Cannabinoid receptor type 2 (CB2)-selective N-aryl-oxadiazolyl-propionamides: synthesis, radiolabelling, molecular modelling and biological evaluation
Tóm tắt
The endocannabinoid system is involved in many physiological and pathological processes. Two receptors (cannabinoid receptor type 1 (CB1) and type 2 (CB2)) are known so far. Many unwanted psychotic side effects of inhibitors of this system can be addressed to the interaction with CB1. While CB1 is one of the most abundant neuroreceptors, CB2 is expressed in the brain only at very low levels. Thus, highly potent and selective compounds for CB2 are desired. N-aryl-((hetero)aromatic)-oxadiazolyl-propionamides represent a promising class of such selective ligands for the human CB2. Here, a library of various derivatives is studied for suitable routes for labelling with 18F. Such 18F-labelled compounds can then be employed as CB2-selective radiotracers for molecular imaging studies employing positron emission tomography (PET). By varying the N-arylamide substructure, we explored the binding pocket of the human CB2 receptor and identified 9-ethyl-9H-carbazole amide as the group with optimal size. Radioligand replacement experiments revealed that the modification of the (hetero)aromatic moiety in 3-position of the 1,2,4-oxadiazoles shows only moderate impact on affinity to CB2 but high impact on selectivity towards CB2 with respect to CB1. Further, we could show by autoradiography studies that the most promising compounds bind selectively on CB2 receptors in mouse spleen tissue. Molecular docking studies based on a novel three-dimensional structural model of the human CB2 receptor in its activated form indicate that the compounds bind with the N-arylamide substructure in the binding pocket. 18F labelling at the (hetero)aromatic moiety at the opposite site of the compounds via radiochemistry was carried out. The synthesized CB2-selective compounds have high affinity towards CB2 and good selectivity against CB1. The introduction of labelling groups at the (hetero)aromatic moiety shows only moderate impact on CB2 affinity, indicating the introduction of potential labelling groups at this position as a promising approach to develop CB2-selective ligands suitable for molecular imaging with PET. The high affinity for human CB2 and selectivity against human CB1 of the herein presented compounds renders them as suitable candidates for molecular imaging studies.
Tài liệu tham khảo
Fowler CJ, Rojo ML, Rodriguez-Gaztelumendi A: Modulation of the endocannabinoid system: neuroprotection or neurotoxicity? Exp Neurol 2010,224(1):37–47.
Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI: Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990,346(6284):561–564.
Alger B: Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids. Prog Neurobiol 2002,68(4):247–286.
Munro S, Thomas KL, Abu-Shaar M: Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993,365(6441):61–65.
Stella N: Cannabinoid signaling in glial cells. Glia 2004,48(4):267–277.
Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG: International Union of Pharmacology. XXVII Classification of cannabinoid receptors Pharmacol Rev 2002,54(2):161–202.
Wilson RI, Nicoll RA: Endocannabinoid signaling in the brain. Science 2002,296(5568):678–682.
Guzmán M, Sánchez C, Galve-Roperh I: Cannabinoids and cell fate. Pharmacol Ther 2002,95(2):175–184.
Witkin JM, Tzavara ET, Davis RJ, Li X, Nomikos GG: A therapeutic role for cannabinoid CB1 receptor antagonists in major depressive disorders. Trends Pharmacol Sci 2005,26(12):609–617.
Shohami E, Novikov M, Bass R: Long-term effect of HU-211, a novel non-competitive NMDA antagonist, on motor and memory functions after closed head injury in the rat. Brain Res 1995,674(1):55–62.
Maas A, Murray G, Henney H, Kassem N, Legrand V, Mangelus M, Muizelaar J, Stocchetti N, Knoller N: Efficacy and safety of dexanabinol in severe traumatic brain injury: results of a phase III randomised, placebo-controlled, clinical trial. Lancet Neurol 2006,5(1):38–45.
Alexander A, Smith PF, Rosengren RJ: Cannabinoids in the treatment of cancer. Cancer Lett 2009,285(1):6–12.
Oesch S, Gertsch J: Cannabinoid receptor ligands as potential anticancer agents - high hopes for new therapies? J Pharm Pharmacol 2009,61(7):839–853.
Pertwee RG, Thomas A: Therapeutic applications for agents that act at CB1 and CB2 receptors. In The cannabinoid receptors. Edited by: Reggio PH. Humana, New York; 2010:361–392.
Mackie K: Cannabinoid receptors as therapeutic targets. Annu Rev Pharmacol Toxicol 2006, 46: 101–122.
Turu G, Hunyady L: Signal transduction of the CB1 cannabinoid receptor. J Mol Endocrinol 2010,44(2):75–85.
Ludányi A, Hu SS-J, Yamazaki M, Tanimura A, Piomelli D, Watanabe M, Kano M, Sakimura K, Maglóczky Z, Mackie K, Freund TF, Katona I: Complementary synaptic distribution of enzymes responsible for synthesis and inactivation of the endocannabinoid 2-arachidonoylglycerol in the human hippocampus. Neuroscience 2011, 174: 50–63.
Lynn AB, Herkenham M: Localization of cannabinoid receptors and nonsaturable high-density cannabinoid binding-sites in peripheral-tissues of the rat - implications for receptor-mediated immune modulation by cannabinoids. J Pharmacol Exp Ther 1994,268(3):1612–1623.
Palazuelos J, Aguado T, Egia A, Mechoulam R, Guzmán M, Galve-Roperh I: Non-psychoactive CB2 cannabinoid agonists stimulate neural progenitor proliferation. FASEB J 2006,20(13):2405–2407.
Skaper S, Buriani A, DalToso R, Petrelli L, Romanello S, Facci L, Leon A: The ALIAmide palmitoylethanolamide and cannabinoids, but not anandamide, are protective in a delayed postglutamate paradigm of excitotoxic death in cerebellar granule neurons. P Natl Acad Sci USA 1996,93(9):3984–3989.
Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K, Stella N, Makriyannis A, Piomelli D, Davison JS, Marnett LJ, Di Marzo V, Pittman QJ, Patel KD, Sharkey KA: Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 2005,310(5746):329–332.
Gong J-P, Onaivi ES, Ishiguro H, Liu Q-R, Tagliaferro PA, Brusco A, Uhl GR: Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. Brain Res 2006,1071(1):10–23.
Onaivi ES, Ishiguro H, Gong J-P, Patel S, Meozzi PA, Myers L, Perchuk A, Mora Z, Tagliaferro PA, Gardner E, Brusco A, Akinshola BE, Hope B, Lujilde J, Inada T, Iwasaki S, Macharia D, Teasenfitz L, Arinami T, Uhl GR: Brain neuronal CB2 cannabinoid receptors in drug abuse and depression: from mice to human subjects. PLoS One 2008,3(2):e1640.
Suárez J, Bermúdez-Silva FJ, Mackie K, Ledent C, Zimmer A, Cravatt BF, de Fonseca FR: Immunohistochemical description of the endogenous cannabinoid system in the rat cerebellum and functionally related nuclei. J Comp Neurol 2008,509(4):400–421.
Atwood BK, Mackie K: CB2: a cannabinoid receptor with an identity crisis. Br J Pharmacol 2010,160(3):467–479.
Ashton JC, Wright JL, McPartland JM, Tyndall JDA: Cannabinoid CB1 and CB2 receptor ligand specificity and the development of CB2-selective agonists. Curr Med Chem 2008,15(14):1428–1443.
Halleskog C, Mulder J, Dahlström J, Mackie K, Hortobágyi T, Tanila H, Kumar Puli L, Färber K, Harkany T, Schulte G: WNT signaling in activated microglia is proinflammatory. Glia 2011,59(1):119–131.
Scotter EL, Abood ME, Glass M: The endocannabinoid system as a target for the treatment of neurodegenerative disease. Br J Pharmacol 2010,160(3):480–498.
Graham ES, Ashton JC, Glass M: Cannabinoid receptors: a brief history and "what's hot". Front Biosci 2009, 14: 944–957.
Evens N, Vandeputte C, Coolen C, Janssen P, Sciot R, Baekelandt V, Verbruggen AM, Debyser Z, Van Laere K, Bormans GM: Preclinical evaluation of [11C]NE40, a type 2 cannabinoid receptor PET tracer. Nuclear Med Biol 2011,39(3):389–399.
Roche M, Finn DP: Brain CB2 receptors: implications for neuropsychiatric disorders. Pharmaceuticals 2010,3(8):2517–2553.
Lavey BJ, Kozlowski JA, Hipkin RW, Gonsiorek W, Lundell DJ, Piwinski JJ, Narula S, Lunn CA: Triaryl bis-sulfones as a new class of cannabinoid CB2 receptor inhibitors: identification of a lead and initial SAR studies. Bioorg Med Chem Lett 2005,15(3):783–786.
Evens N, Muccioli GG, Houbrechts N, Lambert DM, Verbruggen AM, Van Laere K, Bormans GM: Synthesis and biological evaluation of carbon-11- and fluorine-18-labeled 2-oxoquinoline derivatives for type 2 cannabinoid receptor positron emission tomography imaging. Nucl Med Biol 2009,36(4):455–465.
Gao M, Wang M, Miller KD, Hutchins GD, Zheng Q-H: Synthesis and in vitro biological evaluation of carbon-11-labeled quinoline derivatives as new candidate PET radioligands for cannabinoid CB2 receptor imaging. Bioorg Med Chem 2010,18(6):2099–2106.
Evens N, Bormans GM: Non-invasive imaging of the type 2 cannabinoid receptor, focus on positron emission tomography. Curr Top Med Chem 2010,10(15):1527–1543.
Cheng Y, Albrecht BK, Brown J, Buchanan JL, Buckner WH, DiMauro EF, Emkey R, Fremeau RT, Harmange J-C, Hoffman BJ, Huang L, Huang M, Lee JH, Lin F-F, Martin MW, Nguyen HQ, Patel VF, Tomlinson SA, White RD, Xia X, Hitchcock SA: Discovery and optimization of a novel series of N-arylamide oxadiazoles as potent, highly selective and orally bioavailable cannabinoid receptor 2 (CB2) agonists. J Med Chem 2008,51(16):5019–5034.
Shoemaker JL, Joseph BK, Ruckle MB, Mayeux PR, Prather PL: The endocannabinoid noladin ether acts as a full agonist at human CB2 cannabinoid receptors. J Pharmacol Exp Ther 2005,314(2):868–875.
Gullapalli S, Amrutkar D, Gupta S, Kandadi MR, Kumar H, Gandhi M, Karande V, Narayanan S: Characterization of active and inactive states of CB1 receptor and the differential binding state modulation by cannabinoid agonists, antagonists and inverse agonists. Neuropharmacology 2010,58(8):1215–1219.
Massi P, Patrini G, Rubino T, Fuzio D, Parolaro D: Changes in rat spleen cannabinoid receptors after chronic CP-55,940: an autoradiographic study. Pharmacol Biochem Behav 1997,58(1):73–78.
McPartland JM, Glass M, Pertwee RG: Meta-analysis of cannabinoid ligand binding affinity and receptor distribution: interspecies differences. Br J Pharmacol 2007,152(5):583–593.
Shire D, Calandra B, Rinaldi-Carmona M, Oustric D, Pessegue B, Bonnin-Cabanne O, LeFur G, Caput D, Ferrara P: Molecular cloning, expression and function of the murine CB2 peripheral cannabinoid receptor. Biochim Biophys Acta 1996,1307(2):132–136.
Warne T, Moukhametzianov R, Baker JG, Nehmé R, Edwards PC, Leslie AGW, Schertler GFX, Tate CG: The structural basis for agonist and partial agonist action on a β(1)-adrenergic receptor. Nature 2011,469(7329):241–244.
Xu F, Wu H, Katritch V, Han GW, Jacobson KA, Gao Z-G, Cherezov V, Stevens RC: Structure of an agonist-bound human A2A adenosine receptor. Science 2011,332(6027):322–327.
Poso A, Huffman JW: Targeting the cannabinoid CB2 receptor: modelling and structural determinants of CB2 selective ligands. Br J Pharmacol 2008,153(2):335–346.
Wiley EA, Deslongchamps G: PostDock: a novel visualization tool for the analysis of molecular docking. Comput Visual Sci 2006,12(1):1–7.
Sheldrick GM: A short history of SHELX. Acta Crystallogr, A, Found Crystallogr 2008,64(Pt 1):112–122.
Jeffries WB, Waugh D, Abel PW: Analysis of data from “cold saturation” radioligand binding experiments. Methods Mol Biol 1997, 73: 331–342.
Hulme EC, Trevethick MA: Ligand binding assays at equilibrium: validation and interpretation. Br J Pharmacol 2010,161(6):1219–1237.
Cheng Y, Prusoff WH: Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 per cent inhibition (IC50) of an enzymatic reaction. Biochem Pharmacol 1973,22(23):3099–3108.
Foreman JC, Johansen T: Textbook of receptor pharmacology. 2nd edition. CRC, Boca Raton; 2003.
Jaakola V-P, Griffith MT, Hanson MA, Cherezov V, Chien EYT, Lane JR, Ijzerman AP, Stevens RC: The 2.6 Ǻngström crystal structure of a human A2A adenosine receptor bound to an antagonist. Science 2008, 322: 1211–1217.
Ballesteros JA, Weinstein H: Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors. In Receptor molecular biology. Methods in neurosciences, vol 25. Edited by: Sealfon SC. Elsevier, San Diego; 1995:366–428.
Abood ME: Molecular biology of cannabinoid receptors. Handb Exp Pharmacol 2005, 168: 81–115.
Verdonk ML, Cole JC, Hartshorn MJ, Murray CW, Taylor RD: Improved protein–ligand docking using GOLD. Proteins 2003,52(4):609–623.
Gunasekaran K, Nussinov R: How different are structurally flexible and rigid binding sites? Sequence and structural features discriminating proteins that do and do not undergo conformational change upon ligand binding. J Mol Biol 2007,365(1):257–273.