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1.
Compounds 7, 8, and 9, derived from the novel scaffolds 3, 5, and 6, were synthesized and evaluated in vitro. The b,c  c,d shift of the E-phenyl ring resulted in a large decrease (ca. 20- to 1000-fold) in binding to the 5-HT2A, 5-HT2C and H2, receptors, and a modest decrease (ca. 10- to 20-fold) in binding to the 5-HT5A, D2, D5, and α1D, receptors. The b,c  d,e shift resulted in a large decrease in binding to the 5-HT1D, 5-HT2C, 5-HT6, and H1 receptors, a modest decrease in binding to 5-HT1A, 5-HT5A and D2, D5, α2B, and H2 receptors, and a large increase in affinity to the 5-HT3, 5-HT6, and σ1 receptors.  相似文献   

2.
Chen Y  Xu X  Liu X  Yu M  Liu BF  Zhang G 《PloS one》2012,7(4):e35186

Background

It is important to develop novel antipsychotics that can effectively treat schizophrenia with minor side-effects. The aim of our work is to develop novel antipsychotics that act on dopamine D2 and D3, serotonin 5-HT1A and 5-HT2A receptors with low affinity for the serotonin 5-HT2C and H1 receptors, which can effectively cure positive symptoms, negative symptoms and cognitive impairment without the weight gain side-effect.

Methodology/Principal Findings

A series of 2-substituted-5-thiopropylpiperazine (piperidine) -1,3,4-oxadiazoles derivatives have been synthesized and the target compounds were evaluated for binding affinities to D2, 5-HT1A and 5-HT2A receptors. Preliminary results indicated that compounds 14, 16 and 22 exhibited high affinities to D2, 5-HT1A and 5-HT2A receptors among these compounds. Further binding tests showed that compound 22 had high affinity for D3 receptor, and low affinity for serotonin 5-HT2C and H1 receptors. In addition, compound 22 inhibited apomorphine-induced climbing behavior and MK-801-induced hyperactivity with no extrapyramidal symptoms liability in mice. Moreover, compound 22 exhibited acceptable pharmacokinetic properties.

Conclusions/Significance

Compound 22 showed an atypical antipsychotic activity without liability for extrapyramidal symptoms. We anticipate compound 22 to be useful for developing a novel class of drug for the treatment of schizophrenia.  相似文献   

3.
N′-Cyanoisonicotinamidine derivatives, linked to an arylpiperazine moiety, were prepared to identify highly selective and potent 5-HT1A ligands as potential pharmacological tools in studies of wide spread psychiatric disorders. The combination of structural elements (heterocyclic nucleus, alkyl chain and 4-substituted piperazine) known to be critical in order to have affinity on 5-HT1A receptor and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. In binding studies, several molecules showed affinity in nanomolar and subnanomolar range at 5-HT1A and moderate to no affinity for other relevant receptors (5-HT2A, 5-HT2C, D1, D2, α1 and α2). N′-Cyano-N-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)isonicotinamidine (4o) with Ki = 0.038 nM, was the most active and selective derivative for the 5-HT1A receptor with respect to other serotoninergic, dopaminergic and adrenergic receptors.  相似文献   

4.
We report the optimisation of a series of novel amide-piperidine (piperazine) derivatives using the multiple ligand approach with dopamine and serotonin receptors. Of the derivatives, compound 11 exhibited high affinity for the D2, 5-HT1A, and 5-HT2A receptors, but low affinity for the 5-HT2C and histamine H1 receptors and human ether-a-go-go-related gene (hERG) channels. In vivo, compound 11 reduced apomorphine-induced climbing, MK-801-induced hyperactivity and DOI-induced head twitching without observable catalepsy, even at the highest dose tested. In addition, it exhibited suppression in a CAR test. Furthermore, in a novel object recognition task, it displayed procognition properties. Therefore, compound 11 is a promising candidate multi-target antipsychotic.  相似文献   

5.
A novel series of 1H-indole-3-carboxylic acid pyridine-3-ylamides were synthesized and identified to show high affinity and selectivity for 5-HT2C receptor. Among them, 1H-indole-3-carboxylic acid[6-(2-chloro-pyridin-3-yloxy)-pyridin-3-yl]-amide (15k) exhibits the highest affinity (IC50 = 0.5 nM) with an excellent selectivity (>2000 times) over other serotonin (5-HT1A, 5-HT2A, and 5-HT6) and dopamine (D2–D4) receptors.  相似文献   

6.
(Piperazin-1-yl-phenyl)-arylsulfonamides were synthesized and identified to show high affinities for both 5-HT2C and 5-HT6 receptors. Among them, naphthalene-2-sulfonic acid isopropyl-[3-(4-methyl-piperazin-1-yl)-phenyl]-amide (6b) exhibits the highest affinity towards both 5-HT2C (IC50 = 4 nM) and 5-HT6 receptors (IC50 = 3 nM) with good selectivity over other serotonin (5-HT1A, 5-HT2A, and 5-HT7) and dopamine (D2–D4) receptor subtypes. In 5-HT2C and 5-HT6 receptor functional assays, this compound showed considerable antagonistic activity for both receptors.  相似文献   

7.
A series of novel 3β-aminotropane derivatives containing a 2-naphthalene or a 2-quinoline moiety was synthesised and evaluated for their affinity for 5-HT1A, 5-HT2A and D2 receptors. Their affinity for the receptors was in the nanomolar to micromolar range. p-Substitution (6c, 6f, 6i, 6l, 6o), as well as substitution with chlorine atoms (6g, 6h, 6i), led to a significant increase in binding affinity for D2 receptors with compounds 6f (Ki = 0.6 nM), 6c and 6i (Ki = 0.4 nM), having the highest binding affinities. m-Substituted derivatives were the most promising ligands in terms of 5-HT2A receptor binding affinity whereas 2-quinoline derivatives (10a, 10b) displayed the highest affinity for 5-HT1AR and were the most selective ligands with Ki = 62.7 nM and Ki = 30.5 nM, respectively. Finally, the selected ligands 6b, 6d, 6e, 6g, 6h, 6k, 6n and 6o, with triple binding activity for the D2, 5-HT1A and 5-HT2A receptors, were subjected to in vivo tests, such as those for induced hypothermia, climbing behaviour and the head twitch response, in order to determine their pharmacological profile. The tested ligands presented neither agonist nor antagonist properties for the 5-HT1A receptors in the induced hypothermia and lower lip retraction (LLR) tests. All tested compounds displayed antagonistic activity against 5-HT2A, with 6n and 6o being the most active. Four (6b, 6k, 6n and 6o) out of eight tested compounds could be classified as D2 antagonists. Additionally, evaluation of metabolic stability was performed for selected ligands, and introduction of halogen atoms into the benzene ring of 6h, 6k, 6n and 6o improved their metabolic stability. The project resulted in the selection of the lead compounds 6n and 6o, which had antipsychotic profiles, combining dopamine D2-receptor and 5-HT2A antagonism and metabolic stability.  相似文献   

8.
A novel scaffold derived from l-SPD with a substituted thiophene group in the D ring were designed, synthesized, and evaluated for their binding affinities at dopamine (D1, D2 and D3) and serotonin (5-HT1A and 5-HT2A) receptors. Most of the tetracyclic compounds exhibited higher affinities for D2 and 5-HT1A receptors than l-SPD, while compound 23e showed the highest Ki value of 7.54 nM at D2 receptor which was 14 times more potent than l-SPD. Additionally, compounds 23d and 23e were more potent than l-SPD at D3 receptor. According to the functional assays, 23d and 23e were demonstrated as full antagonists at D1 and D2 receptors and full agonists at 5-HT1A receptor. Since the combination of D2 antagonism and 5-HT1A agonism is considered effective in treating both the positive and negative symptoms of schizophrenia, these novel compounds are implicated as potential therapeutic agents.  相似文献   

9.
Several known D2 pharmacophores have been explored as templates for identifying ligands with multiple binding affinities at dopamine and serotonin receptors considered as clinically relevant receptors in the treatment of neuropsychiatric diseases. This approach has resulted in the identification of ligands that target multiple CNS receptors while avoiding others associated with deleterious effects. In particular, compounds 11, 15 and 22 may have potential for further development as antipsychotic agents as they favorably interact with the clinically relevant receptors including D2R, 5-HT1AR, and 5-HT7R. We have also identified the pair of compounds 11 and 10 as high affinity D2R ligands with and without SERT binding affinities, respectively. These differential binding profiles endow the pair with the potential for evaluating SERT contributions to antipsychotic drug activity in animal behavioral models. In addition, compound 11 has no significant affinity for 5-HT2CR and binds only moderately to the H1R, suggesting it may not induce weight gain or sedation when used clinically. Taken together, compound 11 displays an interesting pharmacological profile that necessitates the evaluation of its functional and in vivo effects in animal models which are currently ongoing.  相似文献   

10.
In the pharmacotherapy of schizophrenia, there is a lack of effective drugs, and currently used agents cause a large number of side effects. The D2, 5-HT1A, 5-HT2A receptors are among the most important receptor targets in the treatment of schizophrenia, but antagonism at 5-HT6 and 5-HT7 receptors may bring about additional improvement of cognitive functions. However, doubt exists regarding the importance of 5-HT7R in the pharmacotherapy. In 2010, lurasidone (with high affinity for D2, D3, 5-HT1A, 5-HT2A, 5-HT7 receptors) was approved for the treatment of schizophrenia. Due to the efficacy of the mentioned drug and doubts related to the role of 5-HT7R, we decided to obtain compounds with an activity profile similar to that of lurasidone, but with the reduced affinity for 5-HT7R and increased affinity for 5-HT6R. For this purpose, we chose a flexible hexyl derivative of lurasidone (2-(6-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)hexyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione 1a) as a hit structure. After molecular modeling, we modified it, in the area of the arylpiperazine and imide group, using the moieties found in other known CNS drugs. We received the compounds in accordance with the previously developed method of ecological synthesis in the microwave radiation field. Among the obtained compounds, N-(6-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)hexyl)naphthalene-sulfonamides 1v and 1w were distinguished as multifunctional ligands showing increased affinity for 5-HT6R, and 2-(6-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)hexyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one 1i – a multifunctional ligand showing moderate affinity for 5-HT6R and threefold lower for 5-HT7R. In the paper, we discuss some of the observed dependencies regarding 5-HT6/5-HT7R affinity using molecular docking methods.  相似文献   

11.
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-HT1A, 5-HT2A, 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-HT1A/5-HT7/D2 ligand 5k, dual 5-HT1A/D2 ligand 5j and selective 5-HT1A 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.  相似文献   

12.
More than 300 million people are suffering from depression, one of the civilization diseases in the 21st century. Serotonin 5-HT1AR and dopamine D2R play an important role in the treatment and pathogenesis of depression. Moreover, in recent years, the efficacy of dual 5-HT1A/D2 receptors ligands has been demonstrated in the fight against depression. In this work the new bulky arylpiperazine derivatives (LCAP) were synthesized in microwave radiation field. The affinities for the selected serotonin (5-HT1A,5-HT2A,5-HT6,5-HT7) and dopamine (D2) receptors have been evaluated in vitro. Compounds 5.3a, 5.4, 5.1c, 5.3d, 5.2a are promising dual 5-HT1AR/D2R ligands. The SAR analysis were additionally supported with molecular docking studies.  相似文献   

13.
On the basis that meta-chlorophenylpiperazine (mCPP; 1) is a nonselective 5-HT2C agonist, that benz-fused tryptamines (e.g., 5) display enhanced 5-HT2 affinity, and that certain isotryptamines 3 reportedly bind with enhanced affinity and selectivity at 5-HT2C receptors, we prepared and examined a series of isotryptamine-related analogues as potentially selective 5-HT2C agonists. None of the compounds displayed selectivity for 5-HT2C versus 5-HT2A receptors. Detailed re-examination of a compound previously reported to display 100-fold 5-HT2C selectivity [i.e., S(+)-5,6-difluoro-α-methylisotryptamine] revealed that its selectivity versus 5-HT2A receptors was, at best, only 10-fold.  相似文献   

14.
A novel series of 5-HT2A ligands that contain a (phenylpiperazinyl-propyl)arylsulfonamides skeleton was synthesized. Thirty-seven N-(cycloalkylmethyl)-4-methoxy-N-(3-(4-arylpiperazin-1-yl)propyl)-arylsulfonamide and N-(4-(4-arylpiperazin-1-yl)butan-2-yl)-arylsulfonamide compounds were obtained. The binding of these compounds to the 5-HT2A, 5-HT2C, and 5-HT7 receptors was evaluated. Most of the compounds showed IC50 values of less than 100 nM and exhibited high selectivity for the 5-HT2A receptor. Among the synthesized compounds, 16a and 16d showed good affinity at 5-HT2A (IC50 = 0.7 nM and 0.5 nM) and good selectivity over 5-HT2C (50–100 times) and 5-HT7 (1500–3000 times).  相似文献   

15.
In previous study, a series of benzamides was identified as potent antipsychotic agents. As a continuation of the program to discover novel antipsychotics, herein we reported the evaluation of a series of pyridinecarboxamide derivatives. The most promising compound 7h not only held good activities on dopamine D2, serotonin 5-HT1A and 5-HT2A receptors, but also exhibited low potency for α1A, H1 and 5-HT2C receptors, indicating a low propensity of side effects like orthostatic hypotension and weight gain. Furthermore, 7h exhibited more potent antipsychotic-like effect than aripiprazole in behavioral studies. The preliminary results were promising enough for further research around this scaffold.  相似文献   

16.
17.
All clinically-used antipsychotics display similar affinity for both D2 (D2R) and D3 (D3R) receptors, and they likewise act as 5-HT2A receptor antagonists. They provide therapeutic benefit for positive symptoms, but no marked or consistent improvement in neurocognitive, social cognitive or negative symptoms. Since blockade of D3 and 5-HT6 (5-HT6R) receptors enhances neurocognition and social cognition, and potentially improves negative symptoms, a promising approach for improved treatment for schizophrenia would be to develop drugs that preferentially act at D3R versus D2R and likewise recognize 5-HT6R. Starting from the high affinity 5-HT6R ligands I and II, we identified compounds 11a and 14b that behave as 5-HT6R ligands with significant selectivity for D3R over D2R.  相似文献   

18.
We described herein the design, synthesis, and pharmacological evaluation of N-phenylpiperazine heterocyclic derivatives as multi-target compounds potentially useful for the treatment of schizophrenia. The isosteric replacement of the heterocyclic ring at the biaryl motif generating pyrazole, 1,2,3-triazole, and 2-methylimidazole[1,2-a]pyridine derivatives resulted in 21 analogues with different substitutions at the para-biaryl and para-phenylpiperazine positions. Among the compounds prepared, 4 (LASSBio-579) and 10 (LASSBio-664) exhibited an adequate binding profile and a potential for schizophrenia positive symptoms treatment without cataleptogenic effects. Structural features of this molecular scaffold are discussed regarding binding affinity and selectivity for D2-like, 5-HT1A, and 5-HT2A receptors.  相似文献   

19.
《Life sciences》1995,57(12):A141-A146
The thermodynamic parameters ΔG° , ΔH° and Δs° of the binding equilibrium of serotonin to 5-HT1A, 5-HT2A and 5-HT3 rat-brain membrane receptors have been determined by means of affinity constant measurements at six temperatures in the range 0 –35 ° C and van't Hoff plots. At variance with 5-HT1A and 5-HT3, the binding at the 5-HT2A receptors is strongly endothermic and entropy-driven. Comparison with the results obtained by other authors on 5-HT2A receptors in rats and humans suggests that the observed differences can be explained by a single amino acid difference in the receptor sequence between these two species.  相似文献   

20.
To identify potent dual 5-HT2B and 5-HT7 receptor antagonists, we synthesized a series of novel carbonyl guanidine derivatives and examined their structure–activity relationships. Among these compounds, N-(9-hydroxy-9H-fluorene-2-carbonyl)guanidine (10) had a good in vitro profile, that is, potent affinity for human 5-HT2B and 5-HT7 receptor subtypes (Ki = 1.8 nM and Ki = 17.6 nM, respectively) and high selectivity over 5-HT2A, 5-HT2C, α1, D2 and M1 receptors. Compound 10 also showed a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs when orally administered.  相似文献   

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