Abstract
Piperidine derivatives are known to exhibit analgesic activities and are likely to possess the ability to block the effects of prostaglandins through inhibition of downstream signaling pathways. The present study investigated the activity of five derivatives (PD2-6) of 4-(4′-bromophenyl)-4-piperidinol (PD1), against pain and platelet aggregation mediated by the release of prostaglandins and thromboxane A2, respectively. The results showed that compound PD1 and its two phenacyl derivatives PD3 and PD5 exhibited a highly significant analgesic effect (p < 0.01), whereas PD4 and PD6 also showed significant activity. PD3, the most active analgesic compound when docked to the opioid receptor, had interactions between the oxygen of its nitro group and the amino group of ARG 573, indicating a distance of 1.2563 Å. The antiplatelet data showed that compound PD5 (4-(4′-bromo-phenyl)-4-hydroxy-1-[2-(2″,4″-dimethoxyphenyl)-2-oxo-ethyl]-piperidinium bromide) had an IC50 = 0.06 mM, which was the most active compound, whereas PD3 was the second most active compound against platelet aggregating factor-induced aggregation with an IC50 = 80 mM. Acetyl salicylic acid (IC50 = 150 μM) was used as a positive control.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Becker, D.P., Villamil, C. I., Barta, T. E., Bedell, L. J., Boehm, T. L., Decrescenzo, G. A., Freskos, J. N., Getman, D. P., Hockerman, S., Heintz, R., Howard, S. C., Li, M. H., McDonald, J. J., Carron, C. P., Funckes-Shippy, C. L., Mehta, P. P., Munie, G. E., and Swearingen, C. A., Synthesis and structure-activity relationships of beta- and alpha-piperidine sulfone hydroxamic acid matrix metalloproteinase inhibitors with oral antitumor efficacy. J. Med. Chem., 48, 6713–6730 (2005).
DesJarlais, R.L., Sheridan, R. P., Seibel, G. L., Dixon, J. S., Kuntz, I. D., and Venkataraghavan, R., Docking: successes and challenges. J. Med. Chem., 31, 722–729 (1988).
Di Stasi, L.C., Costa, M., Mendaçolli, S. L., Kirizawa, M., Gomes, C., and Trolin, G., Screening in mice of some medicinal plants used for analgesic purposes in the state of São Paulo. J. Ethnopharmacol., 24, 205–211 (1988).
Erol, D.D. and Demirdamar, R., Analgesic and anti-inflammatory activity screening of 6-acyl-3-piperidinomethyl-2(3H)-benzoxazolone derivatives. Farmaco, 49, 663–666 (1994).
Feng, Z., Gollamudi, R., Dillingham, E. O., Bond, S. E., Lyman, B. A., Purcell, W. P., Hill, R. J., and Korfmacher, W. A., Molecular determinants of the platelet aggregation inhibitory activity of carbamoylpiperidines. J. Med. Chem., 35, 2952–2958 (1992).
Guo, Z., Zheng, X., Thompson, W., Dugdale, M., and Gollamudi, R., New carbamoylpiperidines as human platelet aggregation inhibitors. Bioorg. Med. Chem., 8, 1041–1058 (2000).
Imamura, S., Nishikawa, Y., Ichikawa, T., Hattori, T., Matsushita, Y., Hashiguchi, S., Kanzaki, N., Iizawa, Y., Baba, M., and Sugihara, Y., CCR5 antagonists as anti-HIV-1 agents. Part 3. Synthesis and biological evaluation of piperidine-4-carboxamide derivatives. Bioorg. Med. Chem., 13, 397–416 (2005).
Jones, G., Willett, P., Glen, R. C., Leach, A. R., and Taylor, R., Development and validation of a genetic algorithm for flexible. J. Mol. Biol., 267, 727–748 (1997).
Kordik, C.P., Luo, C., Gutherman, M., Vaidya, A. H., Rosenthal, D. I., Crooke, J. J., McKenney, S. L., Plata-Salaman, C. R., and Reitz, A. B., Diarylacetylene piperidinyl amides as novel anxiolytics. Bioorg. Med. Chem. Lett., 16, 3065–3067 (2006).
Köksal, M. and Bilge, S. S., Synthesis and antidepressantlike profile of novel 1-aryl-3-[(4-benzyl) piperidine-1-yl] propane derivatives. Arch. Pharm. (Weinheim), 340, 299–303 (2007).
Lawrence, W.P., Howell, R. D., and Gollamudi, R., Antiplatelet activity of nipecotamides in experimental thrombosis in mice. J. Pharm. Sci., 83, 222–225 (1994).
Miguel, O.G., Santos, A. R., Calixto, J. B., Delle Monache, F., and Yunes, R. A., Antinociceptive activity of the natural piperidine alkaloid hydrochlorides from Syphocampylus verticellatus. Z. Naturforsch. C, 57, 81–84 (2002).
Montrucchio, G., Alloattig, G., and Camussi, G., Role of platelet-activating factor in cardiovascular pathophysiology. Physiol. Rev., 1669-1699 (2000).
Mushtaq, N., Saify, Z. S., Akhtar, S., Arif, M., Haider, S., and Saba, N., Synthesis of some novel analogues of 4-(1-pyrrolidinyl) Perpridine and their effects on plasma glucose level. Pak. J. Phar. Sci., 23, 220–223 (2010).
Ramachandran, R., Rani, M., Senthan, S., Jeong, Y. T., and Kabilan, S., Biological activity of piperidine derivatives. Eur. J. Med. Chem., 46, 1926–1934 (2011).
Rasheed, H., Tirmizi, A. H., Salahuddin, F., Rizvi, N. B., Arshad, F., Farooq, S. Z., and Saeed, S. A., Calcium signaling in human platelet aggregation mediated by platelet activating factor and calcium ionophore, A23187. J. Biol. Sci., 4, 117–121 (2004a).
Rasheed, H. and Saeed, S. A., Involvement of thromboxane A2 and tyrosine kinase in the synergistic interaction of platelet activating factor and calcium ionophore A23187 in human platelet aggregation. Exp. Mol. Med., 36, 220–225 (2004b).
Saeed, M., Saify, Z. S., Gilani, A. H., Haider, M. S., and Iqbal, Z., Studies on the effects of piperidine derivatives on blood pressure and smooth muscles contractions. Arch. Pharm. Res., 21, 370–373 (1998).
Saify, Z.S., Nisa, M., Azhr, K. F., Azim, M. K., Rasheed, H., Mushtaq, N., Arain, M. A., Haider, S., Khanum, M., and Ahmed, W., Characterization of plasmodium falciparum aspartic protease inhibition by piperidine derivatives. Nat. Prod. Res., 25, 1965–1968 (2011).
Thaler, F., Varasi, M., Carenzi, G., Colombo, A., Abate, A., Bigogno, C., Boggio, R., Carrara, S., Cataudella, R. D. F., Reali, V., Vultaggio, S., Dondio, G., Gagliardi, S., and Mercurio, C., Spiro [chromane-2,4′-piperidine]-based histone deacetylase inhibitors with improved in vivo activity. Chem. Med. Chem., 7, 709–21 (2012).
Zheng, X., Salgia, S. R., Thompson, W. B., Dillingham, E. O., Bond, S. E., Feng, Z., Prasad, K. R., and Gollamudi, R., Design and synthesis of piperidine-3-carboxamides as human platelet aggregation inhibitors. J. Med. Chem., 38, 180–188 (1995).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Saify, Z.S., Rasheed, H., Mushtaq, N. et al. Investigation of piperidine derivatives in ex vivo models of pain and platelet aggregation. Arch. Pharm. Res. 35, 1953–1959 (2012). https://doi.org/10.1007/s12272-012-1112-9
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12272-012-1112-9