Abstract
Peptidic angiotensin II (Ang) antagonists have been mostly reported to behave in a more or less competitive fashion. Thus, reinforcing the view of competitive analogues being compounds which can reversibly bind without producing any biological response to the receptor as well as competing with an agonist (e.g. Ang or other peptidic agonists) for the same site. Recently, a new concept was introduced that changes the classical view of agonist-antagonist action. This concept presents the receptor as a dynamic structure capable of undergoing a conformational change between a biologically active and an inactive form. A bound ligand may shift the equilibrium to either side, according to its pharmacological character as an agonist or an antagonist: An antagonist favoring the inactive form of the receptor represents what is called an “inverse agonist”. All peptidic Ang analogues bind to the same locus on the AT1 receptor but non-peptidic AT1 binding compounds (e.g. L-158,809 and DuP 753) seem to bind to different loci. Furthermore, it has also been shown that non-peptidic Ang antagonists do not possess the ability to recognize Ang receptors from amphibian or avian origins. In the present contribution, we attempt to fathom the molecular parameters that bring the transition from an agonistic to an antagonistic behaviour in order to select the compounds that display most profoundly these antagonistic features. We believe to possess the necessary tools (enlarged but planar aromatic side-chains in position 8) in order to explore the concept of inverse agonism on the mammalian AT1 receptor.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Kjelsberg, M.A., Cotecchia, S., Ostrowski, J., Caron, M.G. and Lefkowitz, R. J., Constitutive Activation of the α1B-Adrenergic Receptor by All Amino Acid Substitution at a Single Site, J. Biol. Chem. 267 (1992) 1430–1433.
Allen, L.F., Lefkowitz, R.J., Caron, M. and Cotecchia, S., G-protein-coupled receptor genes as protooncogenes: Constitutively activating mutation of the α1B-adrenergic receptor enhances mitogenesis and tumorigenecity, Proc. Natl. Acad. Sci. USA 88 (1991) 11354–11358.
Samama, P., Cotecchia, S., Costa, T. and Lefkowitz, R.J., A Mutation-induced Activated State of the β2-Adrenergic Receptor, J. Biol. Chem. 268 (1993) 4625–4636.
Robinson, P.R., Cohen, G.B. Zhukovsky, E.A. and Oprian, D.D., Constitutively active mutants of rhodopsin, Neuron 9 (1992) 719–725.
Schutz, W. and Freissmuth, M., Reverse intrinsic activity of antagonists on G protein-coupled receptors, Trends Pharmacol. Sci. 13 (1992) 376–380.
Costa, T., Ogino, Y., Munson, P.J., Onaran, H.O. and Rodbard, D., Drug efficacy at guanine nucleotide-binding regulatory protein-linked receptors: Thermodynamic interpretation of negative antagonism and receptor activity in the absence of ligand, Mol. Pharmacol. 41 (1992) 549–560.
Barker, E.L., Westphal, R.S. Schmidt, D. and Sanders-Bush, E., Constitutively active 5′-hydroxytryp-tamine 2C receptors reveal novel inverse agonist activity of receptor ligands, J. Biol. Chem. 269 (1994) 11687–11690.
Chidiac, P., Hebert, T., Valiquette, M., Dennis, M. and Bouvier, M., Inverse agonist activity of β-adrenergic antagonists, Mol. Pharmacol. 45 (1994) 490–499.
Parma, J., Duprez, L., Van Sade, J., Cochaux, P., Gervy, P., Mockel, J., Dumont, J. and Vassart, G., Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas, Nature 365 (1993) 649–651.
Shenker, A., Laue, L., Kosug, S., Merendino, J.J., Minegishi, T. and Cutler, J.B., A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty, Nature 365 (1993) 652–654.
Young, D., Waitches, G., Birchmeier, C., Fasano, O. and Wigler, M., Isolation and characterization of a new cellular oncogene encoding a protein with multiple potential transmembrane domains, Cell 45 (1986) 711–719.
Regoli, D., Park, W.K. and Rioux, F., Pharmacology of Angiotensin, Pharmacological Reviews 26 (1974) 69–123.
Griendling, K.K., Lassèque, B. and Alexander, R.W., The Vascular Angiotensin (AT1) Receptor, Thrombosis and Haemostasis 70 (1993) 188–192.
Timmermans, P.B.M.W.M., Wong, P.C., Chiu, A.T., Herblin, W.F., Benfield, P., Carini, D.J., Lee, R.J., Wexler, R.R., Saye, J.A.M. and Smith, R.D., Angiotensin II Receptors and Angiotensin II Receptor Antagonists, Pharmacological Reviews 45 (1993) 205–247.
Dudley, D.T., Panek, R.L., Major, T.C., Lu, G.H., Burns, R.F., Klinkefus, B.A., Hodges, J.C. and Weishaar, R.E., Subclasses of angiotensin II binding sites and their functional significance, Mol. Pharmacol. 38 (1990) 370–377.
Bottari, S.P., King, I.N., Reichlin, S., Dahlstroem, I., Lydon, N. and DeGasparo, M., The angiotensin AT2 receptor stimulates protein tyrosin Phosphatase activity and mediates inhibition of particulate guanylate cyclase, Biochem. Biophys. Res. Commun. 183 (1992) 206–211.
Kambayashi, Y., Bardhan, S., Takahashi, K., Tsuzuki, S. Inui, H., Hamakubo and Inagami, T., Molecular cloning of a novel angiotensin II receptor isoform involved in phosphotyrosine Phosphatase inhibition, J. Biol. Chem. 268 (1993) 24543–24546.
Bernier, S.G., Fournier, A. and Guillemette, G., A specific binding site recognizing a fragment of angiotensin II in bovine adrenal cortex membranes, Eur. J. Pharmacol. 271 (1994) 55–63.
Siemens, I.R., Reagan, L.P., Yee, D.K. and Fluharty, S.J., Biochemical characterizaton of two distinct angiotensin AT2 receptor populations in murine neuroblastoma N1E-115 cells, J. Neurochem. 62 (1994) 2106–2115.
Servant, G., Escher, E. and Guillemette, G., Non-AT1 and non-AT2 binding sites observed in PC12 cells after confluency, (to be published).
Murphy, T.J., Nakamura, Y., Takeuchi, K. and Alexander, R.W., A cloned angiotensin receptor isoform from the turkey adrenal gland is pharmacologically distinct from mammalian angiotensin receptors, Mol. Pharmacol. 44 (1993) 1–7.
Ji, H., Sanberg, K., Zhang, Y., Catt, K.J., Molecualr cloning, sequencing and functional expression of an amphibian angiotensin II receptor, Biochem. Biophys. Res. Commun. 194 (1993) 756–762.
Nishimura, H., Walker, O.E., Patton, C.M., Madison, A.T., Chiu, A.T. and Keiser, J., Novel angiotensin receptor subtypes in fowl, Am. J. Physiol. 267 (1994) R1174–R1181.
Wong, P.C., Hart, S.D., Chiu, A.T., Herblin, W.F. Carini, D.J., Smith, R.D., Wexler, R.R. and Timmermans, P.B.M.W.M., Pharmacology of DuP 532, a Selective and Noncompetitive AT1 Receptor Antagonist, J. Pharmacol. Experm. Therap. 259 (1991) 861–870.
Chang, R.S.L., Siegl, P.K.S., Clineschmidt, B.V., Mantlo, N.B., Chakravarty, P.K., Greenlee, W.J., Patchett, A.A. and Lotti, V.J., In Vitro Pharmacology of L-158, 809, a New Highly Potent and Selective Angiotensin II Receptor Antagonist, J. Pharmacol. Experm. Therap. 262 (1992) 133–138.
Perlman, S. Schambye, H.T., Riviero, R.A., Greenlee, W.J., Hjorth, S.A. and Schwartz, T.W., Non-peptidic angiotensin agonist. Functional and molecular interaction with the AT1 receptor, J. Biol. Chem. 270 (1995) 1493–1496.
Pérodin, J and Escher, E.(unpuplished results).
Fraker, PJ. and Speck, J.C., Protein and cell iodination with a sparingly soluble chloroamine, 1, 3, 4, 6-tetrachloro-3a, 6a-diphenylglycoloryl, Biochem. Biophys. Res. Commun. 80 (1978) 849–857.
Merrifield, R.B., Solid-phase peptide synthesis. I: The synthesis of a tetrapeptide, J. Am. Chem. Soc, 85 (1963)2149–2154.
Leduc, R., Bernier, M. and Escher, E., Angiotensin-II Analogues. I: Synthesis and Incorporation of the Halogenated Amino Acids 3-(4′-Iodophenyl)alanine, 3-(3′, 5′-Dibromo-4′-chlorophenyl)alanine, 3-(3′, 4′, 5′-Tribromophenyl)alanine, and 3-(2′, 3′, 4′, 5′, 6′-Pentabromophenyl)alanine, Helvetica Chimica acta 66 (1983) 960–970.
Escher, E., Bernier, M. and Parent, P., Angiotensin II Analogues. Part II. Synthesis and Incorporation of the Sulfur-Containing Aromatic Amino Acids: L-(4′-SH)Phe, L-(4′-SO2NH2)Phe, L-(4′-SO3 −)Phe and L-(4′-S-CH3)Phe, Helvetica Chimica acta 66 (1983) 1355–1365.
Quang, K.D., Thanei, P., Caviezel, M. and Schwyzer, R., The Synthesis of (S)-(+)-2-Amino-3-(1-adamantyl)-propionic Acid (L-(+)-Adamantylalanine, Ada) as a “Fat” or “Super” Analogue of Leucine and Phenylalanine, Helvetica Chimica acta 62 (1979) 956–964.
Tartar, A., Demarly, A., Sergheraert, C. and Escher, E., Metallocenic angiotensin II analogues, “Peptides ′83” V. Hruby (Ed) Pierce Corp., Rockford, III, 1984, pp. 377-380.
Hsieh, K.H., LaHann, T.R. and Speth, R.C., Topographic Probes of Angiotensin and Receptor: Potent Angiotensin II Agonist Containing Diphenylalanine and Long-Acting Antagonists Containing Bipheny-lalanine and 2-Indan Amino Acid in Position 8, J. Med. Chem. 32 (1989) 898–903.
Samanen, J., Narindray, D., Adams Jr, W., Cash, T., Yellin, T. and Regoli, D., Effects of D-Amino Acid Substitution on Antagonist Activities of Angiotensin II Analogues, J. Med. Chem. 31 (1988) 510–516.
Leukart, O., Caviezel, M., Eberie, A., Escher, E., Tun-Kyi, A. and Schwyzer, R., L-o-Carboranyl, a Boron Analogue of Phenylalanine, Helvetica Chimica Acta 59 (1976) 2184–2187.
Hansch, C., Leo, A., Unger, S.H., Kim, K.H., Nikaitani, D. and Lien, E.J., “Aromatic” Substituent Constants for Structure-Activity Correlations, J. Med. Chem. 16 (1973) 1207–1216.
Holck, M., Bossé, R., Fischli, W., Gerold, H. and Escher, E., An Angiotensin II antagonist with strongly prolonged action, Biochem. Biophys. Res. Commun. 160 (1989) 1350–1356.
Bossé, R., Gerold, H., Fischli, W., Hoick, M. and Escher, E., An angiotensin antagonist with prolonged action and antihypertensive properties, J. Cardiovasc. Pharmacol. 16 (1990) S50–S55.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1996 Springer Science+Business Media New York
About this chapter
Cite this chapter
Pérodin, J. et al. (1996). Structure-Activity Relationship of the Agonist-Antagonist Transition on the Type 1 Angiotensin II Receptor; the Search for Inverse Agonists. In: Raizada, M.K., Phillips, M.I., Sumners, C. (eds) Recent Advances in Cellular and Molecular Aspects of Angiotensin Receptors. Advances in Experimental Medicine and Biology, vol 396. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-1376-0_14
Download citation
DOI: https://doi.org/10.1007/978-1-4899-1376-0_14
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4899-1378-4
Online ISBN: 978-1-4899-1376-0
eBook Packages: Springer Book Archive