F. Ivy Carroll

RTI International, Durham, North Carolina, United States

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Publications (388)1432.85 Total impact

  • Neuropharmacology 11/2015; DOI:10.1016/j.neuropharm.2015.11.024 · 5.11 Impact Factor
  • Kelen Freitas · F Ivy Carroll · S Stevens Negus ·
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    ABSTRACT: Intracranial self-stimulation (ICSS) is one type of preclinical procedure for research on pharmacological mechanisms that mediate abuse potential of drugs acting at various targets, including nicotinic acetylcholine receptors (nAChRs). This study compared effects of the nonselective nAChR agonist nicotine (0.032-1.0 mg/kg) and the α4β2-selective nAChR agonist 5-I-A-85380 (0.01-1.0 mg/kg) on ICSS in male Sprague-Dawley rats. Rats were implanted with electrodes targeting the medial forebrain bundle at the level of the lateral hypothalamus and trained to respond under a fixed-ratio 1 schedule for a range of brain stimulation frequencies (158-56 Hz). A broad range of 5-I-A-85380 doses produced an abuse-related increase (or "facilitation") of low ICSS rates maintained by low brain-stimulation frequencies, and this effect was blocked by both the nonselective nAChR antagonist mecamylamine and the selective α4β2 antagonist dihyrdo-β-erythroidine (DHβE). Conversely, nicotine produced weaker ICSS facilitation across a narrower range of doses, and higher nicotine doses decreased high rates of ICSS maintained by high brain-stimulation frequencies. The rate-decreasing effects of a high nicotine dose were blocked by mecamylamine but not DHβE. Chronic nicotine treatment produced selective tolerance to rate-decreasing effects of nicotine but did not alter ICSS rate-increasing effects of nicotine. These results suggest that α4β2 receptors are sufficient to mediate abuse-related rate-increasing effects of nAChR agonists in this ICSS procedure. Conversely, nicotine effects at non-α4β2 nAChRs appear to oppose and limit abuse-related effects mediated by α4β2 receptors, although tolerance can develop to these non-α4β2 effects. Selective α4β2 agonists may have higher abuse potential than nicotine. (PsycINFO Database Record
    Experimental and Clinical Psychopharmacology 10/2015; DOI:10.1037/pha0000055 · 2.71 Impact Factor
  • M Laudenbach · A.M. Tucker · S.P. Runyon · F.I. Carroll · M Pravetoni ·
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    ABSTRACT: Therapeutic vaccines for nicotine addiction show pre-clinical efficacy. Yet, clinical evaluation of the first-generation nicotine vaccines did not meet expectations because only a subset of immunized subjects achieved effective serum antibody levels. Recent studies suggest that vaccine design affects B cell activation, and that the frequency of the hapten-specific B cell subsets contributes to vaccine efficacy against drugs of abuse. To extend this hypothesis to nicotine immunogens, we synthesized a novel hapten containing a carboxymethylureido group at the 2-position of the nicotine structure (2CMUNic) and compared its efficacy to the previously characterized 6CMUNic hapten. Haptens were conjugated to the keyhole limpet hemocyanin (KLH) carrier protein, and evaluated for efficacy against nicotine in mice using the clinically approved alum adjuvant. Using a novel fluorescent antigen-based magnetic enrichment strategy paired with multicolor flow cytometry analysis, polyclonal hapten-specific B cell subsets were measured in mice immunized with either 6CMUNic-KLH or 2CMUNic-KLH. The 6CMUNic-KLH showed significantly greater efficacy than 2CMUNic-KLH on nicotine distribution to serum and to the brain. The 6CMUNic-KLH elicited higher anti-nicotine serum antibody titers, and a greater frequency of hapten-specific B cells than 2CMUNic-KLH. Within the splenic polyclonal B cell population, a higher number of hapten-specific IgM(high) and germinal centre B cells predicted greater vaccine efficacy against nicotine distribution. These early pre-clinical findings suggest that hapten structure affects activation of B cells, and that variations in the frequency of early-activated hapten-specific B cell subsets underlie individual differences in vaccine efficacy.
    Vaccine 09/2015; 33(46). DOI:10.1016/j.vaccine.2015.09.015 · 3.62 Impact Factor
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    ABSTRACT: The nociceptin/orphanin FQ opioid peptide (NOP) receptor is a widely expressed GPCR involved in the modulation of pain, anxiety, and motor behaviors. Dissecting the functional properties of this receptor is limited by the lack of systemically active ligands that are brain permeant. The small molecule NOP receptor- selective, full agonist 8-(1S,3αS)-(2,3,3a,4,5,6-hexahydro-1H-phenalin-1-yl)-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one (Ro 64-6198) hydrochloride is an orally active ligand, but its difficult and cost-prohibitive synthesis limits its widespread use and availability for animal studies. Here, we detail a more efficient and convenient method of synthesis, and use both in vitro and in vivo pharmacological assays to fully characterize this ligand. Specifically, we characterize the pharmacodynamics of Ro 64-6198 in cAMP and G-protein coupling in vitro and examine, for the first time, the effects of nociceptin/orphanin FQ and Ro 64-6198 in arrestin recruitment assays. Further, we examine the effects of Ro 64-6198 on analgesia, anxiety, and locomotor responses in vivo. This new synthesis and pharmacological characterization provide additional insights into the useful, systemically active, NOP receptor agonist Ro 64-6198.
    ACS Chemical Neuroscience 09/2015; DOI:10.1021/acschemneuro.5b00208 · 4.36 Impact Factor
  • Kelen C Freitas · S Stevens Negus · F Ivy Carroll ·
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    ABSTRACT: Agonists at nicotinic acetylcholine receptors (nAChRs) constitute one drug class being evaluated as candidate analgesics. Previous preclinical studies have implicated α4β2 and α7 nAChRs as potential mediators of the antinociceptive effects of nicotine and other nAChR agonists; however, these studies have relied exclusively on measures of pain-stimulated behavior, which can be defined as behaviors that increase in frequency, rate or intensity after presentation of a noxious stimulus. Pain is also associated with depression of many behaviors, and drug effects can differ in assays of pain-stimulated vs. pain-depressed behavior. Accordingly, this study compared effects of nicotine, the selective α4/6β2 agonist 5-I-A-85380, and the selective α7 agonist PNU 282987 in assays of pain-stimulated and pain-depressed behavior in male Sprague-Dawley rats. Intraperitoneal injection of dilute lactic acid served as an acute noxious stimulus to either stimulate a stretching response or depress operant responding maintained by electrical brain stimulation in an intracranial self-stimulation (ICSS) procedure. Nicotine produced a dose-dependent, time-dependent and mecamylamine-reversible blockade of both acid-stimulated stretching and acid-induced depression of ICSS. 5-I-A-85380 also blocked both acid-stimulated stretching and acid-induced depression of ICSS, whereas PNU 282987 produced no effect in either procedure. Both nicotine and 5-I-A-85380 -were ≥10-fold more potent to block acid-induced depression of ICSS than to block acid-induced stimulation of stretching. These results suggest that stimulation of α4β2 and/or α6β2 nAChRs may be especially effective to alleviate signs of pain-related behavioral depression in rats; however, nonselective behavioral effects may contribute to apparent antinociception.
    Journal of Pharmacology and Experimental Therapeutics 09/2015; 355(2). DOI:10.1124/jpet.115.226803 · 3.97 Impact Factor
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    ABSTRACT: The design and discovery of JDTic as a potent and selective kappa opioid receptor antagonist used the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine pharmacophore as the lead structure. In order to determine if the 3-methyl or 4-methyl groups were necessary in JDTic and JDTic analogs for antagonistic activity, compounds 4a-c, and 4d-f which have either the 3-methyl or both the 3- and 4-methyl groups removed, respectively, from JDTic and analogs were synthesized and evaluated for their in vitro opioid receptor antagonist activities using a [(35)S]GTPγS binding assay. Other ADME properties were also assessed for selected compounds. These studies demonstrated that neither the 3-methyl or 3,4-dimethyl groups present in JDTic and analogs are required to produce potent and selective κ opioid receptor antagonists. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Bioorganic & medicinal chemistry 08/2015; 23(19). DOI:10.1016/j.bmc.2015.08.025 · 2.79 Impact Factor
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    ABSTRACT: Over the last several years we have synthesized and studied the in vitro and in vivo nAChR pharmacological properties of epibatidine (4) analogs. In this study we report the synthesis, nAChR in vitro and in vivo pharmacological properties of 3'-(substituted pyridinyl)-deschloroepibatidine analogs (5a-e and 6a-e). All of the analogs had high binding affinity for α4β2(∗)-nAChRs. Several of the analogs were potent antagonists of α4β2-nAChRs in in vitro efficacy tests and were potent antagonists of nicotine-induced antinociception in the mouse tail-flick test. Compound 6b had a Ki=0.13nM in the binding assay, 25- and 46-fold selectivity for the α4β2(∗)-nAChR relative to the α3β4- and α7-nAChR, respectively, in the in vitro efficacy test and an AD50=0.13μg/kg in the tail-flick test. Combined with favorable calculated physiochemical properties compared to varenicline, our findings suggest that 6b should be considered for development as a potential pharmacotherapy for treating nicotine addiction and other CNS disorders. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Bioorganic & medicinal chemistry 07/2015; 23(17). DOI:10.1016/j.bmc.2015.07.021 · 2.79 Impact Factor
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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; 88(3). DOI:10.1124/mol.115.099150 · 4.13 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; 26(7 Spec No). DOI:10.1097/FBP.0000000000000155 · 2.15 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. 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). Using male Sprague-Dawley rats, we examined if PACAP (.25-1.0 µg, intracerebroventricular infusion) affects motivation as measured in the intracranial self-stimulation test. We also examined if PACAP alters interactions with a conspecific in the social interaction test. Finally, we examined if PACAP affects performance in the 5-choice serial reaction time task, which quantifies attention and error processing. Dose-dependent disruptions in motivation, social interaction, and attention were produced by PACAP, as reflected by increases in reward thresholds, decreases in social behaviors, and decreases in correct responses and alterations in posterror accuracy. Behavior normalized quickly in the intracranial self-stimulation and 5-choice serial reaction time task tests but remained dysregulated in the social interaction test. Effects on attention were attenuated by the corticotropin-releasing factor receptor-1 antagonist antalarmin but not the κ opioid receptor antagonist JDTic. Our findings suggest that PACAP affects numerous domains often dysregulated in mood and anxiety disorders, but that individual signs depend on brain substrates that are at least partially independent. This work may help to devise therapeutics that mitigate specific signs of these disorders. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
    Biological psychiatry 06/2015; DOI:10.1016/j.biopsych.2015.06.013 · 10.26 Impact Factor
  • Kia J. Jackson · Asti Jackson · F. Ivy Carroll · M. Imad Damaj ·
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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 · 5.11 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 · 5.45 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 · 4.36 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; 156(6). DOI:10.1097/j.pain.0000000000000171 · 5.21 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; 40(9). DOI:10.1038/npp.2015.27 · 7.05 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 · 4.51 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 · 5.45 Impact Factor

  • Drug and Alcohol Dependence 07/2014; 140:e157. DOI:10.1016/j.drugalcdep.2014.02.444 · 3.42 Impact Factor
  • Stephen Kohut · P.A. Fivel · F.I. Carroll · Nancy K. Mello ·

    Drug and Alcohol Dependence 07/2014; 140:e108. DOI:10.1016/j.drugalcdep.2014.02.312 · 3.42 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 · 2.97 Impact Factor

Publication Stats

10k Citations
1,432.85 Total Impact Points


  • 2009-2015
    • RTI International
      Durham, North Carolina, United States
  • 1968-2015
    • Research Triangle Park Laboratories, Inc.
      Raleigh, North Carolina, United States
  • 2013
    • McLean Hospital
      Cambridge, Massachusetts, United States
  • 2008-2010
    • Virginia Commonwealth University
      • Department of Pharmacology and Toxicology
      Richmond, Virginia, United States
  • 2007
    • Emory University
      • Department of Radiology
      Atlanta, Georgia, United States
  • 2006
    • Johns Hopkins Bloomberg School of Public Health
      • Department of Environmental Health Sciences
      Baltimore, Maryland, United States
  • 2001
    • Eli Lilly
      • Lilly Research Laboratories
      Indianapolis, Indiana, United States
  • 1996
    • National Institute on Drug Abuse
      Роквилл, Maryland, United States
  • 1991-1995
    • University of Baltimore
      Baltimore, Maryland, United States
  • 1994
    • University of North Carolina at Chapel Hill
      • Department of Psychiatry
      North Carolina, United States
  • 1992
    • Duke Raleigh Hospital
      Raleigh, North Carolina, United States
    • University of Georgia
      • Department of Chemistry
      Атина, Georgia, United States
  • 1987
    • Walter Reed Army Institute of Research
      Silver Spring, Maryland, United States
    • North Carolina State University
      • Department of Textile Engineering, Chemistry and Science
      Raleigh, North Carolina, United States