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Anita Nivedha, Christofer Tautermann, Supriyo Bhattacharya, Sangbae Lee, Paola Casarosa, Ines Kollak, Tobias Kiechle, Nagarajan Vaidehi
G-protein-coupled receptors (GPCRs) mediate multiple signaling pathways in the cell depending on the agonist that activates the receptor and multiple cellular factors. Agonists that show higher potency to specific signaling pathways over others are known as "biased agonists" and have been shown to have better therapeutic index. Although biased agonists are desirable, their design poses several challenges to date. The number of assays to identify biased agonists seems expensive and tedious. Therefore, computational methods that can reliably calculate the possible bias of various ligands ahead of experiments and provide guidance will be both cost and time effective...
January 24, 2018: Molecular Pharmacology
Kremena E Saracheva, Natalia A Prissadova, Valentin I Turiiski, Valeri I Slavchev, Atanas D Krastev, Damianka P Getova
BACKGROUND: In blood vessels 5-HT stimulates sympathetic nerves, the endothelium and vascular smooth muscle cells. Triptans are specific anti-migraine drugs and they activate the serotoninergic 5HT1b/d receptors causing vasoconstriction of the cerebral vessels. AIM: To evaluate the effect of frovatriptan on isolated rat carotid artery. METHODS: Contractile activity of the preparations was registered isometrically. Krebs solution (pH = 7.4) was used for washing smooth muscle (SM) preparations aerated with 95% O2 and 5% CO2 at 37°C...
March 1, 2017: Folia Medica
Amanda E Macone, Michael D Perloff
Recent triptan development has focused on new administration methods and formulations, triptan combination therapies, treatment in menstrually related migraines, and novel serotonin receptor subtype agonists (5HTf). Areas covered: Clinical triptan research related to migraine was reviewed, analyzing EMBASE and PUBMED data bases from 01/01/2011 to 06/29/2016, with a focus on clinical trials of class 1 or 2 level of evidence. There have been advances in drug combination therapies, as well as administration devices that aid in ease of use, increase efficacy, and decrease adverse reactions...
March 2017: Expert Opinion on Pharmacotherapy
Priti Girotra, Aman Thakur, Ajay Kumar, Shailendra Kumar Singh
The complex pathophysiology involved in migraine necessitates the drug treatment to act on several receptors simultaneously. The present investigation was an attempt to discover the unidentified anti-migraine activity of the already marketed drugs. Shared featured pharmacophore modeling was employed for this purpose on six target receptors (β2 adrenoceptor, Dopamine D3, 5HT1B, TRPV1, iGluR5 kainate and CGRP), resulting in the generation of five shared featured pharmacophores, which were further subjected to virtual screening of the ligands obtained from Drugbank database...
March 2017: International Journal of Biological Macromolecules
Mirko Muzzi, Daniela Buonvicino, Francesco De Cesaris, Alberto Chiarugi
Although it is still debated whether vasoconstriction underlies migraine resolution by triptans, they are not recommended in patients at cardiovascular risk. However, relationship between stroke incidence and triptan use is unclear, and it is unknown whether acute or chronic use of these drugs worsens ischemic brain injury. To address this issue, we investigated the effect of clinically-relevant doses of the potent cerebral artery vasoconstrictor eletriptan on cerebral blood flow (CBF) and brain infarct volumes, as well as on expression of genes involved in cerebrovascular regulation...
January 6, 2017: Neuroscience
Keytam S Awad, James D West, Vinicio de Jesus Perez, Margaret MacLean
The proliferative endothelial and smooth muscle cell phenotype, inflammation, and pulmonary vascular remodeling are prominent features of pulmonary arterial hypertension (PAH). Mutations in bone morphogenetic protein type 2 receptor (BMPR2) have been identified as the most common genetic cause of PAH and females with BMPR2 mutations are 2.5 times as likely to develop heritable forms of PAH than males. Higher levels of estrogen have also been observed in males with PAH, implicating sex hormones in PAH pathogenesis...
September 2016: Pulmonary Circulation
Maria Eliza Freitas, Susan H Fox
Parkinson's disease is primarily caused by dysfunction of dopaminergic neurons, however, nondopaminergic (ND) systems are also involved. ND targets are potentially useful to reduce doses of levodopa or to treat nonlevodopa-responsive symptoms. Recent studies have investigated the role of ND drugs for motor and nonmotor symptoms. Adenosine A2A receptor antagonists, mixed inhibitors of sodium/calcium channels and monoamine oxidase-B have recently been found to improve motor fluctuations. N-methyl-d-aspartate receptor antagonists and serotonin 5HT1B receptor agonists demonstrated benefit in levodopa-induced dyskinesia...
June 2016: Neurodegenerative Disease Management
Panayotis K Thanos, Lauren Malave, Foteini Delis, Paul Mangine, Katie Kane, Adam Grunseich, Melissa Vitale, Paul Greengard, Nora D Volkow
Cocaine's enhancement of dopamine signaling is crucial for its rewarding effects but its serotonergic effects are also relevant. Here we examined the role of the protein p11, which recruits serotonin 5HT1B and 5HT4 receptors to the cell surface, in cocaine reward. For this purpose we tested wild-type (WT) and p11 knockout (KO) male and female mice for cocaine conditioned place preference (CPP) and its cocaine-induced reinstatement at different abstinence times, after 8 days of extinction and 28 days of being home-caged...
July 2016: Synapse
Daniele Vandelli, Federica Palazzoli, Patrizia Verri, Cecilia Rustichelli, Filippo Marchesi, Anna Ferrari, Carlo Baraldi, Enrico Giuliani, Manuela Licata, Enrico Silingardi
Triptans are specific drugs widely used for acute treatment of migraine, being selective 5HT1B/1D receptor agonists. A proper assumption of triptans is very important for an effective treatment; nevertheless patients often underuse, misuse, overuse or use triptans inconsistently, i.e., not following the prescribed therapy. Drug analysis in hair can represent a powerful tool for monitoring the compliance of the patient to the therapy, since it can greatly increase the time-window of detection compared to analyses in biological fluids, such as plasma or urine...
April 1, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Anne Francke Christensen, Ann-Louise Esserlind, Thomas Werge, Hreinn Stefánsson, Kári Stefánsson, Jes Olesen
OBJECTIVE: Specific acute treatments of migraine are 5HT1B/D receptor agonists; triptans and ergotamine, but only two-thirds of patients respond well without side effects. No migraine-prophylactic drugs are specific to migraine. Prophylactic drugs are selected by time-consuming "trial and error." Personalized treatment is therefore much needed. The objective of this study was to test the effect of 12 single nucleotide polymorphisms (SNPs) significantly associated with migraine on migraine drug responses...
June 2016: Cephalalgia: An International Journal of Headache
Emily V Ho, Summer L Thompson, William R Katzka, Mitra F Sharifi, James A Knowles, Stephanie C Dulawa
RATIONALE: Serotonin-1B receptor (5-HT1BR) agonist treatment induces obsessive-compulsive disorder (OCD)-like behaviors including locomotor stereotypy, prepulse inhibition deficits, and delayed alternation disruptions, which are selectively prevented by clinically effective OCD treatment. However, the role of 5-HT1BRs in modulating other repetitive behaviors or OCD-like patterns of brain activation remains unclear. OBJECTIVES: We assessed the effects of 5-HT1BR agonism on digging, grooming, and open field behaviors in mice...
January 2016: Psychopharmacology
Roberta Carbonara, Alessia Carocci, Julien Roussel, Giuseppe Crescenzo, Canio Buonavoglia, Carlo Franchini, Giovanni Lentini, Diana Conte Camerino, Jean-François Desaphy
Voltage-gated sodium channels are known to play a pivotal role in perception and transmission of pain sensations. Gain-of-function mutations in the genes encoding the peripheral neuronal sodium channels, hNav1.7-1.9, cause human painful diseases. Thus while treatment of chronic pain remains an unmet clinical need, sodium channel blockers are considered as promising druggable targets. In a previous study, we evaluated the analgesic activity of sumatriptan, an agonist of serotonin 5HT1B/D receptors, and some new chiral bioisosteres, using the hot plate test in the mouse...
2015: Frontiers in Pharmacology
Priyoneel Basu, Naomi Ie, Adrienne L Wensel, Joelle D Baskerville, Victoria M Smith, Michael C Antle
Daily exposure to light synchronizes the circadian clock, located in the suprachiasmatic nucleus (SCN), to external day/night cycles. These responses to light can be modified by serotonergic drugs, such as serotonin 5HT1B receptor agonists. Triptans are specific 5HT1B agonists prescribed to treat migraines. Here, we examined the effects of two triptans (zolmitriptan and sumatriptan) on photic phase resetting in Syrian hamsters. Pre-treatment with intra-SCN sumatriptan significantly attenuates, and at higher doses completely blocks, phase advances to light during the late night...
October 2015: European Journal of Neuroscience
Stephen M Stahl
Vortioxetine is an antidepressant that targets multiple pharmacologic modes of action at sites--or nodes--where serotonergic neurons connect to various brain circuits. These multimodal pharmacologic actions of vortioxetine lead to enhanced release of various neurotransmitters, including serotonin, at various nodes within neuronal networks.
April 2015: CNS Spectrums
Ismail O Ishola, Esther O Agbaje, Moshood O Akinleye, Chris O Ibeh, Olufunmilayo O Adeyemi
ETHNOPHARMACOLOGICAL RELEVANCE: The leaf of Alchornea cordifolia (Euphorbiaceae) is used in traditional African medicine in the treatment of various neurological and psychiatric disorders including depression. Previous studies have shown its potent antidepressant-like effect in the forced swimming test (FST). Hence, this study sought to investigate the involvement of monoaminergic systems in the antidepressant-like effect elicited by hydroethanolic leaf extract of Alchornea cordifolia (HeAC) in the FST...
December 2, 2014: Journal of Ethnopharmacology
Petra Amchova, Jana Kucerova, Valentina Giugliano, Zuzana Babinska, Mary T Zanda, Maria Scherma, Ladislav Dusek, Paola Fadda, Vincenzo Micale, Alexandra Sulcova, Walter Fratta, Liana Fattore
Depression has been associated with drug consumption, including heavy or problematic cannabis use. According to an animal model of depression and substance use disorder comorbidity, we combined the olfactory bulbectomy (OBX) model of depression with intravenous drug self-administration procedure to verify whether depressive-like rats displayed altered voluntary intake of the CB1 receptor agonist WIN55,212-2 (WIN, 12.5 μg/kg/infusion). To this aim, olfactory-bulbectomized (OBX) and sham-operated (SHAM) Lister Hooded rats were allowed to self-administer WIN by lever-pressing under a continuous [fixed ratio 1 (FR-1)] schedule of reinforcement in 2 h daily sessions...
2014: Frontiers in Pharmacology
Greg Dussor
PURPOSE OF REVIEW: The serotonergic system has long been linked to migraine but recent studies highlight how much is still unclear about this link. And recent data add to the uncertainty of where/how triptans act and why they are headache specific. RECENT FINDINGS: Markers of 5HT levels in the brains of migraine patients show no changes between attacks. Several recent meta-analyses show the most convincing data on genetic differences in the serotonergic system for 5HT transporters...
June 2014: Current Opinion in Supportive and Palliative Care
Geovanna Nallely Quiñonez-Bastidas, Claudia Cervantes-Durán, Héctor Isaac Rocha-González, Janet Murbartián, Vinicio Granados-Soto
AIMS: The purpose of this study was to investigate the antinociceptive effect of epicatechin as well as the possible mechanisms of action in diabetic rats. MAIN METHODS: Rats were injected with streptozotocin to produce hyperglycemia. The formalin test was used to assess the nociceptive activity. KEY FINDINGS: Acute pre-treatment with epicatechin (0.03-30 mg/kg, i.p.) prevented formalin-induced nociception in diabetic rats. Furthermore, daily or every other day treatment for 2 weeks with epicatechin (0...
October 17, 2013: Life Sciences
Agnieszka Pałucha-Poniewiera, Piotr Brański, Joanna M Wierońska, Katarzyna Stachowicz, Anna Sławińska, Andrzej Pilc
RATIONALE: Numerous studies indicate the potential antidepressant actions of several mGlu5 receptor antagonists, including 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP). The explanation for the mechanism of these effects might be a key step in finding new antidepressant drugs (AD). OBJECTIVES: The aim of the present study was to investigate the possible role of the serotonergic system in the antidepressant-like activity of MTEP in the tail suspension test (TST) in C57BL/6J mice, using selected antagonists of serotonergic receptors and by applying two different methods of serotonin (5-HT) depletion...
January 2014: Psychopharmacology
María J Mancebo, Francisco C Ceballos, Jorge Pérez-Maceira, Manuel Aldegunde
Mammalian studies have shown a link between serotonin (5-HT) and neuropeptide Y (NPY) in the acute regulation of feeding and energy homeostasis. Taking into account that the actions of 5-HT and NPY on food intake in fish are similar to those observed in mammals, the objective of this study was to characterize a possible short-term interaction between hypothalamic 5-HT and NPY, by examining whether 5-HT regulates NPY gene expression, to help clarify the mechanism underlying the observed anorexigenic action of central 5-HT in the rainbow trout...
September 2013: Comparative Biochemistry and Physiology. Part A, Molecular & Integrative Physiology
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