Supporting Information

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1 Supporting Information Discovery of ovel CB Receptor Ligands by a Pharmacophore-based Virtual Screening Workflow Patrick Markt, a emens Feldmann, a Judith Maria Rollinger, b Stefan Raduner, c Daniela Schuster, a,d Johannes Kirchmair, a,d Simona Distinto, e Gudrun Maria Spitzer, f Gerhard Wolber, d Christian Laggner, a Karl-einz Altmann, c Thierry Langer, a,d Jürg Gertsch c a Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain c, 600 Innsbruck, Austria b Department of Pharmacognosy, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain c, 600 Innsbruck, Austria c Department of Chemistry and Applied BioSciences, Swiss Federal Institute of Technology (ET) Zürich, Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland d Inte:Ligand Softwareentwicklungs- und Consulting Gmb, emens Maria ofbauer-gasse 6, 344 Maria Enzersdorf, Austria e Dipartimento Farmaco Chimico Tecnologico, Universita` degli Studi di Cagliari, Via Università 40, 0914 Cagliari, Italy f Department of Theoretical Chemistry, Institute of General, Inorganic, and Theoretical Chemistry, University of Innsbruck, Innrain a, 600 Innsbruck, Austria S1

2 Table of Contents Figure S1: Results of the camp assay S3 Chart S1: Table S1: Structures of the CB receptor agonist test set compounds S4 CB 1 and CB receptor binding affinities for the compounds from the CB receptor agonist test set S6 References S7 S

3 Figure S1. Results of the camp assay. 0 µm of compounds 8, 1, and 18 were co-incubated with varying concentrations of WI,1- prior to camp stimulation by forskolin (0 µm) in CB receptor expressing C cells (10 cells/ml) (a). Compound 8 is additive with WI,1- and therefore represents a CB receptor agonist (a). Compounds 1 and 18 are antagonistic, thus blocking the effect of WI,1- (a). Concentration-dependent effects of the new CB receptor ligands on forskolin-stimulated camp production in CB receptor expressing C cells (10 cells/ml) in the absence of WI,1-, indicating that compound 18 is an inverse agonist (b). Compound 1 did not inhibit nor superstimulate forskolin-induced camp (b) and acts like a silent antagonist in this assay. Data show mean values ± S.E. of 3 independent experiments. S3

4 Chart S1. Structures of the CB receptor agonist test set compounds S # # # S S # # # CF 3 A AM1714 GW84166X JW-10 JW-11 JW-9 S4

5 JW-68 # CAS registration number S

6 Table S1. CB 1 and CB receptor binding affinities for the compounds from the CB receptor agonist test set. compound CB 1 K i (nm) CB K i (nm) CB 1 K i / CB K i ref #, # 3, # #, #, # A a 0.77 a 46 AM GW84166X > 30,000 b 0 b > 600 JW-10 1, JW-11 > 10, > 333 JW-9 3, JW-68 1, > 10, > , # CAS registration number a IC 0 value b EC 0 value S6

7 References 1. Gallant, M.; Dufresne, C.; Gareau, Y.; Guay, D.; Leblanc, Y.; Prasit, P.; Rochette, C.; Sawyer,.; Slipetz, D. M.; et al. ew class of potent ligands for the human peripheral cannabinoid receptor. Bioorg. Med. Chem. Lett. 1996, 6, Page, D.; Yang,.; Brown, W.; Walpole, C.; Fleurent, M.; Fyfe, M.; Gaudreault, F.; St-nge, S. ew 1,,3,4-tetrahydropyrrolo[3,4-b]indole derivatives as selective CB receptor agonists. Bioorg. Med. Chem. Lett. 007, 17, hta,.; Ishizaka, T.; Tatsuzuki, M.; Yoshinaga, M.; Iida, I.; Yamaguchi, T.; Tomishima, Y.; Futaki,.; Toda, Y.; Saito, S. Imine derivatives as new potent and selective CB cannabinoid receptor agonists with an analgesic action. Bioorg. Med. Chem. 008, 16, Khanolkar, A. D.; Lu, D.; Ibrahim, M.; Duclos, R. I., Jr.; Thakur, G. A.; Malan, T. P., Jr.; Porreca, F.; Veerappan, V.; Tian, X.; George, C.; Parrish, D. A.; Papahatjis, D. P.; Makriyannis, A. Cannabilactones: A ovel ass of CB Selective Agonists with Peripheral Analgesic Activity. J. Med. Chem. 007, 0, uffman, J. W.; Zengin, G.; Wu, M.-J.; Lu, J.; ynd, G.; Bushell, K.; Thompson, A. L. S.; Bushell, S.; Tartal, C.; urst, D. P.; Reggio, P..; Selley, D. E.; Cassidy, M. P.; Wiley, J. L.; Martin, B. R. Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB1 and CB receptors: steric and electronic effects of naphthoyl substituents. ew highly selective CB receptor agonists. Bioorg. Med. Chem. 004, 13, Wiley, J. L.; Beletskaya, I. D.; g, E. W.; Dai, Z.; Crocker, P. J.; Mahadevan, A.; Razdan, R. K.; Martin, B. R. Resorcinol derivatives: a novel template for the development of cannabinoid CB1/CB and CB-selective agonists. J. Pharmacol. Exp. Ther. 00, 301, S7

LigandScout. Automated Structure-Based Pharmacophore Model Generation. Gerhard Wolber* and Thierry Langer

LigandScout. Automated Structure-Based Pharmacophore Model Generation. Gerhard Wolber* and Thierry Langer LigandScout Automated Structure-Based Pharmacophore Model Generation Gerhard Wolber* and Thierry Langer * E-Mail: wolber@inteligand.com Pharmacophores from LigandScout Pharmacophores & the Protein Data