- Email: [email protected]
Inverse agonism: theory and practice
CURRENT
A W A R E N E S S
should greatly facilitate the search for subtype selective prostanoids with novel therapeutic applications. Selected references
Acknowledgments The authors acknowledge the financial support of Allergan, RW Johnson, the National Institute of Health, the Arizona Affiliate of the American Heart Association, and the National Science Foundation.
1 Coleman,R.A.,Smith,W.L.andNarumiya, S. (1994)Pharmacol. Rev.46, 205-229 2 Hirata,M. et al. (1991)Nature 349,617-620 3 Abramovitz,M. et al. (1994)J. BioL Chem. 269,2632-2636 4 Boie, Y. et al. (1994) J. Biol. Chem. 269, 12173-12178 5 Funk,C. D. etal. (1993)J. Biol. Chem. 268, 26767-26772 6 Regan,J. W.et al. (1994)MoL Pharmacol. 46, 213-220 7 Regan,J. W. et al. (1994) Br. ]. Pharmacol. 112,377-385 8 Bastien,L., Sawyer, N., Grygorczyk,R., Metters,K.M. and Adam,M. (1994)J. Biol. Chem. 269,11873-11877
D
E
B
A
T
9 Hirata, M., Kakizuka, A., Aizawa, M., Ushikubi, F. and Narumiya, S. (1994) Proc. Natl Acad. Sci. USA 91, 11192-11196 10 Funk, C. D., Furci, L., Moran, N. and Fitzgerald, G. A. (1993) Mol. Pharmacol. 44 934-939 11 Honda, A. et al. (1993) J. Biol. Chem. 268, 7759-7762 12 Nishigaki, N. et al. (1995) FEBS Lett. 364, 339-341 13 Sugimoto, Y. et al. (1993) J. Biol. Chem. 268, 2712-2718 14 Namba, T. et al. (1993) Nature 365, 166-170 15 An, S., Yang, J., So, S. W., Zeng, L. and Goetzl, E. J. (1994) Biochemistry 33, 14496-14502 16 Schmid, A., Thierauch, K., Schleuning, W. and Dinter, H. (1995) Eur. J. Biochem. 228, 23-30
17 Breyer, R. M. et al. (1994) J. Biol. Chem. 269, 6163-6169
2 5 6
TiPS - August 1995 (Vol. 16)
AH23848: (lc~[Z],213,5c,)-(±)-7-(5-
{[(1,1'-biphenyl)-4-yl]methoxy}2-[4-morpholinyl]-3-oxocydopentyl)-4-heptenoic acid
E
some sort is needed. However, the simplest model of this kind I cannot account for system-dependent variation between agonism and inverse agonism. This behaviour requires extension of the model in the way described below by Terry Kenakin. However, to accept the need for a more complex model we need to be sure that experimental data demand it. Gordon Baxter and Nick Tilford draw attention to the practical
Pharmacological Proteus? One of the central themes in pharmacology is the nature of efficacy. Another has been the proper taxonomy of drugs, that is, the full characterization of the receptor properties of ligands 1. A theoretical new class of receptor ligand may relate to both of these primary questions. The discovery of constitutively active receptor systems and the observation of inverse agonism has raised the possibility for the detection of a new class of ligand. While it is clear that a ligand that destabilizes receptor-G protein coupling, or selectively binds to the inactivated form of the receptor (or both), will be an inverse agonist, theoretically there
Chemical name
18 Lefkowitz, R. J. (1993) Cell 74, 409-412
Inverse agonism: theory and practice The concepts of constitutive receptor activation and inverse agonism are currently the subject of considerable attention. One of the crucial issues that has arisen is whether a ligand can act as an agonist in one system but as an inverse agonist in another. This question needs to be addressed both from a theoretical and a practical point of view. If inverse agonism is accepted as an experimental reality, a two-state receptor model of
19 Negishi, M., Sugimoto, Y., lrie, A., Narumiya, S. and Ichikawa, A. (1993) J. Biol. Chem. 268, 9517-9521 20 Raychowdhury, M. K. et al. (1994) ]. Biol. Chem. 269, 19256-19261 21 Halushka, P. V., Mais, D. E., Mayeux, P. R. and Morinelli, T. A. (1989) Annu. Rev. Pharmacol. Toxicol. 10, 213-239 22 Toh, H., Ichikawa, A. and Narumiya, S. (1995) FEBS Lett. 361, 17-21 23 Niising, R. M. et al. (1993) J. Biol. Chem. 268, 25253-25259
exists the possibility that there are ligands that produce a receptor state that can activate G proteins, but to a lesser extent than the spontaneous active state. Under these circumstances, a spectrum of activity from partial agonism to inverse agonism could be observed. The response to such a ligand would be protean (likened to the Greek god of mythology Proteus who could assume different forms at will) and dependent upon system parameters, not receptor type. In receptor systems where there is little spontaneous formation of the activated receptor state, the receptor-activating property of the ligand will dominate and positive
difficulty of excluding the presence of contaminating agonists. On this basis, they provide an explanation for such variation in agonist activity which avoids complication of the model. Paul Left Astra Research Loughborough, Bakewell Road, Loughborough, UK LE11ORH. Reference
1 Left, P. (1995) Trends Pharmacol. Sci. 16, 89-97
agonism will be observed. In systems where there is considerable formation of the activated receptor state (or the stimulus-response mechanism is tuned to the observation of the resultant of the activated complexes), conversion to the inactivated receptor form will dominate and inverse agonism will result. There would be a spectum of sytem conditions where this would occur therefore a point would also exist for the observance of antagonism. The factors that dictate when these properties will be observed are : (1) the magnitude of the allosteric constant describing the equilibrium between active and inactive receptors; and (2) the stoichiometric ratio of receptors to G proteins.
© 1994, Elsevier Science Ltd
A W A R E N E S S
should greatly facilitate the search for subtype selective prostanoids with novel therapeutic applications. Selected references
Acknowledgments The authors acknowledge the financial support of Allergan, RW Johnson, the National Institute of Health, the Arizona Affiliate of the American Heart Association, and the National Science Foundation.
1 Coleman,R.A.,Smith,W.L.andNarumiya, S. (1994)Pharmacol. Rev.46, 205-229 2 Hirata,M. et al. (1991)Nature 349,617-620 3 Abramovitz,M. et al. (1994)J. BioL Chem. 269,2632-2636 4 Boie, Y. et al. (1994) J. Biol. Chem. 269, 12173-12178 5 Funk,C. D. etal. (1993)J. Biol. Chem. 268, 26767-26772 6 Regan,J. W.et al. (1994)MoL Pharmacol. 46, 213-220 7 Regan,J. W. et al. (1994) Br. ]. Pharmacol. 112,377-385 8 Bastien,L., Sawyer, N., Grygorczyk,R., Metters,K.M. and Adam,M. (1994)J. Biol. Chem. 269,11873-11877
D
E
B
A
T
9 Hirata, M., Kakizuka, A., Aizawa, M., Ushikubi, F. and Narumiya, S. (1994) Proc. Natl Acad. Sci. USA 91, 11192-11196 10 Funk, C. D., Furci, L., Moran, N. and Fitzgerald, G. A. (1993) Mol. Pharmacol. 44 934-939 11 Honda, A. et al. (1993) J. Biol. Chem. 268, 7759-7762 12 Nishigaki, N. et al. (1995) FEBS Lett. 364, 339-341 13 Sugimoto, Y. et al. (1993) J. Biol. Chem. 268, 2712-2718 14 Namba, T. et al. (1993) Nature 365, 166-170 15 An, S., Yang, J., So, S. W., Zeng, L. and Goetzl, E. J. (1994) Biochemistry 33, 14496-14502 16 Schmid, A., Thierauch, K., Schleuning, W. and Dinter, H. (1995) Eur. J. Biochem. 228, 23-30
17 Breyer, R. M. et al. (1994) J. Biol. Chem. 269, 6163-6169
2 5 6
TiPS - August 1995 (Vol. 16)
AH23848: (lc~[Z],213,5c,)-(±)-7-(5-
{[(1,1'-biphenyl)-4-yl]methoxy}2-[4-morpholinyl]-3-oxocydopentyl)-4-heptenoic acid
E
some sort is needed. However, the simplest model of this kind I cannot account for system-dependent variation between agonism and inverse agonism. This behaviour requires extension of the model in the way described below by Terry Kenakin. However, to accept the need for a more complex model we need to be sure that experimental data demand it. Gordon Baxter and Nick Tilford draw attention to the practical
Pharmacological Proteus? One of the central themes in pharmacology is the nature of efficacy. Another has been the proper taxonomy of drugs, that is, the full characterization of the receptor properties of ligands 1. A theoretical new class of receptor ligand may relate to both of these primary questions. The discovery of constitutively active receptor systems and the observation of inverse agonism has raised the possibility for the detection of a new class of ligand. While it is clear that a ligand that destabilizes receptor-G protein coupling, or selectively binds to the inactivated form of the receptor (or both), will be an inverse agonist, theoretically there
Chemical name
18 Lefkowitz, R. J. (1993) Cell 74, 409-412
Inverse agonism: theory and practice The concepts of constitutive receptor activation and inverse agonism are currently the subject of considerable attention. One of the crucial issues that has arisen is whether a ligand can act as an agonist in one system but as an inverse agonist in another. This question needs to be addressed both from a theoretical and a practical point of view. If inverse agonism is accepted as an experimental reality, a two-state receptor model of
19 Negishi, M., Sugimoto, Y., lrie, A., Narumiya, S. and Ichikawa, A. (1993) J. Biol. Chem. 268, 9517-9521 20 Raychowdhury, M. K. et al. (1994) ]. Biol. Chem. 269, 19256-19261 21 Halushka, P. V., Mais, D. E., Mayeux, P. R. and Morinelli, T. A. (1989) Annu. Rev. Pharmacol. Toxicol. 10, 213-239 22 Toh, H., Ichikawa, A. and Narumiya, S. (1995) FEBS Lett. 361, 17-21 23 Niising, R. M. et al. (1993) J. Biol. Chem. 268, 25253-25259
exists the possibility that there are ligands that produce a receptor state that can activate G proteins, but to a lesser extent than the spontaneous active state. Under these circumstances, a spectrum of activity from partial agonism to inverse agonism could be observed. The response to such a ligand would be protean (likened to the Greek god of mythology Proteus who could assume different forms at will) and dependent upon system parameters, not receptor type. In receptor systems where there is little spontaneous formation of the activated receptor state, the receptor-activating property of the ligand will dominate and positive
difficulty of excluding the presence of contaminating agonists. On this basis, they provide an explanation for such variation in agonist activity which avoids complication of the model. Paul Left Astra Research Loughborough, Bakewell Road, Loughborough, UK LE11ORH. Reference
1 Left, P. (1995) Trends Pharmacol. Sci. 16, 89-97
agonism will be observed. In systems where there is considerable formation of the activated receptor state (or the stimulus-response mechanism is tuned to the observation of the resultant of the activated complexes), conversion to the inactivated receptor form will dominate and inverse agonism will result. There would be a spectum of sytem conditions where this would occur therefore a point would also exist for the observance of antagonism. The factors that dictate when these properties will be observed are : (1) the magnitude of the allosteric constant describing the equilibrium between active and inactive receptors; and (2) the stoichiometric ratio of receptors to G proteins.
© 1994, Elsevier Science Ltd