SUPPLEMENTARY DATA

Modelling of ORL1 receptor–ligand interactions

aMilan Senćanski, bMilovan D. Ivanović, bLjiljana Došen-Mićović[*]

aInnovation Centre of the Faculty of Chemistry, bFaculty of Chemistry, University of Belgrade and Center for Chemistry, ICTM, Studentski trg 12–16, P.O. Box 51, 11158 Belgrade, Serbia University of Belgrade, Serbia

Received 14 November 2013; Revised 27 February 2014; Accepted 27 February 2014


a


b

Fig. S1. Ramachandran maps of inactive (a) and active (b) ORL1 receptor model.

Table S1. Selected antagonist and agonist ligands and their experimentally determined binding constants, Ki (nM) or (IC50(nM))

Compound / Name / Protonated compound structure / Ki (IC50)/nM / Reference
Antagonists
I / 1'-((1-(2-Chlorophenyl)-3-methyl-pyrazol-4-yl)methyl)spiro(1H-isobenzofuran-3,4'-piperidine) / / 0.65 / Yoshizumi et al., 2008
II / 2-(4-(6-Chloro-2-(1-ethyl-1-methyl-propyl)sulphanyl-3H-benzimidazol-5-yl)-1-piperidyl)ethanol / / 1.2 / Okamoto et al., 2008
III / 1-(1(Cyclooctylmethyl)-5-(hydroxymethyl)-3,6-dihydro-2H-pyridin-4-yl)-3-ethyl-benzimidazol-2-one / / 2.2 / Trapella et al., 2006
IV / N-(4-Amino-2-ethyl-6-quinolyl)-2-((4-chlorophenoxy)methyl)benzamide / / 1.8 / Shinkai et al., 2000
V / (5S,7S)-7-((4-(2,6-Dichlorophenyl)-1-piperidyl)methyl)-1-methyl-6,7,8,9-tetrahydro-5H-benzo(7)annulen-5-ol / / 0.33 / Zaratin et al., 2004
VI / (2R)-1-Benzyl-N-(3-spiro(1H-isobenzofuran-3,4'-piperidine)-1'-ylpropyl)pyrrolidine-2-carboxamide / / (0.27) / Goto et al., 2006
VII / 1-Ethyl-3-((3R,4R)-3-(hydroxymethyl)-1-((2-methylcyclooctyl)methyl)-4-piperidyl)benzimidazol-2-one / / 1.8i, 0.85ii / iOzaki et al., 2000; iiSmith et al., 2008
VIII / 1-(1-(Cyclooctylmethyl)-4-piperidyl)indolin-2-one / / 6.04 / Zaveri et al., 2004
IX / 4-Chloro-N-(4-(((1R,2S)-2-guanidinocyclohexyl)amino)-6-methyl-quinazolin-2-yl)benzamide / / 1.4 / Okano et al., 2009
Agonists
X / 8-(((1R)-1,2-Dihydroacenaphthylen-1-yl)methyl)-4-phenyl-2,4,8-triazaspiro(4.5)decan-1-one / / 0.25 / Wichmann et al., 1999
XI / 2-(3-(1-(4-Isopropylcyclohexyl)-4-piperidyl)-2-oxo-benzimidazol-1-yl)-N-methyl-acetamide / / 0.7 / Palin et al., 2009
XII / 2-(3-(1-((3R)-3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-pentyl)-4-piperidyl)-2-oxo-benzimidazol-1-yl)-N-methyl-acetamide / / 0.5 / Palin et al., 2007
XIII / 1-(1-((3R)-3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-pentyl)-4-piperidyl)-3-(1H-1,2,4-triazol-5-ylmethyl)benzimidazol-2-one / / 0.9 / Palin et al., 2008
XIV / 1-(bis-O-Tolylmethyl)-4-phenyl-piperidin-4-ol / / 0.3 / Varty et al., 2008
XV / 1-((R)- O -Tolyl(phenyl)methyl)-4-phenyl-piperidin-4-ol / / 0.7 / Ho et al., 2007
XVI / 8-(4-Isopropylcyclohexyl)-4-phenyl-2,4,8-triazaspiro(4.5)decan-1-one / / 0.079 / Röver et al., 2000
XVII / 3-(1-((1S)-1-(2-Chlorophenyl)ethyl)-4-piperidyl)-1H-benzimidazol-2-one / / (5.9) / Kawamoto et al., 1999
XVIII / 1-(1-Cyclooctyl-4-piperidyl)indolin-2-one / / 1.39 / Zaveri et al., 2004
XIX / 8-(4,4-Dimethyltetralin-1-yl)-2-(2-(isopentylamino)ethyl)-4-phenyl-2,4,8-triazaspiro(4.5)decan-1-one / / 0.4 / Liu et al., 2010

Table S2. Identity matrix* for the seven GPCRs : rhodopsin (OPSD), ORL1 (OPRX), k opioid receptor (OPRK), d opioid receptor (OPRD), m opioid receptor (OPRM), adenosine A2A receptor (AA2AR) and b2- adrenergic receptor (ADRB2)

1:00 / sp|P08100|OPSD_HUMAN / 100 / 20.62 / 18.13 / 19.17 / 21.15 / 19.54 / 20.56
2:00 / sp|P41146|OPRX_HUMAN / 20.62 / 100 / 53.09 / 52.63 / 53.76 / 23.55 / 23.97
3:00 / sp|P41145|OPRK_HUMAN / 18.13 / 53.09 / 100 / 60.11 / 60.72 / 24.12 / 24.16
4:00 / sp|P41143|OPRD_HUMAN / 19.17 / 52.63 / 60.11 / 100 / 61.68 / 24.6 / 26.43
5:00 / sp|P35372|OPRM_HUMAN / 21.15 / 53.76 / 60.72 / 61.68 / 100 / 23.36 / 25
6:00 / sp|P29274|AA2AR_HUMAN / 19.54 / 23.55 / 24.12 / 24.6 / 23.36 / 100 / 30.43
7:00 / sp|P07550|ADRB2_HUMAN / 20.56 / 23.97 / 24.16 / 26.43 / 25 / 30.43 / 100

* Bold column gives % identity relative to ORL1.

References

Goto, Y., Arai-Otsuki, S., Tachibana, Y., Ichikawa, D., Ozaki, S., Takahashi, H., Iwasawa, Y., Okamoto, O., Okuda, S., Ohta, H., & Sagara, T. (2006). Identification of a novel spiropiperidine opioid receptor-like 1 antagonist class by a focused library approach featuring 3D-pharmacophore similarity. Journal of Medicinal Chemistry, 49, 847–849. DOI: 10.1021/jm0509851.

Ho, G. D., Bercovici, A., Tulshian, D., Greenlee, W. J., Fawzi, A., Torhan, A. S., & Zhang, H. T. (2007). Synthesis and structure–activity relationships of 4-hydroxy-4-phenylpiperidines as nociceptin receptor ligands: Part 1. Bioorganic & Medicinal Chemistry Letters, 17, 3023–3027. DOI: 10.1016/j.bmcl.2007.03.061.

Kawamoto, H., Ozaki, S., Itoh, Y., Miyaji, M., Arai, S., Nakashima, H., Kato, T., Ohta, H., & Iwasawa, Y. (1999). Discovery of the first potent and selective small molecule opioid receptor-like (ORL1) antagonist: 1-((3R,4R)-1-Cyclooctylmethyl-3-hydroxymethyl-4-piperidyl)-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397). Journal of Medicinal Chemistry, 42, 5061–5063. DOI: 10.1021/jm990517p.

Liu, M., He, L., Hu, X. P., Liu, P. Q., & Luo, H. B. (2010). 3D-QSAR, homology modeling and molecular docking studies on spiropiperidines analogues as agonists of nociceptin/orphanin FQ receptor. Bioorganic & Medicinal Chemistry Letters, 20, 7004–7010. DOI: 10.1016/j.bmcl.2010.09.116.

Okamoto, O., Kobayashi, K., Kawamoto, H., Ito, S., Yoshizumi, T., Yamamoto, I., Hashimoto, M., Shimizu, A., Takahashi, H., Ishii, Y., Ozaki, S., & Ohta, H. (2008). Novel ORL1-selective antagonists with oral bioavailability and brain penetrability. Bioorganic & Medicinal Chemistry Letters, 18, 3282–3285. DOI: 10.1016/j.bmcl.2008.04.037.

Okano, M., Mito, J., Maruyama, Y., Masuda, H., Niwa, T., Nakagawa, S., Nakamura, Y., & Matsuura, A. (2009). Discovery and structure–activity relationships of 4-aminoquinazoline derivatives, a novel class of opioid receptor like-1 (ORL1) antagonists. Bioorganic & Medicinal Chemistry, 17, 119–132. DOI: 10.1016/j.bmc.2008.11.012.

Ozaki, S., Kawamoto, H., Itoh, Y., Miyaji, M., Azuma, T., Ichikawa, D., Nambu, H., Iguchi, T., Iwasawa, Y., & Ohta, H. (2000). In vitro and in vivo pharmacological characterization of J-113397, a potent and selective non-peptidyl ORL1 receptor antagonist. European Journal of Pharmacology, 402, 45–53. DOI: 10.1016/s0014-2999(00)00520-3.

Palin, R., Bom, A., Clark, J. K., Evans, L., Feilden, H., Houghton, A. K., Jones, P. S., Montgomery, B., Weston, M. A., & Wishart, G. (2007). Synthesis and evaluation of N-3 substituted phenoxypropyl piperidine benzimidazol-2-one analogues as NOP receptor agonists with analgesic and sedative properties. Bioorganic & Medicinal Chemistry, 15, 1828–1847. DOI: 10.1016/j.bmc.2006.11.030.

Palin, R., Clark, J. K., Evans, L., Houghton, A. K., Jones, P. S., Prosser, A., Wishart, G., & Yoshiizumi, K. (2008). Structure–activity relationships and CoMFA of N-3 substituted phenoxypropyl piperidine benzimidazol-2-one analogues as NOP receptor agonists with analgesic properties. Bioorganic & Medicinal Chemistry, 16, 2829–2851. DOI: 10.1016/j.bmc.2008.01.005.

Palin, R., Clark, J. K., Evans, L., Feilden, H., Fletcher, D., Hamilton, N. M., Houghton, A. K., Jones, P. S., McArthur, D., Montgomery, B., Ratcliffe, P. D., Smith, A. R. C., Sutherland, A., Weston, M. A., & Wishart, G. (2009). Rapid access towards follow-up NOP receptor agonists using a knowledge based approach. Bioorganic & Medicinal Chemistry Letters, 19, 6441–6446. DOI: 10.1016/j.bmcl.2009.09.028.

Röver, S., Wichmann, J., Jenck, F., Adam, G., & Cesura, A. M. (2000). ORL1 receptor ligands: Structure–activity relationships of 8-cycloalkyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-ones. Bioorganic & Medicinal Chemistry Letters, 10, 831–834. DOI: 10.1016/s0960-894x(00)00111-6.

Shinkai, H., Ito, T., Iida, T., Kitao, Y., Yamada, H., & Uchida, I. (2000). 4-Aminoquinolines: Novel nociceptin antagonists with analgesic activity. Journal of Medicinal Chemistry, 43, 4667–4677. DOI: 10.1021/jm0002073.

Smith, E. D., Vinson, N. A., Zhong, D. S., Berrang, B. D., Catanzaro, J. L., Thomas, J. B., Navarro, H. A., Gilmour, B. P., Deschamps, J., & Carroll, F. I. (2008). A new synthesis of the ORL-1 antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397) and activity in a calcium mobilization assay. Bioorganic & Medicinal Chemistry, 16, 822–829. DOI: 10.1016/j.bmc.2007.10.023.

Trapella, C., Guerrini, R., Piccagli, L., Calo’, G., Carra’, G., Spagnolo, B., Rubini, S., Fanton, G., Hebbes, C., McDonald, J., Lambert, D. G., Regoli, D., & Salvadori, S. (2006). Identification of an achiral analogue of J-113397 as potent nociceptin/orphanin FQ receptor antagonist. Bioorganic & Medicinal Chemistry, 14, 692–704. DOI: 10.1016/j.bmc.2005.08.049.

Varty, G. B., Lu, S. X., Morgan, C. A., Cohen-Williams, M. E., Hodgson, R. A., Smith-Torhan, A., Zhang, H. T., Fawzi, A. B., Graziano, M. P., Ho, G. D., Matasi, J., Tulshian, D., Coffin, V. L., & Carey, G. L. (2008). The anxiolytic-like effects of the novel, orally active nociceptin opioid receptor agonist 8-[bis(2-methylphenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (SCH 221510). The Journal of Pharmacology and Experimental Therapeutics, 326, 672–682. DOI: 0.1124/jpet.108.136937.

Wichmann, J., Adam, G., Röver, S., Cesura, A. M., Dautzenberg, F. M., & Jenck, F. (1999). 8-Acenaphthen-1-yl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one derivatives as orphanin FQ receptor agonists. Bioorganic & Medicinal Chemistry Letters, 9, 2343–2348. DOI: 10.1016/s0960-894x(99)00385-6.

Yoshizumi, T., Miyazoe, H., Ito, H., Tsujita, T., Takahashi, H., Asai, M., Ozaki, S., Ohta, H., & Okamoto, O. (2008). Design, synthesis and structure–activity relationship study of a novel class of ORL1 receptor antagonists based on N-biarylmethyl spiropiperidine. Bioorganic & Medicinal Chemistry Letters, 18, 3778–3782. DOI: 10.1016/j.bmcl.2008.05.036.

Zaratin, P. F., Petrone, G., Sbacchi, M., Garnier, M., Fossati, C., Petrillo, P., Ronzoni, S., Giardina, G. A. M., & Scheideler, M. A. (2004). Modification of nociception and morphine tolerance by the selective opiate receptor-like orphan receptor antagonist(–)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111). The Journal of Pharmacology and Experimental Therapeutics, 308, 454–461. DOI: 10.1124/jpet.103.055848.

Zaveri, N. T., Jiang, F. M., Olsen, C. M., Deschamps, J. R., Parrish, D., Polgar, W., & Toll, L. (2004). A novel series of piperidin-4-yl-1,3-dihydroindol-2-ones as agonist and antagonist ligands at the nociceptin receptor. Journal of Medicinal Chemistry, 47, 2973–2976. DOI: 10.1021/jm034249d.

[*]Corresponding author, e-mail: