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5-HT(1D) inhibition

Piero Barbanti, C Aurilia, G Egeo, L Fofi, R Palmirotta
Research has focused on serotonin (5-HT) 5-HT1D and 5-HT1F receptors to develop drugs acting through non-vasoconstrictive mechanisms for treating acute migraine and those targeting 5-HT2B and 5-HT7 receptors for preventing migraine. Areas covered: This paper reviews antimigraine drugs targeting 5-HT receptors in one phase I trial (sumatriptan iontophoretic transdermal system, TDS) and five phase II clinical trials (PNU-142633, LY334370, lasmiditan, NOX-188). Expert opinion: Data from our overview on investigational drugs in phase I and II clinical trials using the 5-HT1B/1D receptor agonist (sumatriptan TDS), 5-HT1D receptor agonist (PNU-142633), 5-HT1F receptor agonists (LY334370, lasmiditan) and a combined 5-HT1B/1D receptor agonist with nNOS inhibition (NOX-188) provided encouraging data for sumatriptan TDS and lasmiditan, disappointing results for PNU-142633, and promising findings for NOX-188...
March 2017: Expert Opinion on Investigational Drugs
Theeradej Thaweerattanasinp, Charles J Heckman, Vicki M Tysseling
Spinal cord injury (SCI) results in a loss of serotonin (5-HT) to the spinal cord and a loss of inhibition to deep dorsal horn (DDH) neurons, which produces an exaggerated excitatory drive to motoneurons. The mechanism of this excitatory drive could involve the DDH neurons triggering long excitatory postsynaptic potentials in motoneurons, which may ultimately drive muscle spasms. Modifying the activity of DDH neurons with drugs such as NMDA or the 5-HT1B/1D receptor agonist zolmitriptan could have a large effect on motoneuron activity and, therefore, on muscle spasms...
October 1, 2016: Journal of Neurophysiology
Carlos M Villalón, Antoinette Maassen VanDenBrink
Migraine is a highly prevalent neurovascular disorder. Of the many factors that have been implicated over the years, 5-hydroxytryptamine (5-HT; serotonin) has long been involved in the pathophysiology of migraine. Certainly, some lines of evidence suggest: (i) a 5-HT depletion from blood platelets resulting in cranial extracerebral vasodilatation; and (ii) the effectiveness of an intravenous (i.v.) infusion of 5 HT to abort migraine in some patients. More direct evidence comes from some drugs that influence 5-HT release and/or interact (as agonists or antagonists) with 5-HT receptors to treat this disorder...
July 28, 2016: Mini Reviews in Medicinal Chemistry
Kimio Sugaya, Saori Nishijima, Katsumi Kadekawa, Katsuhiro Ashitomi, Tomoyuki Ueda, Hideyuki Yamamoto, Tsuyoshi Hattori
AIMS: We examined the mechanism of action of naftopidil, an α1D/A blocker, on spinal descending serotonergic neurotransmission for the micturition reflex. METHODS: We examined (1) urinary 5-hydroxyindole acetic acid (5-HIAA) after intraperitoneal administration of saline, para-chlorophenylalanine (PCPA; a serotonin synthetic enzyme inhibitor), and/or 5-hydroxytryptophan (5-HTP; a serotonin precursor); (2) isovolumetric cystometry after intraperitoneal administration of saline, PCPA, and/or 5-HTP and intravenous injection of naftopidil; and (3) isovolumetric cystometry before and after intrathecal administration of serotonin (5-HT) receptor antagonists and intravenous injection of naftopidil...
March 2017: Neurourology and Urodynamics
Serge A T Fobofou, Katrin Franke, Andrea Porzel, Wolfgang Brandt, Ludger A Wessjohann
The chemical investigation of the chloroform extract of Hypericum lanceolatum guided by (1)H NMR, ESIMS, and TLC profiles led to the isolation of 11 new tricyclic acylphloroglucinol derivatives, named selancins A-I (1-9) and hyperselancins A and B (10 and 11), along with the known compound 3-O-geranylemodin (12), which is described for a Hypericum species for the first time. Compounds 8 and 9 are the first examples of natural products with a 6-acyl-2,2-dimethylchroman-4-one core fused with a dimethylpyran unit...
April 22, 2016: Journal of Natural Products
H Bennet, A Balhuizen, A Medina, M Dekker Nitert, E Ottosson Laakso, S Essén, P Spégel, P Storm, U Krus, N Wierup, M Fex
Islet produced 5-hydroxy tryptamine (5-HT) is suggested to regulate islet hormone secretion in a paracrine and autocrine manner in rodents. Hitherto, no studies demonstrate a role for this amine in human islet function, nor is it known if 5-HT signaling is involved in the development of beta cell dysfunction in type 2 diabetes (T2D). To clarify this, we performed a complete transcriptional mapping of 5-HT receptors and processing enzymes in human islets and investigated differential expression of these genes in non-diabetic and T2D human islet donors...
September 2015: Peptides
Omar Estrada, Whendy Contreras, Giovana Acha, Eva Lucena, Whitney Venturini, Alfonso Cardozo, Claudia Alvarado-Castillo
Three new lupane-type triterpenoids: 6β,30-dihydroxybetulinic acid glucopyranosyl ester (4), 6β,30-dihydroxybetulinic acid (5) and 6β-hydroxybetulinic acid (6), were isolated from Licania cruegeriana Urb. along with six known compounds. Their structures were elucidated on the basis of spectroscopic methods, including IR, ESIMS, 1D- and 2D-NMR experiments, as well as by comparison of their spectral data with those of related compounds. All compounds were evaluated in vivo for their effects on the mean arterial blood pressure (MABP) and heart rate (HR) of spontaneously hypertensive rats (SHR) and also in vitro for their capacity to inhibit the human platelet aggregation...
2014: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Robert A Comley, Jasper van der Aart, Balázs Gulyás, Martine Garnier, Laura Iavarone, Christer Halldin, Eugenii A Rabiner
5-hydroxytryptamine 1 (5-HT1) receptor blockade in combination with serotonin reuptake inhibition may provide a more rapid elevation of synaptic 5-HT compared to serotonin reuptake alone, by blocking the inhibitory effect of 5-HT1 receptor activation on serotonin release. GSK588045 is a novel compound with antagonist activity at 5-HT1A/1B/1D receptors and nanomolar affinity for the serotonin transporter, which was in development for the treatment of depression and anxiety. Here we present the results of an in vivo assessment of the relationship between plasma exposure and 5-HT1A receptor occupancy...
May 2015: Neuropharmacology
Nilgun Gurbuz, Ahmed A Ashour, S Neslihan Alpay, Bulent Ozpolat
Pancreatic ductal adenocarcinoma is characterized by extensive local tumor invasion, metastasis and early systemic dissemination. The vast majority of pancreatic cancer (PaCa) patients already have metastatic complications at the time of diagnosis, and the death rate of this lethal type of cancer has increased over the past decades. Thus, efforts at identifying novel molecularly targeted therapies are priorities. Recent studies have suggested that serotonin (5-HT) contributes to the tumor growth in a variety of cancers including prostate, colon, bladder and liver cancer...
2014: PloS One
Nilgun Gurbuz, Ahmed A Ashour, S Neslihan Alpay, Bulent Ozpolat
Pancreatic ductal adenocarcinoma is characterized by extensive local tumor invasion, metastasis and early systemic dissemination. The vast majority of pancreatic cancer (PaCa) patients already have metastatic complications at the time of diagnosis, and the death rate of this lethal type of cancer has increased over the past decades. Thus, efforts at identifying novel molecularly targeted therapies are priorities. Recent studies have suggested that serotonin (5-HT) contributes to the tumor growth in a variety of cancers including prostate, colon, bladder and liver cancer...
2014: PloS One
K Adhikari, S Pal, B Chakraborty, S N Mukherjee, A Gangopadhyay
The movement of contaminants through soil imparts a variety of geo-environmental problem inclusive of lithospheric pollution. Near-surface aquifers are often vulnerable to contamination from surface source if overlying soil possesses poor resilience or contaminant attenuation capacity. The prediction of contaminant transport through soil is urged to protect groundwater from sources of pollutants. Using field simulation through column experiments and mathematical modeling like HYDRUS-1D, assessment of soil resilience and movement of contaminants through the subsurface to reach aquifers can be predicted...
October 2014: Environmental Monitoring and Assessment
Andrew Gibb, Emma D Deeks
Vortioxetine is an orally administered small molecule developed by Lundbeck A/S for the once-daily treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD). Vortioxetine received its first global approval for MDD in the USA in September 2013 and regulatory approval for its use in this indication in the EU (where it has received a positive opinion) and Canada is awaited. The drug is a bis-aryl-sulphanyl amine compound that combines serotonin (5-HT) reuptake inhibition with other characteristics, including receptor activity modulation...
January 2014: Drugs
Karly P Garnock-Jones
The sumatriptan iontophoretic transdermal system (ZECUITY®) [hereafter referred to as sumatriptan TDS] is the first transdermal treatment for migraine to be approved by the US FDA. This article reviews the available pharmacologic properties of sumatriptan TDS and its clinical efficacy and tolerability for the acute treatment of adult patients with migraine with or without aura. Sumatriptan, a selective 5-hydroxy-tryptamine receptor subtype 1 (5-HT₁) agonist, is presumed to exert its therapeutic effect on migraine patients by binding to the 5-HT(1B/1D) receptors on intracranial blood vessels and sensory nerves of the trigeminal system, resulting in cranial vessel constriction and the inhibition of the release of pro-inflammatory neuropeptides and plasma extravasation...
September 2013: Drugs
Jean-Philippe Guilloux, Indira Mendez-David, Alan Pehrson, Bruno P Guiard, Christelle Repérant, Sophie Orvoën, Alain M Gardier, René Hen, Bjarke Ebert, Silke Miller, Connie Sanchez, Denis J David
Vortioxetine (Lu AA21004) is an investigational novel antidepressant with multimodal activity that functions as a 5-HT3, 5-HT7 and 5-HT(1D) receptor antagonist, 5-HT(1B) receptor partial agonist, 5-HT(1A) receptor agonist and inhibitor of the 5-HT transporter in vitro. Here we explore its anxiolytic and antidepressant potential in adult mice. Vortioxetine was assessed in BalB/cJ@RJ mice using the open-field and forced-swim tests (acute: p.o. 1 h, repeated: daily p.o. 21 days), and in 129S6/SvEvTac mice using the novelty suppressed feeding paradigm (acute: p...
October 2013: Neuropharmacology
Kenneth J Broadley, Martina Fehler, William R Ford, Emma J Kidd
Trace amines including β-phenylethylamine (β-PEA) and amphetamines classically exert pharmacological actions via indirect sympathomimetic mechanisms. However, there is evidence for other mechanisms and this study explores the receptors mediating vasoconstriction in rat aorta. β-PEA, d-amphetamine, MDMA, cathinone and methylphenidate caused concentration-dependent contractions of rat isolated aortic rings which were unaffected by prazosin (1 μM), ICI-118,551 (1 μM), cocaine (10 μM) and pargyline (10 μM), to inhibit α1- and β2-adrenoceptors, neuronal transport and monoamine oxidase (MAO), respectively...
September 5, 2013: European Journal of Pharmacology
Eriko Masachika, Takeshi Kanno, Takashi Nakano, Akinobu Gotoh, Tomoyuki Nishizaki
BACKGROUND: Naftopidil, an α1-adrenoceptor blocker, has been clinically used for the treatment of benign prostate hyperplasia and hypertension. Emerging evidence has shown that naftopidil exhibits an antitumor effect on a variety of cancer types including prostate cancer. The aim of the present study was to investigate naftopidil-induced apoptosis in human malignant mesothelioma cells and to shed light on the underlying mechanism. MATERIALS AND METHODS: 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining, western blotting, and enzymatic assay of caspase-3, -8, and -9 activities were carried out on human malignant mesothelioma cell lines NCI-H28, NCI-H2052, NCI-H2452, and MSTO-211H cells...
March 2013: Anticancer Research
Saobo Lei
The entorhinal cortex (EC) is considered as the gate to control the flow of information into and out of the hippocampus. The EC is important for numerous physiological functions such as emotional control, learning and memory and pathological disorders including Alzheimer's disease, schizophrenia and temporal lobe epilepsy. Serotonin is a classical neurotransmitter which may modify these physiological functions and pathology of neurological diseases. The EC receives profuse serotonergic innervations from the raphe nuclei in the brainstem and expresses high density of serotonergic receptors including 5-HT(1A), 5-HT(1D), 5-HT(1E), 5-HT(2A), 5-HT(3) and 5-HT(6)...
2012: International Journal of Physiology, Pathophysiology and Pharmacology
Takumi Sakai, Ken-ichi Kasahara, Ken-ichi Tomita, Ichiro Ikegaki, Hiroshi Kuriyama
Naftopidil is an α(1D) and α(1A) subtype-selective α(1)-adrenoceptor antagonist that has been used to treat lower urinary tract symptoms of benign prostatic hyperplasia. In this study, we investigated the effects of naftopidil on 5-hydroxytryptamine (5-HT)-induced rat bladder contraction (10(-8)-10(-4) M). Naftopidil (0.3, 1, and 3 μM) inhibited 5-HT-induced bladder contraction in a concentration-dependent manner. On the other hand, other α(1)-adrenoceptor antagonists, tamsulosin, silodosin or prazosin, did not inhibit 5-HT-induced bladder contraction...
January 30, 2013: European Journal of Pharmacology
Phan Van Kiem, Chau Van Minh, Nguyen Xuan Nhiem, Nguyen Xuan Cuong, Bui Huu Tai, Tran Hong Quang, Hoang Le Tuan Anh, Pham Hai Yen, Ninh Khac Ban, Seung Hyun Kim, Mingjie Xin, Ji-Yun Cha, Young-Mi Lee, Young Ho Kim
Bioassay-guided fractionation based on the anti-inflammatory activity of a methanol extract of Ficus microcarpa leaves led to the isolation of seven galactolipids: 2(S)-3-O-octadeca-9Z,12Z,15Z-trienoylglyceryl-O-β-D-galactopyranoside (1), (2S)-2,3-O-dioctadeca-9Z,12Z,15Z-trienoylglyceryl-O-β-D-galactopyranoside (2), (2S)-2,3-O-dioctadeca-9Z,12Z-dienoylglyceryl-O-β-D-galactopyranoside (3), (2S)-3-O-octadeca-9Z,12Z,15Z-trienoylglyceryl-6'-O-(α-D-galactopyranosyl)-β-D-galactopyranoside (4), (2S)-2,3-O-dioctadeca-9Z,12Z,15Z-trienoylglyceryl-6'-O-(α-D-galactopyranosyl)-β-D-galactopyranoside (5), gingerglycolipid B (6), and (2S)-2,3-O-dioctadeca-9Z,12Z-dienoylglyceryl-6'-O-(α-D-galactopyranosyl)-β-D-galactopyranoside (7)...
December 2012: Archives of Pharmacal Research
Lars Edvinsson, Carlos M Villalón, Antoinette MaassenVanDenBrink
Migraine is a neurovascular disorder characterized by recurrent unilateral headaches accompanied by nausea, vomiting, photophobia and phonophobia. Current theories suggest that the initiation of a migraine attack involves a primary event in the central nervous system (CNS), probably involving a combination of genetic changes in ion channels and environmental changes, which renders the individual more sensitive to environmental factors; this may, in turn, result in a wave of cortical spreading depression (CSD) when the attack is initiated...
December 2012: Pharmacology & Therapeutics
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