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Meysam Amidfar, Yong-Ku Kim
Conventional serotonin-enhancing antidepressants including selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) have shown effectiveness in the treatment of major depression, but their significant limitations such as slowness of action have led to intensive research efforts to develop new antidepressants. Increased synaptic neurotransmission of serotonin (5-hdroxytryptamine; 5-HT) through orchestration of stimulation and blockade of various subtypes of 5-HT receptors is involved in the mechanisms of action of SSRIs...
August 2, 2018: Current Pharmaceutical Design
Mei Huang, Sunoh Kwon, Lakshmi Rajagopal, Wenqi He, Herbert Y Meltzer
RATIONALE: The effect of atypical antipsychotic drugs (AAPDs), e.g., lurasidone, to improve cognitive impairment associated with schizophrenia (CIAS), has been suggested to be due, in part, to enhancing release of dopamine (DA), acetylcholine (ACh), and glutamate (Glu) in cortex and hippocampus. RESULTS: The present study found acute lurasidone reversed the cognitive deficit in novel object recognition (NOR) in subchronic (sc) phencyclidine (PCP)-treated mice, an animal model for CIAS...
July 31, 2018: Psychopharmacology
Kevin M Blattner, Daniel J Canney, Douglas A Pippin, Benjamin E Blass
It is well documented that serotonin (5-HT) exerts its pharmacological effects through a series of 5-HT receptors. The most recently identified member of this family, 5-HT7, was first identified in 1993. Over the course of the last 25 years, this receptor has been the subject of intense investigation, and it has been demonstrated that 5-HT7 plays an important role in a wide range of pharmacological processes. As a result of these findings, modulation of 5HT7 activity has been the focus of numerous drug discovery and development programs...
July 18, 2018: ACS Chemical Neuroscience
Neil C Lax, Stacy-Ann J Parker, Edward J Hilton, Youstina Seliman, Kevin J Tidgewell, Benedict J Kolber
Marine cyanobacteria represent a unique source in the field of drug discovery due to the secondary metabolites they produce and the structural similarity these compounds have to endogenous mammalian receptor ligands. A series of cyanobacteria were subjected to extraction, fractionation by column chromatography and screened for affinity against CNS targets with a focus on serotonin receptors (5-HT). Out of 276 fractions screened, 21% had activity at 5-HT receptors and/or the 5-HT transporter. One sample, a cyanobacterium identified by 16S rRNA sequencing as Leptolyngbya from Las Perlas archipelago in Panama, contained a fraction with noted affinity for the 5-HT7 receptor (5-HT7 R)...
July 10, 2018: Synapse
Cheng Xue Du, Yuan Guo, Qiao Jun Zhang, Jin Zhang, Shu Xuan Lv, Jian Liu
OBJECTIVE: At present, little is known about the role of serotonin7 (5-HT7 ) receptor in anxiety, particularly in Parkinson's disease-related anxiety. Here, we tested whether 5-HT7 receptors in the prelimbic (PrL) cortex are involved in the regulation of anxiety-like behaviors in sham-operated rats and rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle (MFB). METHODS: The open field and elevated plus maze (EPM) tests were performed to study the influence of MFB lesion and intra-PrL injection of 5-HT7 agonist AS19 (0...
July 10, 2018: Neurological Research
Ilhan Elmaci, Meric A Altinoz
Pimozide is currently being used in clinic as a neuroleptic and exerts versatile biological actions. Pimozide is a cationic amphiphilic drug (CAD); CADs block the synthesis of neutral lipids, impair cholesterol homeostasis of cancer cells and increase accumulation of diacylglycerol-3-phosphate. Pimozide exerts tumoricidal activity which was first shown for melanoma and neuroblastoma via proposed anti- dopaminergic effects. Recently, pancreas cancers are shown to elevate dopamine receptor-2 synthesis, which is blocked by pimozide leading growth inhibition...
August 2018: Critical Reviews in Oncology/hematology
Ádám Andor Kelemen, Grzegorz Satała, Andrzej J Bojarski, György M Keserű
Here we report the design and synthesis of spiro[pyrrolidine-3,3'-oxindole] derivatives representing a novel scaffold of 5-HT7 receptor ligands. The synthesized analogues were validated as low nanomolar ligands showing selectivity in a panel of related serotonin receptor subtypes including 5-HT1A R, 5-HT2A R and 5-HT6 R.
August 1, 2018: Bioorganic & Medicinal Chemistry Letters
Wei Zheng, Dong-Bin Cai, Xin-Hu Yang, Lu Li, Qing-E Zhang, Chee H Ng, Gabor S Ungvari, Xian-Bin Li, Yu-Ping Ning, Yu-Tao Xiang
BACKGROUND: Lurasidone, an azapirone derivative, is a novel second generation antipsychotic with potent binding affinity for dopamine D2, serotonin 5-HT2A , 5-HT7, 5-HT1A, and noradrenaline alpha2C receptors. This updated meta-analysis of randomized controlled trials (RCTs) examined the short-term efficacy and tolerability of lurasidone in the treatment of acute schizophrenia. METHODS: Double-blinded RCTs reporting on the short-term effects of lurasidone were included...
August 2018: Journal of Psychiatric Research
Takeshi Chiba, Tomoji Maeda, Kenzo Kudo
 Intrinsic serotonin (5-hydroxytryptamine; 5-HT) synthesized within the mammary epithelium has an important physiological role in milk volume homeostasis in many species including mice, cows, and humans. During lactation, mammary epithelial cells activate 5-HT synthesis by tryptophan hydroxylase 1 (TPH1). TPH1 catalyzes the rate-limiting step in 5-HT biosynthesis within mammary glands. 5-HT synthesized in mammary glands is released into both the apical (milk) and basolateral spaces by a vesicular monoamine transporter...
2018: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
Jianshu Ni, Nailong Cao, Xiaohu Wang, Changsheng Zhan, Jiemin Si, Baojun Gu, Karl-Erik Andersson
OBJECTIVES: To examine the effect of intrathecal (i.t.) serotonin (5-hydroxytryptamine) 5-HT7 agonist administration on voiding function in the urethane-anesthetised rat, and the change in 5-HT7 receptor (5-HT7 R) expression in the lumbosacral cord Onuf's nucleus after spinal cord injury (SCI). MATERIALS AND METHODS: In all, 32 female Sprague-Dawley (SD) rats were equally divided into a spinally intact (SI) group and SCI group (n = 16 each). At 8 weeks after transection, half of the rats underwent continuous cystometry under urethane anaesthesia, and the 5-HT7 R-selective agonist LP44 was given (i...
May 21, 2018: BJU International
Maria N Modica, Enza Lacivita, Sebastiano Intagliata, Loredana Salerno, Giuseppe Romeo, Valeria Pittalà, Marcello Leopoldo
Serotonin 5-HT7 receptor (5-HT7 R) has been the subject of intense research efforts because of its presence in brain areas such as the hippocampus, hypothalamus, and cortex. Preclinical data link the 5-HT7 R to a variety of central nervous system processes including the regulation of circadian rhythms, mood, cognition, pain processing, and mechanisms of addiction. 5-HT7 R blockade has antidepressant effects and may ameliorate cognitive deficits associated with schizophrenia. 5-HT7 R has been recently shown to modulate neuronal morphology, excitability, and plasticity, thus contributing to shape brain networks during development and to remodel neuronal wiring in the mature brain...
June 5, 2018: Journal of Medicinal Chemistry
Krzysztof Marciniec, Rafał Kurczab, Maria Książek, Ewa Bębenek, Elwira Chrobak, Grzegorz Satała, Andrzej J Bojarski, Joachim Kusz, Paweł Zajdel
A series of azinesulfonamide derivatives of long-chain arylpiperazines with variable-length alkylene spacers between sulfonamide and 4-arylpiperazine moiety is designed, synthesized, and biologically evaluated. In vitro methods are used to determine their affinity for serotonin 5-HT1A , 5-HT6 , 5-HT7 , and dopamine D2 receptors. X-ray analysis, two-dimensional NMR conformational studies, and docking into the 5-HT1A and 5-HT7 receptor models are then conducted to investigate the conformational preferences of selected serotonin receptor ligands in different environments...
May 11, 2018: Chemistry Central Journal
Luis D Arreola-Peralta, Frida Altamirano-Reyna, Deni M Galindo-González, Jessica G Solis-Anguiano, Enza Lacivita, Marcello Leopoldo, José A Terrón
A decrease in the activation threshold of primary sensory neurons to transient receptor potential V1 (TRPV1) stimulation by serotonin 5-HT7 receptors has been reported but no confirmation if this might translate into facilitation of neurogenic inflammation has been provided. We analysed the modulation of capsaicin (CAP)-induced neurogenic inflammation in the rat hind paw by the selective 5-HT7 receptor agonist, LP-44, and the involvement of calcitonin gen-related peptide (CGRP) in this effect. Animals received intra-plantar injections (30 μL) of vehicle, CAP (0...
July 2018: Peptides
Katarzyna Pańczyk, Karolina Pytka, Magdalena Jakubczyk, Anna Rapacz, Kinga Sałat, Anna Furgała, Agata Siwek, Monika Głuch-Lutwin, Anna Gryboś, Karolina Słoczyńska, Elżbieta Pękala, Paweł Żmudzki, Adam Bucki, Marcin Kołaczkowski, Dorota Żelaszczyk, Henryk Marona, Anna M Waszkielewicz
Aim of the study was evaluation of anxiolytic, antidepressant, anticonvulsant and analgesic activity in a series of a consistent group of compounds. A series of eleven new N-(phenoxyalkyl)- or N-{2-[2-(phenoxy)ethoxy]ethyl}piperazine derivatives has been obtained. Their affinity towards 5-HT1A , 5-HT2A , 5-HT6 , 5-HT7 , D2 and α1 receptors has been assessed, and then functional assays were performed. The compounds were evaluated in mice, i.p. for their antidepressant-like (forced swim test), locomotor, anxiolytic-like (four-plate test) activities as well as - at higher doses - for anticonvulsant potential (MES) and neurotoxicity (rotarod)...
June 15, 2018: Bioorganic & Medicinal Chemistry Letters
Yanan Xu, Xiaoyin Zhu, Hongbo Wang, Shanyue Sun, Xin Yue, Jingwei Tian
PCC0104005 is a novel drug candidate for treating schizophrenia that displays high affinity for serotonin, dopamine, and noradrenaline receptors, including partial agonism at dopamine D2 , D3 , D4 , serotonin 5-HT1A , and 5-HT2A receptors and antagonism at 5-HT2B , 5-HT6 , and 5-HT7 receptors. PCC0104005 blocks MK-801-induced hyperactivity in rats, consistent with the reduction in dopamine D2 receptor stimulation and increased dopamine release in the medial prefrontal cortex. PCC0104005 inhibits 5-HTP-induced head twitches in rats, due to its moderate affinity for human 5-HT2A receptors (Ki = 5...
May 2, 2018: Scientific Reports
A S Tsybko, T V Ilchibaeva, D V Bazovkina, V S Naumenko
The effects of chronic 5-HT1A receptor activation on the behavior, functional activity of 5-HT1A receptors, and expression of key genes of the brain 5-HT system were studied in mice of the catalepsy-prone CBA strain and the catalepsy-resistant C57BL/6 strain. Chronic treatment with 8-Hydroxy-2-(di-n-propyl-amino)tetralin (8-OH-DPAT) (1.0 mg/kg i.p., 14 days) led to a significant decrease in the hypothermic response to acute administration of 8-OH-DPAT in CBA and C57BL/6 mice, which indicates the desensiti-zation of 5-HT1A receptors in both strains...
March 2018: Molekuliarnaia Biologiia
Sabina Podlewska, Rafał Kafel, Enza Lacivita, Grzegorz Satała, Albert J Kooistra, Márton Vass, Chris de Graaf, Marcello Leopoldo, Andrzej J Bojarski, Stefan Mordalski
Identifying desired interactions with a target receptor is often the first step when designing new active compounds. However, attention should also be focused on contacts with other proteins that result in either selective or polypharmacological compounds. Here, the search for the structural determinants of selectivity between selected serotonin receptor subtypes was carried out. Special attention was focused on 5-HT7 R and the cross-interactions between its ligands and the 5-HT1A R, 5-HT1B R, 5-HT2A R, 5-HT2B R, and 5-HT6 R subtypes...
May 10, 2018: European Journal of Medicinal Chemistry
Alexander V Kulikov, Raul R Gainetdinov, Evgeni Ponimaskin, Allan V Kalueff, Vladimir S Naumenko, Nina K Popova
Selective serotonin reuptake inhibitors (SSRIs) are the most effective and most used antidepressant drugs. Acting by inhibiting serotonin (5-HT) transporter, SSRIs display a typical 3-4-week delay in their therapeutic effects, with nearly 40% of depressed patients remaining treatment-resistant. Recent evidence suggests complex interplay between 5-HT receptors and key proteins of 5-HT metabolism in molecular mechanisms of such delay and resistance to SSRIs. Area covered: This paper concentrates on the interplay between 5-HT receptors in the delay of therapeutic effect of SSRIs, and the interaction between tryptophan hydroxylase 2 and 5-HT transporter in the SSRI resistance...
April 2018: Expert Opinion on Therapeutic Targets
Miriam A Snider, David L Harmon, James L Klotz
Prior work using a contractility bioassay determined that the serotonin (5-HT) receptor subtype 5-HT2A is present in bovine lateral saphenous veins and plays a role in ergot alkaloid (EA)-induced vascular contraction in steers grazing endophyte-infected (Epichloë coenophiala) tall fescue (Lolium arundinaceum). Ergot alkaloids have also been shown to be vasoactive in bovine gut vasculature. To determine what 5-HT receptors are involved in vasoconstriction of gut vasculature, contractility of ruminal and mesenteric arteries and veins collected from cattle was evaluated in the presence of agonists selective for 5-HT1B (CP 93129), 5-HT1D (L-694, 247), 5-HT2A (TCB-2), 5-HT2B (BW 723C86), 5-HT4 (BIMU-8), and 5-HT7 (LP 44) receptors...
April 14, 2018: Journal of Animal Science
Karolina Słoczyńska, Katarzyna Wójcik-Pszczoła, Vittorio Canale, Paweł Żmudzki, Paweł Zajdel, Elżbieta Pękala
The aim of the study was to investigate the metabolism of 4-fluoro-N-(1-{2-[(propan-2-yl)phenoxy]ethyl}-8-azabicyclo[3.2.1]octan-3-yl)-benzenesulfonamide (PZ-1150), a novel 5-HT7 receptor antagonist with antidepressant-like and anxiolytic properties, by the following three ways: in vitro with microsomes; in vitro employing Cunninghamella echinulata, and in silico using MetaSite. Biotransformation of PZ-1150 with microsomes resulted in five metabolites, while transformation with C. echinulata afforded two metabolites...
May 2018: Journal of Biochemical and Molecular Toxicology
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