Synthetic route towards potential bivalent ligands possessing opioid and D2/D3 pharmacophores
Main Article Content
Abstract
A scalable, cost-efficient and simple synthetic pathway towards potential bivalent opioid/dopamine receptor ligands was developed and optimized. Three novel compounds that contain both opioid and dopamine pharmacophores linked by the four methylene group chain were synthesized in 33, 35 and 39 % overall yield after a four-step synthetic route starting from three commercially available N-aryl piperazines. The anilino piperidine precursor was easily prepared in three steps, as previously published, starting from 4-piperidone. The synthesis presented in this paper could be of interest for heterocyclic and general organic chemistry. The newly designed compounds possessing two pharmacophores, opioid and D2/D3, are potentially useful pharmacological probes. Of particular interest would be the simultaneous binding to both opioid and D2/D3 receptors, and the resulting pharmacological responses may be useful for the further understanding of tolerance and dependence phenomena in opioid clinical use and/or abuse.
Downloads
Metrics
Article Details
Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution license 4.0 that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
References
R. S. Vardanyan, V. J. Hruby, Future Med. Chem. 6 (2014) 385 (https://doi.org/10.4155/fmc.13.215)
S. Deekonda, L. Wugalter, D. Rankin, T. M. Largent-Milnes, P. Davis, Y. Wang, N. M. Bassirirad, J. Lai, V. Kulkarni, T. W. Vanderah, F. Porreca, V. J. Hruby, Bioorg. Med. Chem. Lett. 25 (2015) 4683 (https://doi.org/10.1016/j.bmcl.2015.07.064)
S. Deekonda, L. Wugalter, V. Kulkarni, D. Rankin, T. M. Largent-Milnes, P. Davis, N. M. Bassirirad, J. Lai, T.W. Vanderah, F. Porreca, V. J. Hruby, Bioorg. Med. Chem. 23 (2015) 6185 (https://doi.org/10.1016/j.bmc.2015.07.071)
R. S. Vardanyan, J. P. Cain, S. M. Haghighi, V. K. Kumirov, M. I. McIntosh, A. J. Sandweiss, F. Porreca, V. J. Hruby, J. Heterocycl. Chem. 54 (2017) 1228 (https://doi.org/10.1002/jhet.2696)
J. Kühhorn, A. Götz, H. Hübner, D. Thompson, J. Whistler, P. Gmeiner, J. Med. Chem. 54 (2011) 7911 (https://doi.org/10.1021/jm2009919)
V. Soskic, V. Sukalovic, S. Kostic-Rajacic, Mini-Rev. Med. Chem. 15 (2015) 988 (https://doi.org/10.2174/138955751512150731112448)
Y. Chen, Y. Fu, Y. An, J. Cao, J. Wang, J. Zhang, Clin. Exp. Pharmacol. Physiol. 45 (2018) 335 (https://doi.org/10.1111/1440-1681.12889)
D. J. Heal, M. Hallam, M. Prow, J. Gosden, S. Cheetham, Y. K. Choi, F. Tarazi, P. Hutson, J. Psychopharmacol. 31 (2017) 770 (https://doi.org/10.1177/0269881117699607)
S. C. Weber, B. Beck-Schimmer, M.-E. Kajdi, D. Müller, P. N. Tobler, B. B. Quednow, Transl. Psychiatry 6 (2016) 850 (https://doi.org/10.1038/tp.2016.113)
R. I. Desai, D. K. Grandy, C. R. Lupica, J. L. Katz, J. Pharmacol. Exp. Ther. 348 (2014) 106 (https://doi.org/10.1124/jpet.113.208538)
V. Kumar, A. Bonifazi, M. P. Ellenberger, T. M. Keck, E. Pommier, R. Rais, B. S. Slusher, E. Gardner, Z.-B. You, Z.-X. Xi, A. Hauck Newman, J. Med. Chem. 59 (2016) 7634 (https://doi.org/10.1021/acs.jmedchem.6b00860)
N. D. Volker, Biol. Psychiatry 68 (2010) 685 (https://doi.org/10.1016/j.biopsych.2010.08.002)
D. C. German, S. G. Speciale, K. F. Manaye, M. Sadeq, J. Neural Transm. 91 (1993) 39 (https://doi.org/10.1007/BF01244917)
C. Colantuoni, J. Schwenker, J. McCarthy, P. Rada, B. Ladenheim, J.-L. Cadet, G. J. Schwartz, T. H. Moran, B. G. Hoebel, NeuroReport 12 (2001) 3549 (https://doi.org/10.1097/00001756-200111160-00035)
R. Vardanyan, G. Vijay, G. S. Nichol, L. Liu, I. Kumarasinghe, P. Davis, T. Vanderah, F. Porreca, J. Lai, V. J. Hruby, Bioorg. Med. Chem. 17 (2009) 5044 (https://doi.org/10.1016/j.bmc.2009.05.065)
A. Mollica, S. Pelliccia, V. Famiglini, A. Stefanucci, G. Macedonio, A. Chiavaroli, G. Orlando, L. Brunetti, C. Ferrante, S. Pieretti, E. Novellino, S. Benyhe, F. Zador, A. Erdei, E. Szucs, R. Samavati, S. Dvoracsko, C. Tomboly, R. Ragno, A. Patsilinakos, R. Silvestri, J. Enzyme Inhib. Med. Chem. 32 (2017) 444 (https://doi.org/10.1080/14756366.2016.1260565)
L. M. Harwood, Aldrichim. Acta 18 (1985) 25 (ISSN 0002-5100)
B. S. Furniss, A. J. Hannaford, P. W. G. Smith, A. R. Tatchell, Vogels textbook of practical organic chemistry, 5th ed., Wiley, New York, 1989, p. 216 (https://doi.org/10.1002/pola.1991.080290821)
I. V. Mićović, M. D. Ivanović, D. M. Piatak, V. D. Bojić, Synthesis 11 (1991) 1043 (https://doi.org/10.1055%2Fs-1991-26642)
A. J. Walz, F.-L. Hsu, Org. Prep. Proced. Int. 49 (2017) 467 (https://doi.org/10.1080/00304948.2017.1374129)
L.-Y. Hu, T. R. Ryder, M. F. Rafferty, C. P. Taylor, M. Rose Feng, B.-S. Kuo, S. M. Lotarski, G. P. Miljanich, E. Millerman, M. Siebers, B. G. Szoke, Bioorg. Med. Chem. 8 (2000) 1203 (https://doi.org/10.1016/S0968-0896(00)00077-8)
J. Popović-Djordjević, S. Stepanović, L. Došen-Mićović, E. Ivanović, M. D. Ivanović, Green Chem. Lett. Rev. 9 (2016) 61 (https://doi.org/10.1080/17518253.2016.1145744)
Y.-C. Xu, A. L. Roughton, R. Plante, S. Goldstein, P. Deslongchamps, Can. J. Chem. 71 (1993) 1152 (https://doi.org/10.1139/v93-152)
I. V. Μićονίć, M. D. Ivanović, S. Vučković, D. Jovanović-Mićić, D. Beleslin, Lj. Došen-Mićović, V. D. Kiricojević, Heterocycl. Commun. 4 (1998) 171 (https://doi.org/10.1515/HC.1998.4.2.171)
I. I. Jevtić, L. Došen-Mićović, E. R. Ivanović, N. M. Todorović, M. D. Ivanović, Synthesis 49 (2017) 3126 (http://dx.doi.org/10.1055/s-0036-1588985)
G. M. Wuts, T. W. Greene, Greenes Protective Groups in Organic Synthesis, 4th ed., Wiley, Hoboken, NJ, 2006 (http://doi.org/10.1002/0470053488).