Abstract
Messenger molecules assume the task of conveying and transmitting information between cells. These molecules can be as small as single ions, but can also attain the formidable size of signaling peptides all the way to proteins. They bind to a membrane-bound receptor on the extracellular side to transmit signals. There are hardly any alternative pathways for these messenger molecules because substances such as dopamine, histamine, or adrenaline, and also peptides and proteins such as insulin, interleukins, angiotensin, endothelin, or neurokinin cannot cross the cell membrane. Ligand-binding signals are transmitted to the interior of the cell by a transition of the conformational state of the receptors. In the case of activation, the bound ligand stabilizes the active receptor conformation. For inhibition, the ligand binds to the receptor from the outside, which does not change the conformational equilibrium, but stabilizes the inactive conformation. Signal transmission does not occur. Both approaches can be beneficial for drug therapy. On the one hand, agonists are spoken of, and on the other, antagonists or inverse agonists are meant. G protein–coupled receptors (GPCR), which transect the membrane with seven helices, encompass a huge group of membrane-bound receptors. Agonists stimulate an activation of the coupled G protein in GPCRs, which initiates subsequent processes in the cell. The second class is made up by receptors that also penetrate the cell membrane with a helical segment. Dimerization is a prerequisite for their activation. The attached cytosolic tyrosine kinase domains in the interior of the cell begin to mutually phosphorylate one another. This transforms them into a state in which the functions of other proteins are turned on by phosphorylation. Another group of oligomeric membrane-bound receptors binds interleukins as messenger molecules. They also initiate kinase-dependent intracellular signaling pathways as a result of ligand binding. About a third of our pharmaceuticals act on GPCRs in a regulatory fashion. The picture is much less clear for the second class of membrane-bound receptors. These receptors are all regulated by large ligands making the development of a competitive, small xenobiotic extremely difficult (Sect. 10.6).
Keywords
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Bibliography
General Literature
Buck LB (2005) Unraveling the sense of smell (Nobel lecture). Angew Chem Int Ed Engl 44:6128–6140
Martin YC et al (1991) Molecular modeling-based design of novel, selective, potent D1 dopamine agonists, in QSAR: rational approaches to the design of bioactive compounds. Elsevier, Amsterdam, pp 469–482
Rexler RR et al (1996) Nonpeptide angiotensin II receptor antagonists: the next generation in antihypertensive therapy. J Med Chem 39:625–656
Timmermans PBMWM, Wong PC, Chiu AT, Herblin WF (1991) Nonpeptide angiotensin II receptor antagonists. Trends Pharmacol Sci 12:55–61
Special Literature
Bianco R et al (2007) Rational bases for the development of EGFR inhibitors or cancer treatment. Int J Biochem Cell Biol 39:1416–1431
Cherezov V et al (2007) High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor. Science 318:1258–1265
Copeland RA, Pompliano DL, Meek TD (2007) Drug–target residence time and its implications for lead optimization. Nat Rev Drug Discov 5:730–739
De Meyts P, Whittaker J (2002) Structural biology of insulin and IGF1 receptors: implications for drug design. Nat Rev Drug Discov 1:769–783
Eklind-Cervenka M, Benson L et al (2011) Association of Candesartan vs. Losartan With All-Cause Mortality in Patients With Heart failure. J Am Med Assoc 305:175–182
Ji H, Zheng W, Zhang Y, Catt KJ, Sandberg K (1995) Genetic transfer of a nonpeptidic antagonist binding site to a previously unresponsive angiotensin receptor. Proc Natl Acad Sci USA 92:9240–9244
Keller A, Zhuang H, Chi Q, Vosshall LB, Matsunami H (2007) Genetic variations in a human odorant receptor alters odour preception. Nature 449:468–472
Rasmussen SG et al (2007) Crystal structure of the human β2 adrenergic G-protein coupled receptor. Nature 450:383–387
Rosenbaum DM, Cherezov V et al (2007) GPCR engineering yields high-resolution structural insights into β2-adrenergic receptor function. Science 318:1266–1273
Standfuss J, Edwards PC et al (2011) The structural basis of agonist-induced activation in constitutively active rhodopsin. Nature 471:656–661
Timmermans PBMWM et al (1993) Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev 45:205–242
Warne T, Serrano-Vega MJ et al (2008) Structure of a β1-adrenergic G-protein-coupled receptor. Nature 454:486–491
Warne T, Moukhametzianov R et al (2011) The structural basis for agonist and partial agonist action on a β1-adrenergic receptor. Nature 469:241–245
Wu B, Chien EYT et al (2011) Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonist. Science 330:1066–1071
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer-Verlag Berlin Heidelberg
About this entry
Cite this entry
Klebe, G. (2013). Agonists and Antagonists of Membrane-Bound Receptors. In: Klebe, G. (eds) Drug Design. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-17907-5_29
Download citation
DOI: https://doi.org/10.1007/978-3-642-17907-5_29
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-17906-8
Online ISBN: 978-3-642-17907-5
eBook Packages: Biomedical and Life SciencesReference Module Biomedical and Life Sciences