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Alpha 2c antagonist

Juha O Rinne, Keith Wesnes, Jeffrey L Cummings, Pasi Hakulinen, Merja Hallikainen, Jutta Hänninen, Michael Murphy, Henry Riordan, Mika Scheinin, Hilkka Soininen, Juha Rouru
INTRODUCTION: ORM-12741 is a novel selective antagonist of alpha-2C adrenoceptors. This trial evaluated the safety and efficacy of ORM-12741 in patients with Alzheimer's disease (AD). METHODS: A randomized, double-blind, placebo-controlled, exploratory phase 2a trial was conducted in 100 subjects with AD and neuropsychiatric symptoms. Participants were randomized to receive one of two flexible doses of ORM-12741 (30-60 mg or 100-200 mg) or placebo b.i.d. for 12 weeks in addition to standard therapy with cholinesterase inhibitors...
January 2017: Alzheimer's & Dementia: Translational Research & Clinical Interventions
Özgür Devrim Can, Nazlı Turan, Ümide Demir Özkay, Yusuf Öztürk
AIMS: This study was planned to examine the antidepressant potency of gallic acid (30 and 60mg/kg), a phenolic acid widely distributed in nature, together with its possible underlying monoaminergic mechanisms. MAIN METHODS: Antidepressant-like activity was assessed using the tail suspension (TST) and the modified forced swimming tests (MFST). Locomotor activity was evaluated in an activity cage. KEY FINDINGS: Administration of gallic acid at 60mg/kg reduced the immobility duration of mice in both the TST and MFST without any changes in the locomotor activity...
December 1, 2017: Life Sciences
Niraj Narendra Ravani, Pramod H Katke
Disorders of ejaculation are the consequences of surgical procedures and with the use of various drugs. Until date, most drugs reported to induce ejaculatory dysfunctions such as retrograde ejaculation or dry orgasms share the capacity to significantly antagonize alpha 1-adrenergic receptor. Iloperidone, a new dopamine Type 2 and serotonin Type 2A antagonist similar to risperidone, provides better efficacy with lesser extra-pyramidal side effects. In addition, it also antagonize alpha 1-adrenergic receptor and alpha-2C receptors...
January 2016: Indian Journal of Psychiatry
Gongliang Zhang, Xian Wu, Yong-Mei Zhang, Huan Liu, Qin Jiang, Gang Pang, Xinrong Tao, Liuyi Dong, Robert W Stackman
Opioid abuse and dependence have evolved into an international epidemic as a significant clinical and societal problem with devastating consequences. Repeated exposure to the opioid, for example morphine, can induce profound, long-lasting behavioral sensitization and physical dependence, which are thought to reflect neuroplasticity in neural circuitry. Central serotonin (5-HT) neurotransmission participates in the development of dependence on and the expression of withdrawal from morphine. Serotonin 5-HT(2C) receptor (5-HT(2C)R) agonists suppress psychostimulant nicotine or cocaine-induced behavioral sensitization and drug-seeking behavior; however, the impact of 5-HT(2C)R agonists on behaviors relevant to opioid abuse and dependence has not been reported...
February 2016: Neuropharmacology
Alain H Altamirano-Espinoza, Guadalupe Manrique-Maldonado, Bruno A Marichal-Cancino, Carlos M Villalón
Several lines of evidence have shown an association of diabetes with a catecholamines' aberrant homeostasis involving a drastic change in the expression of adrenoceptors. This homeostatic alteration includes, among other things, atypical actions of α2 -adrenoceptor agonists within central and peripheral α2 -adrenoceptors (e.g. profound antinociceptive effects in diabetic subjects). Hence, this study investigated the pharmacological profile of the α2 -adrenoceptor subtypes that inhibit the vasopressor sympathetic out-flow in streptozotocin-pre-treated (diabetic) pithed rats...
July 2015: Basic & Clinical Pharmacology & Toxicology
Dalma Kurko, Zoltán Kapui, József Nagy, Balázs Lendvai, Sándor Kolok
Although G protein-coupled receptors (GPCRs) are traditionally categorized as Gs-, Gq-, or Gi/o-coupled, their signaling is regulated by multiple mechanisms. GPCRs can couple to several effector pathways, having the capacity to interact not only with more than one G protein subtype but also with alternative signaling or effector proteins such as arrestins. Moreover, GPCR ligands can have different efficacies for activating these signaling pathways, a characteristic referred to as biased agonism or functional selectivity...
August 2014: Brain Research Bulletin
Fatih İlkaya, S Sırrı Bilge, Ayhan Bozkurt, Duygu B Baş, Arzu Erdal, Engin Çiftçioğlu, Yüksel Kesim
It has been shown that imipramine, a tricyclic antidepressant (TCA), is a potent analgesic agent. However, the effect of imipramine on visceral pain has not been extensively investigated. In the current study, our aim was to characterise the putative analgesic effect of intravenous imipramine on visceral pain in rats. Our second aim was to assess the involvement of serotonergic (5-HT₂,₃,₄) and noradrenergic (α(2A, 2B, 2C)) receptor subtypes in this putative antinociceptive effect of imipramine. Male Sprague Dawley rats (250-300 g) were implanted with venous catheters for drug administration and implanted with enamelled nichrome electrodes for electromyography of the external oblique muscles...
July 2014: Pharmacology, Biochemistry, and Behavior
Akiko Yabuki, Hitoshi Higuchi, Tatsushi Yoshitomi, Yumiko Tomoyasu, Minako Ishii-Maruhama, Shigeru Maeda, Takuya Miyawaki
BACKGROUND AND OBJECTIVES: Recent research shows that locally injected dexmedetomidine enhances the local anesthetic potency of lidocaine via the α-2A adrenoceptor subtype in guinea pigs. However, little is known about the effect of locally injected dexmedetomidine on the peripheral vascular response. This study aimed to evaluate the effect of locally injected dexmedetomidine on the peripheral vascular response, measuring skin blood flow in the injected area in guinea pigs. METHODS: Dexmedetomidine was intracutaneously injected at a volume of 0...
March 2014: Regional Anesthesia and Pain Medicine
Ma Trinidad Villamil-Hernández, Oscar Alcántara-Vázquez, Araceli Sánchez-López, David Centurión
α2-Adrenoceptors were first described as presynaptic receptors inhibiting the release of various transmitters from neurons in the central and peripheral nervous systems. In vitro studies have confirmed that α2A, α2B and α2C subtypes inhibited noradrenaline release from postganglionic sympathetic neurons but no study has been reported their involvement in the vasopressor sympathetic outflow in vivo. Thus, this study analysed the subtype(s) involved in the inhibition produced by the α2-adrenoceptor agonist, B-HT 933, on the vasopressor sympathetic outflow...
October 15, 2013: European Journal of Pharmacology
Annie Delaunois, Pierrette De Ron, Paul Dedoncker, Marie-Luce Rosseels, Miranda Cornet, Eric Jnoff, Etienne Hanon, Michel Guyaux, Brigitte Olympe Depelchin
A selective α2C -adrenoceptor (AR) agonist was developed for the treatment of neuropathic pain. The objective was to dissociate analgesic activity from cardiovascular and sedative side effects commonly observed with nonselective agents. A 2-amino-oxazoline derivative (compound A), identified as a dual α2C -AR agonist/α2A -AR antagonist in in vitro-binding assays, exhibited in vivo efficacy in rodent pain models. Its safety profile was compared with that of clonidine in six different in vivo models. Contrary to clonidine, compound A did not induce hypotension in pentobarbital-anesthetized rats, in conscious spontaneous hypertensive rats, or in telemetered dogs...
August 2014: Fundamental & Clinical Pharmacology
Thomas A Munro, Xi-Ping Huang, Carmela Inglese, Maria Grazia Perrone, Ashlee Van't Veer, F Ivy Carroll, Cécile Béguin, William A Carlezon, Nicola A Colabufo, Bruce M Cohen, Bryan L Roth
BACKGROUND: Nor-BNI, GNTI and JDTic induce selective κ opioid antagonism that is delayed and extremely prolonged, but some other effects are of rapid onset and brief duration. The transient effects of these compounds differ, suggesting that some of them may be mediated by other targets. RESULTS: In binding assays, the three antagonists showed no detectable affinity (K(i)≥10 µM) for most non-opioid receptors and transporters (26 of 43 tested). There was no non-opioid target for which all three compounds shared detectable affinity, or for which any two shared sub-micromolar affinity...
2013: PloS One
Ryan G Aleong, William H Sauer, Alastair D Robertson, Stephen B Liggett, Michael R Bristow
BACKGROUND: β-blockers prevent cardiac arrhythmias in patients with chronic heart failure and reduced left ventricular ejection fraction, including ventricular tachycardia/ventricular fibrillation (VT/VF). We hypothesized that prevention of ventricular arrhythmias by the β-blocker/sympatholytic agent bucindolol is influenced by genetic variation in adrenergic receptors. METHODS AND RESULTS: From a substudy of the β-Blocker Evaluation of Survival Trial (n=1040), we identified those with the high functioning 389Arg versus the lower function 389Gly β(1) adrenergic receptor variant, and the loss of function α(2c)322-325 adrenergic receptor deletion versus the 322 to 325 wild-type (Wt)/deletion variant...
February 2013: Circulation. Arrhythmia and Electrophysiology
Peter W Abel, Neha Jain
α-Adrenoceptors mediate responses to activation of both peripheral sympathetic nerves and central noradrenergic neurons. They also serve as autoreceptors that modulate the release of norepinephrine (NE) and other neurotransmitters. There are two major classes of α-adrenoceptors, the α(1)- and α(2). Each class is subdivided into three subtypes: α(1A), α(1B), α(1D), and α(2A), α(2B), α(2C). Described in this unit are in vitro isolated tissue methods used to study α-adrenoceptor functions and to identify novel ligands for these receptors...
December 2012: Current Protocols in Pharmacology
Trent F Reardon, James A Brock
Reactive oxygen species contribute to regulating the excitability of vascular smooth muscle. This study investigated the actions of the relatively stable reactive oxygen species, H(2)O(2), on nerve-evoked contractions of mouse distal tail artery. H(2)O(2) (10-100 μM) increased nerve-evoked contractions of isometrically mounted segments of tail artery. Endothelium denudation increased nerve-evoked contractions and abolished the facilitatory effect of H(2)O(2). Inhibition of nitric oxide synthase with L-nitroarginine methyl ester (0...
January 5, 2013: European Journal of Pharmacology
Radica M Stepanović-Petrović, Ana M Micov, Maja A Tomić, Nenad D Ugrešić
BACKGROUND: We have recently shown that levetiracetam, administered systemically, exerts an antihyperalgesic effect in a rat inflammatory pain model. In this study, we examined whether levetiracetam has local peripheral antihyperalgesic/anti-edematous effects in the same model of localized inflammation and whether opioidergic, adrenergic, purinergic, 5-HTergic, and GABAergic receptors are involved in its antihyperalgesic action. METHODS: Rats were intraplantarly (IPL) injected with carrageenan...
December 2012: Anesthesia and Analgesia
Özgür Devrim Can, Ümide Demir Özkay, Umut İrfan Üçel
The present study was designed to investigate the putative effect of vitexin, a flavone C-glucoside present in some drugs, medicinal plants and nutraceuticals, on the central nervous system. Vitexin (10-30 mg/kg) did not show significant alterations in the behaviour of mice tested in hole-board, plus-maze or activity cage tests. However, immobility time of the mice significantly reduced by vitexin administrations in both the tail-suspension and modified forced swimming tests. The anti-immobility effect of vitexin in the tail-suspension test was reversed with α-methyl-para-tyrosine methyl ester (AMPT, an inhibitor of catecholamine synthesis, 100mg/kg, i...
January 15, 2013: European Journal of Pharmacology
Christopher M O'Connor, Mona Fiuzat, Peter E Carson, Inder S Anand, Jonathan F Plehn, Stephen S Gottlieb, Marc A Silver, JoAnn Lindenfeld, Alan B Miller, Michel White, Ryan Walsh, Penny Nelson, Allen Medway, Gordon Davis, Alastair D Robertson, J David Port, James Carr, Guinevere A Murphy, Laura C Lazzeroni, William T Abraham, Stephen B Liggett, Michael R Bristow
BACKGROUND: Pharmacogenetics involves complex interactions of gene products affecting pharmacodynamics and pharmacokinetics, but there is little information on the interaction of multiple genetic modifiers of drug response. Bucindolol is a β-blocker/sympatholytic agent whose efficacy is modulated by polymorphisms in the primary target (β(1) adrenergic receptor [AR] Arg389 Gly on cardiac myocytes) and a secondary target modifier (α(2C) AR Ins [wild-type (Wt)] 322-325 deletion [Del] on cardiac adrenergic neurons)...
2012: PloS One
Rafael Barra, Rubén Soto-Moyano, Luis Valladares, Carlos Morgan, Hernán Pérez, Héctor Burgos, Ricardo Olivares, Patricio Sáez-Briones, Claudio Laurido, Alejandro Hernández
Moderate reduction in the protein content of the mother's diet calorically compensated by carbohydrates (the so-called "hidden" prenatal malnutrition) leads to increased neocortical expression of the α(2C)-adrenoceptor subtype, together with decreased cortical release of noradrenaline and impaired long-term potentiation (LTP) and visuospatial memory performance during the rat postnatal life. In order to study whether overexpression of the α(2C)-adrenoceptor subtype is causally related to the decreased indices of neocortical plasticity found in prenatally malnourished rats, we evaluated the effect of intracortical (occipital cortex) administration of an antisense oligodeoxynucleotide (ODN) raised against the α(2C)-adrenoceptor mRNA on the LTP elicited in vivo in the occipital cortex of hidden prenatally malnourished rats...
October 2012: Neurobiology of Learning and Memory
Eduardo Moura, Elisabete Silva, Maria Paula Serrão, Joana Afonso, Carina Esteves Pinto Kozmus, Maria Augusta Vieira-Coelho
Targeted deletion or selective pharmacological inhibition of α(2C)-adrenoceptors in mice results in increased brain tissue levels of dopamine and its precursor l-3,4-dihydroxyphenylalanine (l-DOPA), without significant changes in l-DOPA synthesis. l-DOPA uptake is considered the rate-limiting step in dopamine synthesis in the kidney. Since α(2C)-adrenoceptors may influence the transport of l-DOPA, we investigated the effect of α(2C)-adrenoceptor activation on l-DOPA uptake in a kidney cell line (opossum kidney cells)...
October 2012: American Journal of Physiology. Renal Physiology
István Gacsályi, Katalin Nagy, Katalin Pallagi, György Lévay, László G Hársing, Krisztina Móricz, Szabolcs Kertész, Péter Varga, József Haller, Gábor Gigler, Gábor Szénási, József Barkóczy, Judit Bíró, Michael Spedding, Ferenc A Antoni
Classical antipsychotics, e.g. haloperidol, chlorpromazine, are potent at controlling the positive symptoms of schizophrenia but frequently elicit extrapyramidal motor side-effects. The introduction of atypical antipsychotics such as risperidone, olanzapine and clozapine has obviated this problem, but none of the current drugs seem to improve the cognitive deficits accompanying schizophrenia. Thus there is an unmet need for agents that not only suppress the psychotic symptoms but also ameliorate the impairment of cognition...
January 2013: Neuropharmacology
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