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NIDA - Director's Report - May, 2010 NIDA - Director's Report - May, 2010 NIDA Home > Publications > Director's Reports Director's Report to the National Advisory Council on Drug Abuse - May, 2010 Report Index Index Report for February, 2010 Research Findings Older Reports - go to the Archives Basic Neurosciences Research Basic Behavioral Research Behavioral and Brain Development Research Clinical Neuroscience Research NACDA Epidemiology and Etiology Research Legislation Prevention Research Research on Behavioral and Combined Treatments for Drug Abuse Research on Pharmacotherapies for Drug Abuse Research on Medical Consequences of Drug Abuse and Co-Occurring Infections (HIV/AIDS, HCV) Services Research Clinical Trials Network Research International Research Intramural Research Program Activities Extramural Policy and Review Activities Congressional Affairs International Activities Meetings and Conferences Media and Education Activities Planned Meetings Publications Staff Highlights Grantee Honors https://archives.drugabuse.gov/DirReports/DirRep510/[11/17/16, 11:27:56 PM] NIDA - Director's Report - May, 2010 Archive Home | Accessibility | Privacy | FOIA (NIH) | Current NIDA Home Page The National Institute on Drug Abuse (NIDA) is part of the National Institutes of Health (NIH) , a component of the U.S. Department of Health and Human Services. Questions? _ See our Contact Information. https://archives.drugabuse.gov/DirReports/DirRep510/[11/17/16, 11:27:56 PM] NIDA - Director's Report - May, 2010 NIDA Home > Publications > Director's Reports > May, 2010 Index Director's Report to the National Advisory Council on Drug Abuse - May, 2010 Index Research Findings - Basic Neuroscience Research Research Findings PDZ binding of PICK1 Basic Neurosciences Research The protein PICK1 (protein that interacts with C kinase 1) functions as a Basic Behavioral Research scaffolding or anchoring protein for the assembly of various protein partners, including protein kinase Calpha, AMPA receptor subunits 2-4, metabatropic Behavioral and Brain glutamate receptors, transmembrane transporters, ion channels, and G Development Research protein-coupled receptors. Its binding to these varied partners can affect their Clinical Neuroscience level of surface plasma membrane expression in various cells, or, in some Research cases, their intracellular levels. PICK1 is highly expressed in the brain, Epidemiology and Etiology including neuronal synapses. For binding, PICK1 possesses a single so-called Research "PDZ domain" near its N-terminus, consisting of amino acid residues 22-105, which provides a binding pocket for the PDZ-binding region of other proteins, Prevention Research primarily accommodating only several residues of the C-terminus of these Research on Behavioral and proteins, with low micromolar affinity constants. A recent report by Dr. Gether Combined Treatments for and colleagues described the discovery of a small molecule known as FSC231, Drug Abuse which serves as an inhibitor of the PICK1 PDZ domain. This molecule was found Research on in a chemical library of approximately 44,000 compounds, using a competition Pharmacotherapies for Drug assay for the inhibition of fluorescence of Oregon green-labeled DAT13 (a 13 Abuse amino acid C-terminus peptide of the DAT). This research has provided evidence for the disruption of the PICK1 PDZ-GluR2 complex by a small Research on Medical molecule with moderate binding affinity in the micromolar range. It may Consequences of Drug provide a starting point for the development of additional small molecule Abuse and Co-Occurring inhibitors, which may have the property of reducing hippocampal LTP induced Infections (HIV/AIDS, HCV) by cocaine exposure and reversing the resulting redistribution of synaptic GluR Services Research subunits. Thorsen TS, Madsen KL, Rebola N, Rathje M, Anggono V, Bach A, Clinical Trials Network Moreira I S, Stuhr-Hansen N, Dyhring T, Peters D, Beuming T, Huganir R, Research Weinstein H, Mulle C, Stromgaard K, Ronn LCB, Gether U. Identification of a International Research small-molecule inhibitor of the PICK1 PDZ domain that inhibits hippocampal LTP and LTD. PNAS. 2010; 107(1): 413-418. Intramural Research Program Activities Characterization of Tunable Piperidine and Piperazine Carbamates as Inhibitors of Endocannabinoid Hydrolases Extramural Policy and Review Activities Monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) are two enzymes from the serine hydrolase superfamily that degrade the Congressional Affairs endocannabinoids 2-arachidonoylglycerol and anandamide, respectively. A group led by Dr. Benjamin Cravatt has recently discovered that MAGL and International Activities FAAH are both inhibited by carbamates bearing an N-piperidine/piperazine group. Piperidine/piperazine carbamates show excellent in vivo activity, raising Meetings and Conferences brain endocannabinoid levels and producing CB1-dependent behavioral effects in mice, suggesting that they represent a promising class of inhibitors for Media and Education studying the endogenous functions of MAGL and FAAH. Herein, they disclose a Activities full account of the syntheses, structure-activity relationships, and inhibitory https://archives.drugabuse.gov/DirReports/DirRep510/DirectorReport1.html[11/17/16, 11:27:59 PM] NIDA - Director's Report - May, 2010 activities of piperidine/piperazine carbamates against members of the serine Planned Meetings hydrolase family. These scaffolds can be tuned for MAGL-selective or dual MAGL-FAAH inhibition by the attachment of an appropriately substituted Publications bisarylcarbinol or aryloxybenzyl moiety, respectively, on the piperidine/piperazine ring. Modifications to the piperidine/piperazine ring Staff Highlights ablated inhibitory activity, suggesting a strict requirement for a six-membered ring to maintain potency. Long JZ, Jin X, Adibekian A, Li W, Cravatt BF. Grantee Honors Characterization of tunable piperidine and piperazine carbamates as inhibitors of endocannabinoid hydrolases. J Med Chem. 2010; 53: 1830-1842. Synthesis and Pharmacological Evaluation of Highly Potent [Dmt1]DALDA Analogs Chemical structure variation of the highly potent and µ-opioid selective, peripheral analgesic, DALDA ([D-Arg2, Lys4] dermorphin-(1,4)-amide) led to the synthesis of a new compound [Dmt1] DALDA which had 12 fold higher affinity than DALDA at µ-opioid receptors, and a potency 180 fold higher. Authors had access to protected analogs of [Dmt1] DALDA which they used to synthesize gram quantities of three antioxidant peptides: SS-02 (Dmt-D-Arg- Phe-Lys-NH2). SS-31 (D-Arg-Dmt-Lys-Phe-NH2), and SS-20 (Phe-D-Arg-Phe- Lys-NH2), and then examined their bioactivity. Synthesis of these three peptides involved routinely used side chain protecting groups for amino acid building blocks. Opioid activities and potency varied at the at µ-opioid and δ- opioid receptors among these chemical structures. Reddy PA, Lewin AH, Schiller PW. Synthesis and pharmacological evaluation of highly potent [Dmt1] DALDA analogs. Adv Exp Med Biol. 2009; 611:473-474. PET Imaging of Cortical Activation During Cocaine Self- Administration and Extinction Dr. Leonard Howell and his colleagues at Emory University and Yerkes National Primate Research Center were among the first to use functional brain imaging to show cocaine-induced changes in brain activity during active drug taking in primates. Using PET imaging with O15-labeled water to quantify changes in cerebral blood flow, the PI and his colleagues studied the effects of cocaine administered noncontingently in na•ve monkeys, and the effects when the animals self-administered the drug or later, when saline was substituted for the cocaine. They found that noncontingent drug administration was associated with robust activation of the dorsolateral regions of the prefrontal cortex; by contrast, the effects of the drug when self-administered were to activate anterior cingulate cortex. During times when saline was substituted for cocaine, the stimuli previously paired with cocaine also induced a similar robust activation in prefrontal cortex. Dr. Howell and his colleagues interpret these findings to indicate that the effects of cocaine and associated cues extend further than the limbic system and utilize brain areas involved in cognitive processes. The recognition that neural circuits underlie the direct pharmacological and conditioned stimulus effects of cocaine may provide important new clues for the development of medications for the treatment of cocaine abuse. Howell LL, Votow JR, Goodman MM, Lindsey KP. Cortical activation during cocaine use and extinction in rhesus monkeys. Psychopharmacology. 2010; 208: 191-199. Cannabinoid Receptor Agonist, THC, Inhibits Macrophage Migration to the Tat Protein of HIV-1 Macrophages and macrophage-like cells are important targets of HIV-1 infection at peripheral sites and in the central nervous system. After infection, these cells secrete a plethora of toxic factors, including the viral regulatory trans-activating protein (Tat). This protein is highly immunogenic and also https://archives.drugabuse.gov/DirReports/DirRep510/DirectorReport1.html[11/17/16, 11:27:59 PM] NIDA - Director's Report - May, 2010 serves as a potent chemoattractant for monocytes. In the present study, the exogenous cannabinoids THC and CP55940 were shown to significantly inhibit migration of human U937 macrophage-like cells to the Tat protein in a concentration-related manner. The CB1 receptor-selective agonist ACEA had no effect on Tat-mediated migration. In contrast, the CB2 receptor-selective
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