Abstract
Highly selective heterocyclic opioid ligands with potent δ-antagonist activity have been developed on the basis of the “message-address” concept. Using this strategy, benzofuran derivatives corresponding to the non-selective opioid antagonist, naloxone, and to the μ-opioid receptor selective agonists, oxymorphone and oxycodone, were synthesized. In vitro opioid receptor binding profiles and agonist/antagonist character of these compounds were determined in rat brain membrane preparations with highly selective radioligands. All three benzofuran derivatives displayed high affinities for the δ-opioid receptor, much less potency toward the μ-binding site, and were the least effective at the κ-site. The results indicated that the addition of the bezofuran moiety to these fused ring opioids confers δ-receptor selectivity. The Na+ indices suggested a partial agonist character for oxymorphone- and oxycodone-benzofuran, and an antagonist character for naloxone-benzofuran. These compounds were capable of irreversible inhibition of opioid binding sites in a dosedependent.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
REFERENCES
Borsodi, A., and Tóth, G. 1995. Characterization of opioid receptor types and subtypes with new ligands. Ann. NY Acad. Sci. 757:339-352.
Schiller, P. W. 1991. Development of receptor-specific opioid peptide analogues. Pages 301-340, in Ellis, G. P., and West, G. B. (eds.), Progress in Medicinal Chemistry, Vol. 28, Elsevier Science Publishers, Amsterdam.
Takemori, A. E., and Portoghese, P. S. 1992. Selective naltrexone-derived opioid receptor antagonists. Annu. Rev. Pharmacol. Toxicol. 32:239-269.
Gold, M. S., Dackis, C. A., Pottash, A. L., Sternbach, H. H., and Anitto, W. J. 1982. Naltrexone, opiate addiction and endorphins. Med. Res. Rev. 2:211-246.
Zimmerman, D. M., and Leander, J. D. 1990. Selective opioid receptor agonists and antagonists: research tools and potential therapeutic agents. J. Med. Chem 33:895-902.
Schwyzer, R. 1977. ACTH: a short introductory review. Ann. NY Acad. Sci. 247:3-36.
Portoghese, P. S. 1989. Bivalent ligands and the message-address concept in the design of selective opioid receptor antagonists. Trends Pharmacol. Sci. 10:230-235.
Portoghese, P. S., Sultana, M., Nagase, N., and Takemori, A. E. 1988. Application of the message-address concept in the design of highly potent and selective non-peptide δ opioid receptor antagonist. J. Med. Chem. 31:281-282.
Portoghese, P. S., Sultana, M., and Takemori, A. E. 1990. Design of peptidomimetic δ opioid receptor antagonists using the message-address concept. J. Med. Chem. 33:1714-1720.
Portoghese, P. S., Nagase, H., MaloneyHuss, K. E., Lin, A.-E., and Takemori, A. E. 1991. Role of spacer and address components in peptidomimetic δ opioid receptor antagonists related to naltrindole. J. Med. Chem. 34:1715-1720.
Krizsan, D., Varga, E., Hosztafi, S., Benyhe, S., Szücs, M., and Borsodi, A. 1991. Irreversible blockade of the high and low affinity [3H]naloxone binding sites by C-6 derivatives of morphinane-6-ones. Life Sci. 48:439-451.
Fürst, S., Fiederman, T., Hosztafi, S., and Borsodi, A. 1994. Different μ opioid receptor subtypes may mediate C-6 substitutes oxycodone derivatives induced antinociceptive, gastrointestinal and respiratory actions. Regul. Pept. Suppl 1:S105-S106.
Tóth, G., Krámer, T. H., Sirokman, F., Borsodi, A., and Ronái, A. Z. 1982. Preparation of [7,8,19,20-3H]naloxone of high specific activity. J. Label. Com. Radiopharm. 19:1021-1030.
Yamamura, M. S., Horvath, R., Tóth, G., Ötvös, F., Malatynska, E., Knapp, R. J., Porreca, F., Hruby, V. J., and Yamamura, H. I. 1992. Characterization of [3H]naltrindole binding to delta opioid receptors in rat brain. Life Sci. 50:PL119-PL124.
Borsodi, A., Ozdemirler, G., Nevin, S. T., Kabasakal, L., Ötvös, F., and Tóth, G. 1993. Binding characteristics of the delta antagonist [1,5′-3H]naltrindole in rat brain membranes. Br. J. Pharmacol. 109:17.
Nevin, S. T., Kabasakal, L., Ötvös, F., Tóth, G., and Borosodi A. 1994. Binding characteristics of the novel highly specific delta agonist [3H]Ile5,6deltorphin II. Neuropeptides 26:261-265.
Nevin, S. T., Tóth, G., Weltrowska, G., Schiller, P. W., and Borsodi, A. 1995. Synthesis and binding characteristics of tritiated TIPP[ω], a highly specific and stable delta opioid antagonist. Life Sci. 56:PL225-PL230.
Simon, J., Benyhe, S., Abutidze, K., Borsodi, A., Szücs, M., and Wollemann, M. 1986. Kinetics and physical parameters of rat brain opioid receptors solubilized by digitonin and CHAPS. J. Neurochem. 46:695-701.
Vaughn, L. K., Knall, R. J., Tóth, G., Wan, Y.-P., Hruby, V. J., and Yamamura, H. I. 1989. A high affinity, highly selective ligand for the delta opioid receptor: [3H]-[D-Pen2,pCl-Phe4,D-Pen5]enkephalin. Life Sci. 45:1001-1008.
Bradford, M. M. 1986. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of dye-binding. Anal. Biochem. 72:248-254.
Munson, P. J., and Rodbard, D. 1980. LIGAND: a versatile computerized approach for characterization of ligand binding studies. Anal. Biochem. 107:220-227.
Ötkem, H. A., Varga, E., Hepp, J., Medzihradzky, K., Lajtha, A., and Borsodi, A. 1991. Opioid receptor labelling with the chlormethyl ketone derivative of [3H]-Tyr-D-Ala-Gly-(Me)Phe-Gly-ol (DAMGO) I: Binding properties of [3H]-Tyr-D-Ala-Gly-(Me)Phechlormethyl ketone. Life Sci. 48:1757-1762.
Handa, B. K., Lane, A. C., Lord, J. A. H., Morgan, B. A., Rance, M. J., Smith, C. F. C. 1981. Analogues of β-LPH61–64 possessing selective agonist activity at μ-opiate receptors. Eur. J. Pharmacol. 70:531-540.
Lahti, R. A., Mickelson, M. M., McCall, J. M., and Von Voightlander, P. F. 1985. [3HU69-593, a highly selective ligand for the opioid κ receptor. Eur. J. Pharmacol. 109:281-284.
Pert, C. B., and Snyder, S. H. 1973. Properties of opiate-receptor binding in rat brain. Proc. Natl. Acad. Sci. 70:2243-2247.
Oguri, K., Yamada-Mori, I., Shigezane, J., Hirano, T., and Yoshimura, H. 1987. Enhanced binding of morphine and nalorphine to opioid delta receptor by glucuronate and sulfate conjugation at the 6-position. Life Sci. 41:1457-1467.
Chen, Z. R., Irvine, R. J., Somogyi, A. A., and Bochner, F. 1991. Mu receptor binding of some commonly used opioids and their metabolites. Life Sci. 48:2165-2171.
Mignat, C., Wille, U., and Ziegler, A. 1995. Affinity profiles of morphine, codeine, dihydrocodeine and their glucuronides at opioid receptor subtypes. Life Sci. 56:793-799.
Pasternak, G. W., Bodnar, R. J., Clark, J. A., and Inturrisi, C. E. 1987. Morphine-6-glucuronide, a potent mu agonist. Life Sci. 41:2845-2849.
Rónai, A. Z., Gyires, K., Schmidhammer, H., Hosztafi, S., Borsodi, A., Spetea, M., Friedmann, M., Riba, P., and Fürst, Zs. 1997. In vitro and in vivo pharmacology of novel, naltrindole-related compounds. Med. Sci. Monit. 3:1-5.
Kosterlitz, H. W., and Paterson, S. J. 1980. Characterization of opioid receptors in nervous tissue. Proc. R. Soc. London Ser B. 210:113-122.
Pert, C. B., and Snyder, S. 1974. Opiate receptor binding of agonists and antagonists affected differentially by sodium. Mol. Pharmacol. 10:808-879.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Spetea, M., Nevin, S.T., Hosztafi, S. et al. Affinity Profiles of Novel δ-Receptor Selective Benzofuran Derivatives of Non-Peptide Opioids. Neurochem Res 23, 1211–1216 (1998). https://doi.org/10.1023/A:1020738304036
Issue Date:
DOI: https://doi.org/10.1023/A:1020738304036