F. Ivy Carroll

RTI International, Durham, North Carolina, United States

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Publications (484)1602.81 Total impact

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    ABSTRACT: Comprehensive studies that consolidate selective ligands, quantitative comparisons of G-protein versus arrestin2/3 coupling, together with structure-activity relationship models (SAR) for G-protein coupled receptor (GPCR) systems are less commonly employed. Here we examine biased signaling at the nociceptin/orphanin FQ opioid receptor (NOPR), the most recently identified member of the opioid receptor family. Using real-time, live-cell assays we've identified the signaling profiles of several NOPR-selective ligands in upstream GPCR signaling (G-protein and arrestin pathways), in order to determine their relative transduction coefficients and signaling bias. Complementing this analysis, we designed novel ligands based on the NOPR antagonist J-113,397 to explore structure activity relationships. Our study shows that NOPR is capable of biased signaling, and further the NOPR selective ligands MCOPPB and NNC 63-0532 are G-protein biased agonists. Additionally, minor structural modification of J-113,397 can dramatically shift signaling from antagonist to partial agonist activity. We explore these findings with in silico modeling of binding poses. This work is the first to demonstrate functional selectivity and identification of biased ligands at the nociceptin opioid receptor. The American Society for Pharmacology and Experimental Therapeutics.
    Molecular pharmacology 07/2015; DOI:10.1124/mol.115.099150 · 4.12 Impact Factor
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    ABSTRACT: Accumulating evidence indicates that kappa-opioid receptors (KORs) and their endogenous ligand, dynorphin (DYN), can play important roles in regulating the effects of stress. Here, we examined the role of KOR systems in the molecular and behavioral effects of acute (1-day) and chronic (10-day) social defeat stress (SDS) in mice. We found that acute SDS increased DYN mRNA levels within the nucleus accumbens, a key element of brain dopamine (DA) systems. In contrast, chronic SDS produced long-lasting decreases in DYN mRNA levels. We then examined whether disruption of KOR function would affect development of SDS-induced depressive-like behaviors, as measured in the intracranial self-stimulation and social interaction tests. Ablation of KORs from DA transporter-expressing neurons delayed the development of SDS-induced anhedonia in the intracranial self-stimulation test, suggesting increased stress resilience. However, administration of the long-lasting KOR antagonist JDTic (30 mg/kg, intraperitoneally) before the SDS regimen did not affect anhedonia, suggesting that disruption of KOR function outside DA systems can oppose stress resilience. Social avoidance behavior measured after the 10-day SDS regimen was not altered by ablation of KORs in DA transporter-expressing neurons or by JDTic administration before testing. Our findings indicate that KORs expressed in DA systems regulate the effects of acute, but not chronic, social stress.
    Behavioural pharmacology 06/2015; DOI:10.1097/FBP.0000000000000155 · 2.19 Impact Factor
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    ABSTRACT: Severe or prolonged stress can trigger psychiatric illnesses including mood and anxiety disorders. Recent work indicates that pituitary adenylate cyclase-activating polypeptide (PACAP) plays an important role in regulating stress effects. In rodents, exogenous PACAP administration can produce persistent elevations in the acoustic startle response, which may reflect anxiety-like signs including hypervigilance. Here we investigated whether PACAP causes acute or persistent alterations in behaviors that reflect other core features of mood and anxiety disorders (motivation, social interaction, and attention).
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    ABSTRACT: Kappa opioid receptor (KOR) signaling has been implicated in mediating behavioral and biochemical effects associated with drug dependence. The most commonly used KOR antagonists, norbinaltorphimine (norBNI) and (3R)-7-Hydroxy-N{(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl}-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide (JDTic), have provided a wealth of information in this area; however, the delayed onset and long-lasting effects of these antagonists complicate experimental design and interpretation of results, and make them less than ideal for clinical studies. Initial studies with the recently developed KOR antagonist, LY2456302, show that the compound is a short acting, high-affinity, selective KOR antagonist with therapeutic potential for mood disorders and ethanol use in animal models, and is well tolerated in humans. The goal of the current study was to evaluate the effectiveness of LY2456302 in alleviating the nicotine withdrawal syndrome in mice. Mice were chronically treated with nicotine for 14 days and physical and affective nicotine withdrawal signs were measured using a spontaneous nicotine withdrawal model and conditioned place aversion (CPA) following pre-treatment with LY2456302, administered orally. Vehicle treated nicotine withdrawn mice displayed significant anxiety-related behavior, somatic signs, hyperalgesia, and CPA. Similar to previous studies with norBNI and JDTic, LY2456302 alleviated the nicotine withdrawal syndrome, as evidenced by decreased expression of nicotine withdrawal induced anxiety-related behavior, somatic signs, and CPA, and increased hotplate latency in nicotine withdrawn mice following pre-treatment. Given the current results, and with its favorable pharmacokinetic and pharmacodynamic profile, LY2456302 may be a useful therapeutic agent for treatment of multiple aspects of the nicotine withdrawal syndrome. Copyright © 2015. Published by Elsevier Ltd.
    Neuropharmacology 06/2015; 97. DOI:10.1016/j.neuropharm.2015.05.023 · 4.82 Impact Factor
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    ABSTRACT: We hypothesized that an anti-METH mAb could be used in combination with a METH-conjugate vaccine (MCV) to safely improve the overall quality and magnitude of the anti-METH immune response. The benefits would include immediate onset of action (from the mAb), timely increases in the immune responses (from the combined therapy) and duration of antibody response that could last for months (from the MCV). A novel METH-like hapten (METH-SSOO9) was synthesized and then conjugated to immunocyanin monomers of Keyhole limpet hemocyanin (ICKLH) to create the MCV, ICKLH-SOO9. The vaccine, in combination with previously discovered anti-METH mAb7F9, was then tested in rats for safety and potential efficacy. The combination antibody therapy allowed safe achievement of an early high anti-METH antibody response, which persisted throughout the study. Indeed, even after four months the METH vaccine antibodies still had the capacity to significantly reduce METH brain concentrations resulting from a 0.56 mg/kg METH dose.
    Journal of Medicinal Chemistry 05/2015; 58(11). DOI:10.1021/acs.jmedchem.5b00220 · 5.48 Impact Factor
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    ABSTRACT: Pyrido[3,4]homotropane[PHT], a conformationally rigid, high affinity analog of nicotine. (+)-PHT was previously shown to be 266 times more potent than (-)-PHT for inhibition of [3H]epibatidine binding to nAChRs, but had no antinociceptive activity in mouse tail-flick or hot-plate tests and was not a nicotinic antagonist even when administered intrathecally. (-)-PHT had no agonist activity, but was a potent antagonist. Here, electrophysiological studies with rat nAChRs show (+)-PHT to be a low efficacy partial agonist selective for α4β2-nAChRs, relative to α3β4-nAChRs (15-fold) and α7-nAChRs (45-fold). (-)-PHT was an antagonist with selectivity for α3β4, relative to α4β2- (3-fold) and α7- (11-fold) nAChRs. In [3H] DA release studies in mice, (+)-PHT was 10-fold more potent than (-)-PHT at α4β2*-nAChRs and 30-fold more potent at α6β2*-nAChRs. Studies using α5KO mice suggested that much of the activity at α4β2*-nAChRs is mediated by the α4β2α5-nAChR subtype. In Conditioned Place Preference studies, (-)-PHT was more potent than (+)-PHT in blocking nicotine reward. Off-target screens showed (+)- and (-)-PHT to be highly selective for nAChRs. The high potency, full agonism of (+)- and ( )-PHT at α6*-nAChR contrasts with the partial agonism observed for α4*-nAChR, making these ligands intriguing probes for learning more about the pharmacophores for various nAChRs.
    ACS Chemical Neuroscience 04/2015; 6(6). DOI:10.1021/acschemneuro.5b00077 · 4.21 Impact Factor
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    ABSTRACT: Pain-related functional impairment and behavioral depression are diagnostic indicators of pain and targets for its treatment. Nesting is an innate behavior in mice that may be sensitive to pain manipulations and responsive to analgesics. The goal of this study was to develop and validate a procedure for evaluation of pain-related depression of nesting in mice. Male ICR mice were individually housed and tested in their home cages. On test days, a 5cm x 5cm Nestlet™ was subdivided into six pieces, the pieces were evenly distributed on the cage floor, and Nestlet consolidation was quantified during 100-min sessions. Baseline nesting was stable within and between subjects, and nesting was depressed by two commonly used inflammatory pain stimuli [intraperitoneal injection of dilute acid; intraplantar injection of complete Freund's adjuvant (CFA)]. Pain-related depression of nesting was alleviated by drugs from two classes of clinically effective analgesics (the nonsteroidal anti-inflammatory drug ketoprofen and the mu opioid receptor agonist morphine) but not by a drug from a class that has failed to yield effective analgesics (the centrally acting kappa opioid agonist U69,593). Neither ketoprofen nor morphine alleviated depression of nesting by U69,593, suggesting that ketoprofen and morphine effects were selective for pain-related depression of nesting. In contrast to ketoprofen and morphine, the kappa opioid receptor antagonist JDTic blocked depression of nesting by U69,593 but not by acid or CFA. These results support utility of this procedure to assess expression and treatment of pain-related depression in mice.
    Pain 03/2015; DOI:10.1097/j.pain.0000000000000171 · 5.84 Impact Factor
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    ABSTRACT: Preclinical studies with bupropion in rodent models of nicotine dependence have generated equivocal findings with regard to translating the clinical efficacy of the antidepressant as a smoking cessation agent. Given that rats are poor metabolizers of bupropion, the present experiments examined (2S,3S)-hydroxybupropion, the major active metabolite, on the positive reinforcing and aversive stimulus properties of nicotine in rats. In male hooded Lister rats, (2S,3S)-hydroxybupropion (1.0-10.0 mg/kg IP) was tested on intravenous nicotine (0.03 mg/kg/inf) self-administration behaviour for three sessions (n = 8), and in another experiment, the same doses of (2S,3S)-hydroxybupropion were tested in a conditioned taste aversion procedure to assess the aversive stimulus properties of nicotine, a function implicated in the regulation of nicotine intake. (2S,3S)-hydroxybupropion attenuated nicotine intake in a manner similar to that produced by mecamylamine pretreatment (1.0 mg/kg SC). This effect on nicotine-taking was specific since these doses had no effect on responding maintained by sucrose presented orally (200 μl of 5 % w/v). (2S,3S)-hydroxybupropion (1, 3 and 10 mg/kg IP) pretreatment failed to modify the aversive effects produced by a small dose of nicotine (0.1 mg/kg SC). These results demonstrate this metabolite to specifically modify the positive reinforcing effects of nicotine without affecting its aversive motivational effects. We propose that the clinical efficacy of bupropion may be due to a combination of effects produced by bupropion and/or its active metabolite (2S,3S)-hydroxybupropion involving the inhibition of reuptake of dopamine and noradrenaline in reward centres of the brain and the noncompetitive antagonism of neuronal nicotinic receptors.
    Psychopharmacology 03/2015; DOI:10.1007/s00213-015-3908-z · 3.99 Impact Factor
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    ABSTRACT: Animal studies suggest that kappa opioid receptor antagonists (KORAn) potentially could treat a wide variety of addictive and depressive disorders. We assessed the KORAn JDTic for safety, tolerability, and pharmacokinetics in a double-blind, placebo-controlled, randomized trial evaluating single oral doses in healthy adult males. Predose and postdose safety assessments included orthostatic vital signs; 6-lead continuous telemetry monitoring (approximately 16 h predose to 24 h postdose); 12-lead electrocardiograms (ECGs); clinical chemistry, hematology, coagulation, and urinalysis; psychomotor functioning (using the Wayne Saccadic Fixator [WSF]); and adverse events. As a potential indicator of JDTic effects on affect, the POMS Standard™ instrument was administered predose and daily postdose Days 1 through 6. At 1 mg, 2 of 6 JDTic (and 0/6 placebo) subjects experienced a single, asymptomatic event of multiple beats of nonsustained ventricular tachycardia (NSVT). Their events were temporally similar with respect to time postdose (and the postdose timing of an NSVT event in a monkey). These events triggered a study stopping rule. No differences were observed between the placebo and JDTic subjects with respect to clinical chemistry, hematology, coagulation, urinalysis, orthostatic vital signs, WSF, or 12-lead ECG parameters. Plasma JDTic levels were below the lower limit of quantitation (0.1 nM) in all subjects. There were no significant differences in POMS scores between the placebo and JDTic groups. Although the evidence is circumstantial, it suggests NSVT is a potential JDTic toxicity in humans. Given the therapeutic potential of KORAn, further investigation is needed to determine if a significant JDTic human cardiac effect indeed exists, and if so whether it is specific to JDTic or represents a KORAn class effect.Neuropsychopharmacology accepted article preview online, 23 January 2015. doi:10.1038/npp.2015.27.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 01/2015; DOI:10.1038/npp.2015.27 · 7.83 Impact Factor
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    ABSTRACT: Control of small molecule hapten epitope densities on antigenic carrier proteins is essential for development and testing of optimal conditions for vaccines. Yet, accurate determination of epitope density can be extremely difficult to accomplish, especially with the use of small haptens, large molecular weight carrier proteins, and limited amounts of protein. Here we report a simple radiometric method that uses (14)C-labeled cystine to measure hapten epitope densities during sulfhydryl conjugation of haptens to maleimide activated carrier proteins. The method was developed using a (+)-methamphetamine (METH)-like hapten with a sulfhydryl terminus, and two prototype maleimide activated carrier proteins, bovine serum albumin (BSA) and immunocyanin monomers of keyhole limpet hemocyanin. The method was validated by immunochemical analysis of the hapten-BSA conjugates, and least-squares linear regression analysis of epitope density values determined by the new radiometric method versus values determined by matrix-assisted laser desorption/ionization mass spectrometry. Results showed that radiometric epitope density values correlated extremely well with the mass spectrometrically derived values (r(2) = 0.98, y = 0.98x + 0.91). This convenient and simple method could be useful during several stages of vaccine development including the optimization and monitoring of conditions for hapten-protein conjugations, and choosing the most effective epitope densities for conjugate vaccines.
    Bioconjugate Chemistry 11/2014; 25(12). DOI:10.1021/bc500456z · 4.82 Impact Factor
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    ABSTRACT: JDTic analogues 4-15 which have the hydroxyl groups replaced with other groups were synthesized and their in vitro efficacy at the mu, delta, and kappa opioid receptors determined and compared to JDTic using [S-35]GTP gamma S assays. Compounds 4, 5, 6, 13, 14, and 15 had K-e = 0.024, 0.01, 0.039, 0.02, 0.11, and 0.041 nM compared to the K-e = 0.02 nM for JDTic at the kappa receptor and were highly selective for the kappa receptor relative to the mu and delta opioid receptors. Unexpectedly, replacement of the 3-hydroxyl substituent of the 4-(3-hydroxyphenyl) group of JDTic with a H, F, or Cl substituent leads to potent and selective KOR antagonists. In vitro studies to determine various ADME properties combined with calculated TPSA, clogP, and logBB values suggests that the potent and selective kappa opioid receptors 4, 5, 13, and 14 deserve consideration for further development toward potential drugs for CNS disorders.
    Journal of Medicinal Chemistry 08/2014; 57(17). DOI:10.1021/jm5008177 · 5.48 Impact Factor
  • Drug and Alcohol Dependence 07/2014; 140:e157. DOI:10.1016/j.drugalcdep.2014.02.444 · 3.28 Impact Factor
  • Drug and Alcohol Dependence 07/2014; 140:e92-e93. DOI:10.1016/j.drugalcdep.2014.02.269 · 3.28 Impact Factor
  • Drug and Alcohol Dependence 07/2014; 140:e108. DOI:10.1016/j.drugalcdep.2014.02.312 · 3.28 Impact Factor
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    ABSTRACT: A long-acting, thermostable bacterial cocaine esterase (CocE) has been identified that rapidly degrades cocaine with a KM of 1.33+0.085 μM. In vivo evaluation of CocE has shown protection against convulsant and lethal effects of cocaine in rodents, confirming the therapeutic potential of CocE against cocaine overdose. However, the current study is the first to evaluate the effects of CocE on cocaine brain levels. Positron emission tomogrpahy neuroimaging of [(11)C]cocaine was used to evaluate the time course of cocaine elimination from brain in the presence and absence of CocE in nonhuman primates. Systemic administration of CocE eliminated cocaine from the rhesus-monkey brain approximately three times faster than control conditions via peripheral actions through attenuating the input function from blood plasma. The efficiency of this process is sufficient to alleviate or prevent adverse central nervous system effects induced by cocaine. Although the present study used tracer doses of cocaine to access brain clearance, these findings further support the development of CocE for the treatment of acute cocaine toxicity.
    Translational Psychiatry 07/2014; 4(7):e407. DOI:10.1038/tp.2014.48 · 4.36 Impact Factor
  • F. Ivy Carroll, Roland E. Dolle
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    ABSTRACT: N-Substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines are a class of pure opioid receptor antagonists with a novel pharmacophore. This opioid receptor antagonist pharmacophore was used as a lead structure to design and develop several interesting and useful opioid receptor antagonists. In this review we describe: 1) early SAR studies that led to the discovery of LY255582 and analogues that are nonselective opioid receptor antagonists developed for the treatment of obesity; 2) the discovery and commercialization of LY246736 (alvimopan; ENTEREG®), a peripherally selective opioid receptor antagonist that accelerates the time to upper and lower GI recovery following surgeries that include partial bowel resection with primary anastomosis; and 3) the discovery and development of the potent and selective κ opioid receptor antagonist JDTic and analogues as potential pharmacotherapies for treating depression, anxiety, and substance abuse (nicotine, alcohol, and cocaine). In addition, the use of JDTic for obtaining the X-ray structure of the human κ opioid receptor is discussed.
    ChemMedChem 06/2014; 45(43). DOI:10.1002/cmdc.201402142 · 3.05 Impact Factor
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    ABSTRACT: The opioid receptor family is made up of four structurally homologous but functionally distinct receptors, the mu (MOP), delta (DOP), kappa (KOP), and nociceptin (NOP). Given that most opioid agonists are selective but not specific, a broad spectrum of behaviors due to activation of different opioid receptors is expected. In this study, we examine whether other opioid receptor systems influence KOP-mediated antinociception.
    British Journal of Pharmacology 06/2014; DOI:10.1111/bph.12810 · 4.99 Impact Factor
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    ABSTRACT: Rationale: Receptor mechanisms underlying the in vivo effects of nicotinic acetylcholine receptor (nAChR) drugs need to be determined to better understand possible differences in therapeutic potential. Objective: This study compared the effects of agonists that are reported either to differ in intrinsic activity (i.e., efficacy) at α4β2 nAChR in vitro or to have in vivo effects consistent with differences in efficacy. The drugs included nicotine, varenicline, cytisine, epibatidine, and three novel epibatidine derivatives: 2′-fluoro-3′-(4-nitrophenyl)deschloroepibatidine (RTI-7527-102), 2′-fluorodeschloroepibatidine (RTI-7527-36), and 3′-(3″-dimethylaminophenyl)-epibatidine (RTI-7527-76). Methods: Mice discriminated nicotine base (1 mg/kg base) from saline; other mice were used to measure rectal temperature. Results: In the nicotine discrimination assay, the maximum percentage of nicotine-appropriate responding varied: 92 % for nicotine, 84 % for epibatidine, 77 % for RTI-7527-36, and 71 % for varenicline and significantly less for RTI-7527-76 (58 %), RTI-7527-102 (46 %), and cytisine (33 %). Each drug markedly decreased rectal temperature by as much as 12ºC. The rank-order potency in the discrimination and hypothermia assays was epibatidine>RTI-7527-36>nicotine>RTI-7527- 102>varenicline=cytisine=RTI-7527-76. The nAChR antagonist mecamylamine (3.2 mg/kg) antagonized the discriminative stimulus effects of epibatidine and RTI-7527-102, as well as the hypothermic effects of every drug except cytisine. The β2-subunit selective nAChR antagonist dihydro-β- erythroidine (DHβE; up to 10 mg/kg) antagonized hypothermic effects but less effectively so than mecamylamine. Conclusions: The marked hypothermic effects of all drugs except cytisine are due in part to agonism at nAChR containing β2- subunits. Differential substitution for the nicotine discriminative stimulus is consistent with differences in α4β2 nAChR efficacy; however, collectively the current results suggest that multiple nAChR receptor subtypes mediate the effects of the agonists.
    Psychopharmacology 05/2014; DOI:10.1007/s00213-014-3589-z · 3.99 Impact Factor
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    ABSTRACT: N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines (2a-b) are opioid receptor antagonists where the antagonist properties are not due to the type of N-substituent. In order to gain a better understanding of the contribution that the 3- and 4-methyl groups make to the pure antagonist properties of 2a-b, we synthesized analogues of 2a-b which lacked the 4-methyl (5a-b), 3-methyl (6a-b) and both the 3- and 4-methyl group (7a-b) and compared their opioid receptor properties. We found that (1) all N-methyl and N-phenylpropyl substituted compounds were non-selective opioid antagonists (2) all N-phenylpropyl analogues were more potent than their N-methyl counterparts and (3) compounds 2a-b which have both a 3- and 4-methyl substituent, were more potent antagonists than analogs 5a-b, 6a-b and 7a-b. We also found that the removal of 3-methyl substituent of N-methyl and N-phenylpropyl 3-methyl-4-(3-hydroxyphenyl)piperazines (8a-b) gives (4a-b) which are opioid antagonists.
    Journal of Medicinal Chemistry 03/2014; 57(7). DOI:10.1021/jm500184j · 5.48 Impact Factor
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    ABSTRACT: 2'-Fluoro-3-(substituted pyridine)epibatidine analogues 7a-e and 8a-e were synthesized and their in vitro and in vivo nAChR properties determined. 2'-Fluoro-3'-(4"-pyridinyl)deschloroepibatidine (7a) and 2'-fluoro-3'-(3"-pyridinyl)deschloroepibatidine (8a) were synthesized as bioisosteres of the 4'-nitrophenyl lead compounds 5a and 5g. Comparison of the in vitro nAChR properties of 7a and 8a to those of 5a and 5g showed that 7a and 8a had in vitro nAChR properties similar to those of 5a and 5g, but both were more selective for the α4β2-nAChR relative to the α3β4- and α7-nAChRs than 5a and 5g. The in vivo nAChR properties in mice of 7a were similar to those of 5a. In contrast, 8a was an agonist in all four mouse acute tests, whereas 5g was active only in a spontaneous activity test. In addition, 5g was a nicotine antagonist in both the tail-flick and hot-plate tests, whereas as 8a was only an antagonist in the tail-flick test.
    Journal of Medicinal Chemistry 01/2014; 57(3). DOI:10.1021/jm401602p · 5.48 Impact Factor

Publication Stats

10k Citations
1,602.81 Total Impact Points

Institutions

  • 2007–2015
    • RTI International
      Durham, North Carolina, United States
  • 1999–2014
    • Emory University
      • Department of Radiology and Imaging Sciences
      Atlanta, Georgia, United States
  • 1974–2014
    • Research Triangle Park Laboratories, Inc.
      Raleigh, North Carolina, United States
  • 2013
    • McLean Hospital
      Cambridge, Massachusetts, United States
  • 1992–2010
    • Virginia Commonwealth University
      • Department of Pharmacology and Toxicology
      Richmond, Virginia, United States
    • Johns Hopkins Medicine
      • Division of Nuclear Medicine
      Baltimore, MD, United States
    • University of Georgia
      • Department of Chemistry
      Атина, Georgia, United States
  • 1998–2004
    • Eli Lilly
      • Lilly Research Laboratories
      Indianapolis, Indiana, United States
  • 1997
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 1993–1996
    • National Institute on Drug Abuse
      Роквилл, Maryland, United States
  • 1995
    • National Institute on Drug Abuse
      • Division of Intramural Research (IRP)
      베서스다, Maryland, United States
  • 1991–1995
    • University of Baltimore
      Baltimore, Maryland, United States
    • Duke University Medical Center
      • Department of Medicine
      Durham, North Carolina, United States
  • 1994
    • University of North Carolina at Chapel Hill
      • Department of Psychiatry
      North Carolina, United States
  • 1991–1992
    • Duke Raleigh Hospital
      Raleigh, North Carolina, United States
  • 1987
    • North Carolina State University
      • Department of Textile Engineering, Chemistry and Science
      Raleigh, North Carolina, United States
  • 1986–1987
    • Walter Reed Army Institute of Research
      Silver Spring, Maryland, United States