共查询到20条相似文献,搜索用时 31 毫秒
1.
I. B. Sukhov K. V. Derkach O. V. Chistyakova V. M. Bondareva A. O. Shpakov 《Cell and Tissue Biology》2016,10(4):314-323
The functioning of the serotonergic system of the brain is impaired in type II diabetes (T2D), and this leads to metabolic and hormonal dysfunction. The elevation of serotonin level in the CNS is one of the approaches for correcting of the serotonergic system of the brain. The aim of the present work was to investigate the effect of intranasal serotonin (InS) administration for 5 weeks at a daily dose of 20 μg on the metabolic parameters and functional activity of adenylate cyclase signaling system (ACSS) sensitive to peptide hormones and biogenic amines in the hypothalamus of male rats with neonatal T2D. Neonatal model of T2D was induced by injecting streptozotocin (70 mg/kg) into 5-day-old rat pups. Four-month-old animals with apparent T2D manifestations were divided into two groups: an untreated group (D0, n = 6) and a group that received InS treatment (DIS, n = 6). InS administration to diabetic rats restored ACSS regulation by the agonists of type 2 dopamine receptors (DA2R) and type 4 melanocortin receptors (MC4R) and enhanced the inhibitory effect of serotonin on adenylate cyclase activity. Elevated expression of genes encoding DA2R, MC4R, and serotonin receptor of the 1B subtype (5-HT1BR) was among the main causes of this change. The relative activity of signaling cascades involving various types of serotonin (Gs-coupled 5-HT4,6,7R/Gi-coupled 5-HT1R), dopamine (DA1R/ DA2R), and melanocortin (MC3R/MC4R) receptors involved in ACSS regulation was also altered in the animals of the DIS group. InS administration restored hormonal regulation in the hypothalamus, improved glucose tolerance, and increased the sensitivity of tissues to insulin. The data obtained show that the elevation of serotonin level in the CNS is a promising approach for the recovery of hypothalamic signaling pathways in T2D and correction of the metabolic disturbances dependent on these pathways. 相似文献
2.
Przemysław Zaręba Jolanta Jaśkowska Paweł Śliwa Grzegorz Satała 《Bioorganic & medicinal chemistry letters》2019,29(16):2236-2242
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
3.
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4.
Chul Min Park So Young Kim Woo Kyu Park Jung Hwan Choi Churl Min Seong 《Bioorganic & medicinal chemistry letters》2010,20(17):5221-5224
(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
5.
《Bioorganic & medicinal chemistry》2016,24(16):3671-3679
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
6.
Park CM Kim SY Park WK Park NS Seong CM 《Bioorganic & medicinal chemistry letters》2008,18(14):3844-3847
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
7.
Mingshuo Xu Yu Wang Feipu Yang Chunhui Wu Zhen Wang Bin Ye Xiangrui Jiang Qingjie Zhao Jianfeng Li Yongjian Liu Junchi Zhang Guanghui Tian Yang He Jingshan Shen Hualiang Jiang 《Bioorganic & medicinal chemistry letters》2018,28(4):606-611
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
8.
Przemysław Zaręba Jolanta Jaśkowska Izabela Czekaj Grzegorz Satała 《Bioorganic & medicinal chemistry》2019,27(15):3396-3407
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
9.
《Bioorganic & medicinal chemistry letters》2020,30(20):127506
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
10.
Harri?t Schellekens Wesley E. P. A. van Oeffelen Timothy G. Dinan John F. Cryan 《The Journal of biological chemistry》2013,288(1):181-191
G protein-coupled receptors (GPCRs), such as the ghrelin receptor (GHS-R1a), the melanocortin 3 receptor (MC3), and the serotonin 2C receptor (5-HT2C), are well known for their key role in the homeostatic control of food intake and energy balance. Ghrelin is the only known gut peptide exerting an orexigenic effect and has thus received much attention as an anti-obesity drug target. In addition, recent data have revealed a critical role for ghrelin in dopaminergic mesolimbic circuits involved in food reward signaling. This study investigates the downstream signaling consequences and ligand-mediated co-internalization following heterodimerization of the GHS-R1a receptor with the dopamine 1 receptor, as well as that of the GHS-R1a-MC3 heterodimer. In addition, a novel heterodimer between the GHS-R1a receptor and the 5-HT2C receptor was identified. Interestingly, dimerization of the GHS-R1a receptor with the unedited 5-HT2C-INI receptor, but not with the partially edited 5-HT2C-VSV isoform, significantly reduced GHS-R1a agonist-mediated calcium influx, which was completely restored following pharmacological blockade of the 5-HT2C receptor. These results combined suggest a potential novel mechanism for fine-tuning GHS-R1a receptor-mediated activity via promiscuous dimerization of the GHS-R1a receptor with other G protein-coupled receptors involved in appetite regulation and food reward. These findings may uncover novel mechanisms of significant relevance for the future pharmacological targeting of the GHS-R1a receptor in the homeostatic regulation of energy balance and in hedonic appetite signaling, both of which play a significant role in the development of obesity. 相似文献
11.
12.
Stéphane Doly Jesus Bertran-Gonzalez Jacques Callebert Alexandra Bruneau Sophie Marie Banas Arnauld Belmer Katia Boutourlinsky Denis Hervé Jean-Marie Launay Luc Maroteaux 《PloS one》2009,4(11)
The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) reverses dopamine and serotonin transporters to produce efflux of dopamine and serotonin, respectively, in regions of the brain that have been implicated in reward. However, the role of serotonin/dopamine interactions in the behavioral effects of MDMA remains unclear. We previously showed that MDMA-induced locomotion, serotonin and dopamine release are 5-HT2B receptor-dependent. The aim of the present study was to determine the contribution of serotonin and 5-HT2B receptors to the reinforcing properties of MDMA.We show here that 5-HT2B
−/− mice do not exhibit behavioral sensitization or conditioned place preference following MDMA (10 mg/kg) injections. In addition, MDMA-induced reinstatement of conditioned place preference after extinction and locomotor sensitization development are each abolished by a 5-HT2B receptor antagonist (RS127445) in wild type mice. Accordingly, MDMA-induced dopamine D1 receptor-dependent phosphorylation of extracellular regulated kinase in nucleus accumbens is abolished in mice lacking functional 5-HT2B receptors. Nevertheless, high doses (30 mg/kg) of MDMA induce dopamine-dependent but serotonin and 5-HT2B receptor-independent behavioral effects.These results underpin the importance of 5-HT2B receptors in the reinforcing properties of MDMA and illustrate the importance of dose-dependent effects of MDMA on serotonin/dopamine interactions. 相似文献
13.
《Bioorganic & medicinal chemistry》2014,22(21):5838-5846
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
14.
Laura Carro Enrique Raviña Eduardo Domínguez José Brea María I. Loza Christian F. Masaguer 《Bioorganic & medicinal chemistry letters》2009,19(21):6059-6062
A series of 8 new tetrahydroquinazolinone derivatives was synthesized and evaluated for binding affinity to D2 and 5-HT2A human receptors; in addition, some properties related to blood–brain barrier penetration were calculated. From the results of these assays, three compounds were selected for further binding tests on D1, D3, and 5-HT2C human receptors, which are thought to be involved in schizophrenia. From these data, compound 19b emerged as the most promising candidate based on its good binding affinities for D1, D2, and D3 receptors, high affinity for 5-HT2A, low affinity for 5-HT2C receptors, and a Meltzer’s ratio characteristic of an atypical antipsychotic profile. 相似文献
15.
Norimasa Kanegawa 《FEBS letters》2010,584(3):599-2362
We found that Tyr-Leu (YL) dose-dependently exhibits potent anxiolytic-like activity (0.1-1 mg/kg, i.p.) comparable to diazepam in the elevated plus-maze test in mice. YL was orally active (0.3-3 mg/kg). A retro-sequence peptide or a mixture of Tyr and Leu was inactive. The anxiolytic-like activity of YL was inhibited by antagonists for serotonin 5-HT1A, dopamine D1 and GABAA receptors; however, YL had no affinity for them. We also determined the order of their activation is 5-HT1A, D1 and GABAA receptors using selective agonists and antagonists. Taken together, YL may exhibit anxiolytic-like activity via activation of 5-HT1A, D1 and GABAA receptors. 相似文献
16.
Si YG Gardner MP Tarazi FI Baldessarini RJ Neumeyer JL 《Bioorganic & medicinal chemistry letters》2008,18(14):3971-3973
We synthesized several novel 2-O- or 11-O-substituted N-alkylnoraporphines and assessed their affinities at dopamine D1 and D2, and serotonin 5-HT1A receptors in rat forebrain tissue. Tested compounds displayed moderate to high affinities to D2 receptors but low affinities to D1 and 5HT1A receptors. The findings accord with previous evidence of a lipophilic cavity on the surface of the D2 receptor to accommodate N-alkyl moieties of aporphines. The most D2-potent (Ki = 97 nM) and selective novel agent (>100-fold vs. D1 and 5-HT1A sites) was R(−)-2-(2-hydroxyethoxy)-11-hydroxy-N-n-propylnoraporphine (compound 11). 相似文献
17.
Borroto-Escuela DO Romero-Fernandez W Tarakanov AO Marcellino D Ciruela F Agnati LF Fuxe K 《Biochemical and biophysical research communications》2010,401(4):605-610
In view of the co-distribution of dopamine D2LR and 5-hydroxytryptamine 5-HT2A receptors (D2LR and 5-HT2AR, respectively) within inter alia regions of the dorsal and ventral striatum and their role as a target of antipsychotic drugs; in this study we assessed the potential existence of D2LR-5-HT2AR heteromers in living cells and the functional consequences of this interaction. Thus, by means of a proximity-based bioluminescence resonance energy transfer (BRET) approach we demonstrated that the D2LR and the 5-HT2AR form stable and specific heteromers when expressed in HEK293T mammalian cells. Furthermore, when the D2LR-5-HT2AR heteromeric signaling was analyzed we found that the 5-HT2AR-mediated phospholipase C (PLC) activation was synergistically enhanced by the concomitant activation of the D2LR as shown in a NFAT-luciferase reporter gene assay and a specific and significant rise of the intracellular calcium levels were observed when both receptors were simultaneously activated. Conversely, when the D2LR-mediated adenylyl cyclase (AC) inhibition was assayed we showed that costimulation of D2LR and 5-HT2AR within the heteromer led to inhibition of the D2LR functioning, thus suggesting the existence of a 5-HT2AR-mediated D2LR trans-inhibition phenomenon. Finally, a bioinformatics study reveals that the triplet amino acid homologies LLT (Leu-Leu-Thr) and AIS (Ala-Ile-Ser) in TM1 and TM3, respectively of the D2R-5-HT2AR may be involved in the receptor interface. Overall, the presence of the D2LR-5-HT2AR heteromer in discrete brain regions is postulated based on the existence of D2LR-5-HT2A receptor-receptor interactions in living cells and their codistribution inter alia in striatal regions. Possible novel therapeutic strategies for treatment of schizophrenia should be explored by targeting this heteromer. 相似文献
18.
Thierry Wurch Christiane Palmier Francis C. Colpaert Petrus J. Pauwels 《Journal of neurochemistry》1997,68(1):410-418
Abstract: This study was undertaken to investigate the pharmacology of cloned guinea pig and rat 5-hydroxytryptamine (serotonin; 5-HT)1D receptor sites. Guinea pig, rat, and mouse 5-HT1D receptor genes were cloned, and their amino acid sequences were compared with those of the human, dog, and rabbit. The overall amino acid sequence identity between these 5-HT1D receptors is high and varies between 86 and 99%. The sequence homology is slightly more divergent (13–27%) in the N-terminal extracellular region of these 5-HT1D receptors. Guinea pig and rat 5-HT1D receptors, stably and separately expressed in rat C6 glial cells, are negatively coupled to cyclic AMP formation upon stimulation with agonists, as previously found for cloned human 5-HT1D receptor sites. The cyclic AMP data show some common pharmacological features for the 5-HT1D receptors of guinea pig, rat, and human: an almost similar rank order of potency for the investigated 5-HT1D receptor agonists, stereoselectivity for the binding affinity and agonist potency of R(+)-8-hydroxy-2-(di-n-propylamino)tetralin, and equal 5-HT1D receptor-mediated antagonist potency for methiothepin and the 5-HT2 receptor antagonists ritanserin and ketanserin. In conclusion, the pharmacology of the cloned 5-HT1D receptor subtype seems, unlike the 5-HT1B receptor subtype, conserved among various mammal species such as the human, guinea pig, and rat. 相似文献
19.
《Bioorganic & medicinal chemistry letters》2014,24(2):576-579
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
20.
《Life sciences》1995,56(14):PL249-PL253
We assessed the relation between serotonin 5-HT2 receptor availability and aging and compared it with that for dopamine D2 receptors on 19 healthy male volunteers (age range, 21–49 years) using positron emission tomography (PET) and F-18 N-methylspiperone (NMS). 5-HT2 Receptor availability was obtained using the ratio of the distribution volume in the region of interest to that in the cerebellum (). 5-HT2 Receptor measures were obtained in frontal and occipital cortices. D2 receptor availability in striatum was measured using the “ratio index”. 5-HT2 Receptor availability decreased significantly with age. This effect was significantly more accentuated for 5-HT2 receptor availability in the frontal (r = 0.92, p ≤ 0.0001) than in the occipital (r = 0.67, p ≤ 0.0016) cortex (df = l, p < 0.025). Dopamine D2 receptors were also found to decrease significantly with age (r = 0.63, p ≤ 0.007). In a given subject, striatal D2 receptor availability significantly correlated with 5-HT2 receptor availability in the frontal (r = 0.51, p ≤ 0.035) but not in the occipital cortex. These results document a decline in 5-HT2 and D2 receptor availability with age and showed an association between frontal 5-HT2 and striatal D2 receptors. 相似文献