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F. Ivy Carroll

Bio: F. Ivy Carroll is an academic researcher from Research Triangle Park. The author has contributed to research in topics: Nicotinic agonist & Dopamine transporter. The author has an hindex of 52, co-authored 301 publications receiving 10411 citations. Previous affiliations of F. Ivy Carroll include RTI International & St. Joseph's Hospital and Medical Center.


Papers
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Journal ArticleDOI
01 Jan 2001-Synapse
TL;DR: In vitro methods determined the neurochemical mechanism of action of amphetamine, 3,4‐methylenedioxymethamphetamine (MDMA), (+)‐methamphetamine, ephedrine, phentermine, and aminorex, and demonstrated that the most potent effect of these stimulants is to release NE.
Abstract: A large body of evidence supports the hypothesis that mesolimbic dopamine (DA) mediates, in animal models, the reinforcing effects of central nervous system stimulants such as cocaine and amphetamine. The role DA plays in mediating amphetamine-type subjective effects of stimulants in humans remains to be established. Both amphetamine and cocaine increase norepinephrine (NE) via stimulation of release and inhibition of reuptake, respectively. If increases in NE mediate amphetamine-type subjective effects of stimulants in humans, then one would predict that stimulant medications that produce amphetamine-type subjective effects in humans should share the ability to increase NE. To test this hypothesis, we determined, using in vitro methods, the neurochemical mechanism of action of amphetamine, 3,4-methylenedioxymethamphetamine (MDMA), (+)-methamphetamine, ephedrine, phentermine, and aminorex. As expected, their rank order of potency for DA release was similar to their rank order of potency in published self-administration studies. Interestingly, the results demonstrated that the most potent effect of these stimulants is to release NE. Importantly, the oral dose of these stimulants, which produce amphetamine-type subjective effects in humans, correlated with the their potency in releasing NE, not DA, and did not decrease plasma prolactin, an effect mediated by DA release. These results suggest that NE may contribute to the amphetamine-type subjective effects of stimulants in humans.

884 citations

Journal ArticleDOI
17 May 2012-Nature
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

Journal ArticleDOI
TL;DR: It is remarkable that varenicline is a potent, full agonist at α7 receptors with an EC50 of 18 ± 6 μM and an efficacy of 93 ± 7% (relative to acetylcholine).
Abstract: Varenicline, a new nicotinic ligand based on the structure of cytisine, has recently been approved by the U.S. Food and Drug Administration for use as a smoking cessation aid. Varenicline has been shown to be a partial agonist of α4β2 receptors, and in equilibrium binding assays, it is highly selective for the α4β2 receptor. In this study, we have examined the functional activity of varenicline at a variety of rat neuronal nicotinic receptors expressed in Xenopus laevis oocytes and assayed under two-electrode voltage clamp. We also find that varenicline is a potent, partial agonist at α4β2 receptors, with an EC50 of 2.3 ± 0.3 μM and an efficacy (relative to acetylcholine) of 13.4 ± 0.4%. Varenicline has lower potency and higher efficacy at α3β4 receptors, with an EC50 of 55 ± 8 μM and an efficacy of 75 ± 6%. Varenicline also seems to be a weak partial agonist at α3β2 and α6-containing receptors, with an efficacy

528 citations

Journal ArticleDOI
TL;DR: Depression and stress are two states during cocaine abstinence which users identify as precipitating relapse, and JDTic may have properties which attenuate both.
Abstract: Stress and depression have been linked to relapse of cocaine abuse Antagonism of the kappa opioid receptor (KOR) has been reported to attenuate some effects of stressors, and antagonism of the KOR has been reported to have antidepressant-like properties Our objective was to determine whether the potent and selective KOR antagonist, (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), can reduce the ability of a stressor (intermittent footshock) to reinstate cocaine-seeking behavior and to have antidepressant-like effects in the forced swim test (FST) Male Long–Evans hooded rats were trained to lever-press, reinforced with 05 mg/kg iv infusion of cocaine, according to fixed ratio 1 reinforcement schedules during daily 2-h experimental sessions After performance had stabilized, lever pressing was extinguished for 12 consecutive sessions, and doses of 0 (vehicle), 3, 10, and 30 mg/kg JDTic were then administered ig to separate groups of 12 rats Twenty four hours later, the rats were given 15 min of intermittent footshock (087 mA, 05 s activation time, average interactivation interval of 40 s) or a 17-mg/kg ip administration of cocaine prime followed by a 2-h reinstatement test session JDTic was also evaluated for its ability to block diuresis induced by the KOR agonist, U50,488H (10 mg/kg, sc), during 5-h test sessions beginning 1 h after footshock reinstatement tests to verify its KOR antagonist activity In the FST, male Sprague–Dawley rats were treated with either nor-binaltorphimine (nor-BNI) or JDTic (both at 03, 1, 3, or 10 mg/kg, injected sc 23 h before), or desipramine (56, 10, or 17 mg/kg, injected ip 23, 5, and 1 h before) and placed in a cylinder of water, during which the predominance of immobility, swimming, and climbing were scored during 5-s intervals for 5 min The 10- and 30-mg/kg doses of JDTic significantly reduced footshock-induced reinstatement of responding previously reinforced by cocaine and significantly attenuated U50,488H-induced diuresis In contrast, JDTic did not affect cocaine-prime-induced reinstatement Both nor-BNI and JDTic decreased immobility and increased swimming time in the FST, similar to the antidepressant desipramine Depression and stress are two states during cocaine abstinence which users identify as precipitating relapse, and JDTic may have properties which attenuate both

295 citations

Journal ArticleDOI
11 Jan 2018-Cell
TL;DR: A crystal structure of human KOP in complex with the potent epoxymorphinan opioid agonist MP1104 and an active-state-stabilizing nanobody is provided and key residues that propagate larger-scale structural rearrangements and transducer binding are illuminated that elucidate the structural determinants of KOP pharmacology, function, and biased signaling.

277 citations


Cited by
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Journal ArticleDOI
06 Jun 1986-JAMA
TL;DR: The editors have done a masterful job of weaving together the biologic, the behavioral, and the clinical sciences into a single tapestry in which everyone from the molecular biologist to the practicing psychiatrist can find and appreciate his or her own research.
Abstract: I have developed "tennis elbow" from lugging this book around the past four weeks, but it is worth the pain, the effort, and the aspirin. It is also worth the (relatively speaking) bargain price. Including appendixes, this book contains 894 pages of text. The entire panorama of the neural sciences is surveyed and examined, and it is comprehensive in its scope, from genomes to social behaviors. The editors explicitly state that the book is designed as "an introductory text for students of biology, behavior, and medicine," but it is hard to imagine any audience, interested in any fragment of neuroscience at any level of sophistication, that would not enjoy this book. The editors have done a masterful job of weaving together the biologic, the behavioral, and the clinical sciences into a single tapestry in which everyone from the molecular biologist to the practicing psychiatrist can find and appreciate his or

7,563 citations

Journal ArticleDOI
TL;DR: Privileged substructures are believed to achieve this through the mimicry of common protein surface elements that are responsible for binding, such as β- and gamma;-turns.
Abstract: Privileged substructures are of potentially great importance in medicinal chemistry. These scaffolds are characterized by their ability to promiscuously bind to a multitude of receptors through a variety of favorable characteristics. This may include presentation of their substituents in a spatially defined manner and perhaps also the ability to directly bind to the receptor itself, as well as exhibiting promising characteristics to aid bioavailability of the overall molecule. It is believed that some privileged substructures achieve this through the mimicry of common protein surface elements that are responsible for binding, such as β- and gamma;-turns. As a result, these structures represent a promising means by which new lead compounds may be identified.

2,620 citations

Journal ArticleDOI
TL;DR: This Review gives a brief summary of conventional fluorination reactions, including those reactions that introduce fluorinated functional groups, and focuses on modern developments in the field.
Abstract: Over the past decade, the most significant, conceptual advances in the field of fluorination were enabled most prominently by organo- and transition-metal catalysis. The most challenging transformation remains the formation of the parent C-F bond, primarily as a consequence of the high hydration energy of fluoride, strong metal-fluorine bonds, and highly polarized bonds to fluorine. Most fluorination reactions still lack generality, predictability, and cost-efficiency. Despite all current limitations, modern fluorination methods have made fluorinated molecules more readily available than ever before and have begun to have an impact on research areas that do not require large amounts of material, such as drug discovery and positron emission tomography. This Review gives a brief summary of conventional fluorination reactions, including those reactions that introduce fluorinated functional groups, and focuses on modern developments in the field.

1,897 citations

Journal ArticleDOI
TL;DR: This critical review is focussed on the most recently developed coupling reagents with particular attention paid to the pros and cons of the plethora of "acronym" based reagents.
Abstract: Amide bond formation is a fundamentally important reaction in organic synthesis, and is typically mediated by one of a myriad of so-called coupling reagents. This critical review is focussed on the most recently developed coupling reagents with particular attention paid to the pros and cons of the plethora of “acronym” based reagents. It aims to demystify the process allowing the chemist to make a sensible and educated choice when carrying out an amide coupling reaction (179 references).

1,686 citations

Journal ArticleDOI
TL;DR: This review summarizes current data indicating the extent to which cannabinoid receptor ligands undergo orthosteric or allosteric interactions with non- CB1, non-CB2 established GPCRs, deorphanized receptors such as GPR55, ligand-gated ion channels, transient receptor potential (TRP) channels, and other ion channels or peroxisome proliferator-activated nuclear receptors.
Abstract: There are at least two types of cannabinoid receptors (CB1 and CB2). Ligands activating these G protein-coupled receptors (GPCRs) include the phytocannabinoid Δ9-tetrahydrocannabinol, numerous synthetic compounds, and endogenous compounds known as endocannabinoids. Cannabinoid receptor antagonists have also been developed. Some of these ligands activate or block one type of cannabinoid receptor more potently than the other type. This review summarizes current data indicating the extent to which cannabinoid receptor ligands undergo orthosteric or allosteric interactions with non-CB1, non-CB2 established GPCRs, deorphanized receptors such as GPR55, ligand-gated ion channels, transient receptor potential (TRP) channels, and other ion channels or peroxisome proliferator-activated nuclear receptors. From these data, it is clear that some ligands that interact similarly with CB1 and/or CB2 receptors are likely to display significantly different pharmacological profiles. The review also lists some criteria that any novel “CB3” cannabinoid receptor or channel should fulfil and concludes that these criteria are not currently met by any non-CB1, non-CB2 pharmacological receptor or channel. However, it does identify certain pharmacological targets that should be investigated further as potential CB3 receptors or channels. These include TRP vanilloid 1, which possibly functions as an ionotropic cannabinoid receptor under physiological and/or pathological conditions, and some deorphanized GPCRs. Also discussed are 1) the ability of CB1 receptors to form heteromeric complexes with certain other GPCRs, 2) phylogenetic relationships that exist between CB1/CB2 receptors and other GPCRs, 3) evidence for the existence of several as-yet-uncharacterized non-CB1, non-CB2 cannabinoid receptors; and 4) current cannabinoid receptor nomenclature.

1,439 citations