anti-Xa assays.It is concluded that the high-affinity binding of a heparin fragment to antithrombin III does not by itself impair venous thrombogenesis, and that the anti-Factor Xa activity of heparin is only a partial expression of its therapeutic potential.

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