Author
Scott P. Runyon
Other affiliations: RTI International, University of Minnesota
Bio: Scott P. Runyon is an academic researcher from Research Triangle Park. The author has contributed to research in topics: Agonist & Opioid receptor. The author has an hindex of 20, co-authored 67 publications receiving 883 citations. Previous affiliations of Scott P. Runyon include RTI International & University of Minnesota.
Papers published on a yearly basis
Papers
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TL;DR: The data show that it is possible to design multiple immunogens from a small molecule such as nicotine which elicit independent immune responses and could be applicable to other addiction vaccines or small molecule targets as well.
65 citations
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TL;DR: In vitro receptor binding assays showed that antibody-bound oxycodone does not activate mu opioid receptors, which supports further study of OXY-dKLH as a potential treatment for oxy codone abuse and suggests that vaccination might also reduce the severity of oxycod one overdose.
Abstract: Among vaccines aimed at treating substance use disorders, those targeting opioids present several unique medication development challenges. 1) Opioid overdose is a common complication of abuse, so it is desirable for an opioid vaccine to block the toxic as well as the addictive effects of opioids. 2) It is important that an opioid vaccine not interfere with the action of opioid antagonists used to reverse opioid overdose or treat addiction. 3) Some opioids are immunosuppressive and chronic ongoing opioid use could interfere with vaccine immunogenicity. 4) Although antibody-bound oxycodone is unable to enter the brain because of its size, it might still be able to activate peripheral opioid receptors. To assess vaccine impact on opioid toxicity, rats vaccinated with oxycodone conjugated to keyhole limpet hemocyanin subunit dimer (OXY-dKLH) adsorbed to alum or controls vaccinated with dKLH were compared with regard to oxycodone-induced hotplate analgesia and oxycodone-induced respiratory depression and bradycardia. Vaccination shifted the dose-response curves to the right, representing protection, for each of these endpoints. Naloxone was equally effective in both OXY-dKLH and control groups, providing complete and rapid reversal of respiratory depression. The administration of a long-acting naltrexone formulation during vaccination did not impair vaccine immunogenicity in mice. Similarly, serum anti-oxycodone antibody titers were not altered by continuous morphine infusion during vaccination compared to opioid-naive controls. Competitive ELISA assay showed negligible or low affinity of immune antiserum for endogenous opioids or opioid antagonists. In vitro receptor binding assays showed that antibody-bound oxycodone does not activate mu opioid receptors. These data support further study of OXY-dKLH as a potential treatment for oxycodone abuse and suggest that vaccination might also reduce the severity of oxycodone overdose.
64 citations
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TL;DR: It is suggested that studies using SB-334867 (and any other 2-methylbenzoxazole-containing compound) should be performed with great care to avoid the confounding effects of the rapid hydrolytic decomposition of this susceptible structure.
56 citations
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TL;DR: Development of metabolically stable ligands of apelin receptor and their effects in various models over the coming years will hopefully lead to establishment of this receptor as a validated target for cardiovascular indications.
Abstract: Apelin peptides and the apelin receptor represent a relatively new therapeutic axis for the potential treatment of cardiovascular disease. Several reports suggest apelin receptor activation with apelin peptides results in cardioprotection as noted through positive ionotropy, angiogenesis, reduction of mean arterial blood pressure, and apoptosis. Considering the potential therapeutic benefit attainable through modulation of the apelinergic system, research is expanding to develop novel therapies that limit the inherent rapid degradation of endogenous apelin peptides and produce metabolically stable small molecule agonists and antagonists to more rigorously interrogate the apelin receptor system. This review details the structure–activity relationships for chemically modified apelin peptides and recent disclosures of small molecule agonists and antagonists and summarizes the peer reviewed and patented literature. Development of metabolically stable ligands of apelin receptor and their effects in various mod...
41 citations
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TL;DR: Heroin vaccines formulated with either EcoCRM or KLH were equally effective in reducing heroin-induced antinociception and distribution to the brain of heroin and its metabolites in mice and identifies vaccine candidates and vaccine components for further development.
Abstract: Vaccines may offer a new treatment strategy for opioid use disorders and opioid-related overdoses To speed translation, this study evaluates opioid conjugate vaccines containing components suitable for pharmaceutical manufacturing and compares analytical assays for conjugate characterization Three oxycodone-based haptens (OXY) containing either PEGylated or tetraglycine [(Gly)4] linkers were conjugated to a keyhole limpet hemocyanin (KLH) carrier protein via carbodiimide (EDAC) or maleimide chemistry The EDAC-conjugated OXY(Gly)4-KLH was most effective in reducing oxycodone distribution to the brain in mice Vaccine efficacy was T cell-dependent The lead OXY hapten was conjugated to the KLH, tetanus toxoid, diphtheria cross-reactive material (CRM), as well as the E coli-expressed CRM (EcoCRM) and nontoxic tetanus toxin heavy chain fragment C (rTTHc) carrier proteins All vaccines induced early hapten-specific B cell expansion and showed equivalent efficacy against oxycodone in mice However, some hap
36 citations
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28 Jul 2005
TL;DR: PfPMP1)与感染红细胞、树突状组胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作�ly.
Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1(PfPMP1)与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员,通过启动转录不同的var基因变异体为抗原变异提供了分子基础。
18,940 citations
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TL;DR: An overview of Pd-catalyzed N-arylation reactions found in both basic and applied chemical research from 2008 to the present is provided.
Abstract: Pd-catalyzed cross-coupling reactions that form C–N bonds have become useful methods to synthesize anilines and aniline derivatives, an important class of compounds throughout chemical research. A key factor in the widespread adoption of these methods has been the continued development of reliable and versatile catalysts that function under operationally simple, user-friendly conditions. This review provides an overview of Pd-catalyzed N-arylation reactions found in both basic and applied chemical research from 2008 to the present. Selected examples of C–N cross-coupling reactions between nine classes of nitrogen-based coupling partners and (pseudo)aryl halides are described for the synthesis of heterocycles, medicinally relevant compounds, natural products, organic materials, and catalysts.
1,709 citations
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TL;DR: Analysis of site-directed mutagenesis and ligand structure–activity relationships confirms the interactions observed in the crystal structure, thereby providing a molecular explanation for κ-OR subtype selectivity, and essential insights for the design of compounds with new pharmacological properties targeting the human λ-OR.
Abstract: Here we report the crystal structure of the humank-OR in complex with the selective antagonist JDTic, arranged in parallel dimers, at 2.9 Aresolution. The structure reveals important features of the ligand-binding pocket that contribute to the high affinity and subtype selectivity of JDTic for the human k-OR. Modelling of other important k-OR-selective ligands, including the morphinan-derived antagonists norbinaltorphimine and 59-guanidinonaltrindole, and the diterpene agonist salvinorin A analogue RB-64, reveals both common and distinct features for binding these diverse chemotypes. Analysis of site-directed mutagenesis and ligand structure-activity relationships confirms the interactions observed in the crystal structure, thereby providing a molecular explanation for k-OR subtype selectivity, and essential insights for the design of compounds with new pharmacological properties targeting the human k-OR.
785 citations
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TL;DR: The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice.
360 citations
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06 Jul 2013
TL;DR: In this article, the role of apelin in human cardiovascular physiology and pathophysiology was investigated in patients with heart failure and compared with a single oral dose of aspirin or a matched placebo.
Abstract: Background The apelin system is a novel peptidic pathway widely expressed in the
heart and vasculature. In preclinical studies, apelin receptor agonism mediates
nitric oxide-dependent vasodilatation, reduces ventricular preload and afterload and
potently increases myocardial contractility. In preclinical models of heart failure,
expression of the apelin pathway is down regulated but the haemodynamic effects of
apelin receptor agonism are preserved. These changes in expression appear to be
paralleled in patients with chronic heart failure but the cardiovascular actions of
apelin in vivo in man are, to date, unknown. Detailed clinical investigation is
therefore required to establish the role of apelin in human cardiovascular physiology
and pathophysiology and to explore the therapeutic potential of apelin receptor
agonism in patients with heart failure.
Objectives Through a series of in vivo clinical studies: 1) to establish the direct
vascular actions of apelin in the peripheral venous, peripheral arterial and coronary
arterial circulations; 2) to determine the contribution of the endothelium-derived
vasodilators, nitric oxide and prostacyclin, to the vascular actions of apelin; 3) to
establish the effects of apelin on cardiac contractility and systemic haemodynamics;
4) to compare the direct vascular and systemic haemodynamic effects of the fulllength
mature apelin peptide, apelin-36, with a shorter, biologically active carboxyl
(C)-terminal fragment, (Pyr1)apelin-13); and 5) to establish whether the local
vascular and systemic haemodynamic effects of apelin are altered in patients with
chronic heart failure.
Methods The cardiovascular effects of apelin were assessed in 32 healthy
volunteers, 6 patients undergoing elective diagnostic coronary angiography,
18 patients with stable New York Heart Association (NYHA) class II-III chronic
heart failure and 18 age- and sex-matched healthy controls. Dorsal hand vein tone
was assessed by the Aellig hand vein technique during local intravenous
infusions (0.1-3 nmol/min) of apelin-36, (Pyr1)apelin-13, and sodium nitroprusside
(SNP; 0.6 nmol/min). Forearm blood flow was measured by venous occlusion
plethysmography during intrabrachial infusions of apelin-36 and (Pyr1)apelin-13
(0.01-30 nmol/min) and subsequently in the presence or absence of a ‘nitric oxide
clamp’ (nitric oxide synthase inhibitor, L-NG-monomethylarginine (L-NMMA;
8 μmol/min), co-infused with SNP (90-900 ng/min)), or a single oral dose of aspirin
(600 mg) or matched placebo. Coronary blood flow was evaluated by quantitative
coronary angiography (QCA) and Doppler flow wire, and left ventricular pressures
measured by pressure wire before and after intracoronary injection of apelin-36
(20 and 200 nM), 0.9% saline and glyceryl trinitrate (GTN) (100 μg). Blood
pressure, heart rate, cardiac output and peripheral vascular resistance were assessed
by sphygmomanometry and thoracic electrical bioimpedance (TEB) during systemic
intravenous infusion of apelin-36 and (Pyr1)apelin-13 (30-300 nmol/min). Forearm
blood flow and systemic haemodynamic responses to (Pyr1)apelin-13 in patients with
chronic heart failure were then compared with age- and sex-matched healthy
controls.
Results Although SNP caused venodilatation (P<0.0001), apelin-36 and
(Pyr1)apelin-13 had no effect on dorsal hand vein diameter (P=0.2). Both apelin
isoforms caused vasodilatation in forearm resistance vessels (P<0.0001) but the
offset was slower with apelin-36. (Pyr1)apelin-13-mediated vasodilatation was
attenuated by the nitric oxide clamp (P=0.004) but unaffected by aspirin (P=0.7).
Intracoronary bolus of apelin-36 increased coronary blood flow and the maximum
rate of rise in left ventricular pressure, and reduced peak and end-diastolic left
ventricular pressures (all P<0.05). Both (Pyr1)apelin-13 and apelin-36 increased
heart rate and cardiac output whilst reducing peripheral vascular resistance (P<0.01
for all) with no overall effect on blood pressure. Intrabrachial infusions of
(Pyr1)apelin-13, acetylcholine and SNP caused forearm vasodilatation in patients and
controls (P<0.0001 for all). Vasodilatation to acetylcholine (P=0.01) but not apelin
(P=0.3) or SNP (p=0.9) was attenuated in patients with heart failure. Systemic
infusions of (Pyr1)apelin-13 increased cardiac index and lowered mean arterial
pressure and peripheral vascular resistance index in patients and matched controls
(all P<0.01) but increased heart rate only in controls (P<0.01).
Conclusions Although having no apparent effect on venous tone, acute apelin
receptor agonism causes peripheral and coronary vasodilatation and increases cardiac
contractility and output. Local vascular and systemic haemodynamic responses to
apelin are preserved in patients with stable symptomatic chronic heart failure. The
apelin system merits further clinical investigation to determine its role in
cardiovascular homeostasis and represents a novel potential therapeutic target for
patients with heart failure.
243 citations