Biomedical Engineering Reference
In-Depth Information
Orthosteric binding site
125
Allosteric
binding site
Glutamate
100
Glu + 1 μM CPCCOEt
Glu + 3 μM CPCCOEt
75
Glu + 20 μM CPCCOEt
50
25
0
-25
-6
-5
-4
log [ L -Glu]
-3
-2
-1
(A)
(B)
FIGURE 12.13 Schild analysis of the noncompetitive antagonist CPCCOEt on cells expressing the
metabotropic glutamate receptor subtype mGluR1. (A) Concentration-response curves of the agonist glu-
tamate (l-Glu) were generated in the presence of varying concentrations of CPCCOEt. In contrast to the
Schild analysis shown in Figure 12.10, a clear depression of the maximal response is seen with increasing
antagonist concentrations. This shows that the antagonist is noncompetitive. (Adapted from Litschig, S. et al.,
Mol. Pharmacol ., 55, 453, 1999. With permission.) (B) Cartoon showing overall structure of a family
C receptor with the orthosteric (endogenous agonist) and allosteric binding sites pointed out.
12.4 CONCLUDING REMARKS
The previous decade of receptor research has provided many breakthroughs in our understanding
of receptor structure, function, and pharmacology. The many new 3D structures of either full recep-
tors or important domains have provided detailed knowledge about ligand-receptor interactions and
receptor activation mechanisms. It has been shown that most receptors can activate several different
signaling pathways, which may also be selectively activated/inhibited by drugs. Finally, inverse
agonism and allosteric modulation have pointed to novel ways that receptors can be regulated in
vivo . Collectively, these new developments have created the foundation for structure-based drug
design and new concepts of pharmacological intervention.
FURTHER READINGS
Bond, R.A. and IJzerman, A.P. 2006. Recent developments in constitutive receptor activity and inverse
agonism, and their potential for GPCR drug discovery. Trends Pharmacol. Sci . 27:92-96.
Bräuner-Osborne, H., Egebjerg, J., Nielsen, E.Ø., Madsen, U., and Krogsgaard-Larsen, P. 2000. Ligands for glu-
tamate receptors: Design and therapeutic prospects. J. Med. Chem . 43:2609-2645.
Bräuner-Osborne, H., Wellendorph, P., and Jensen, A.A. 2007. Structure, pharmacology and therapeutic prospects
of family C G-protein-coupled receptors. Curr. Drug Targets . 8:169-184.
Gronemeyer, H., Gustafsson, J.Å., and Laudet, V. 2004. Principles for modulation of the nuclear receptor super-
family. Nat. Rev. Drug Discov . 3:950-964.
Ji, T.H., Grossmann, M., and Ji, I. 1998. G Protein-coupled receptors. I. Diversity of receptor-ligand interac-
tions. J. Biol. Chem . 273:17299-17302.
Lefkowitz, R.J. 2007. Seven transmembrane receptors: Something old, something new. Acta Physiol . 190:9-19.
Lefkowitz, R.J. and Shenoy, S.K., 2005. Science 308:512.
Madsen, U., Bräuner-Osborne, H., Greenwood, J.R., Johansen, T.N., Krogsgaard-Larsen, P., Liljefors, T.,
Nielsen, M., and Frølund, B. 2005. GABA and glutamate receptor ligands and their therapeutic potential
in CNS disorders. In Drug Discovery Handbook , ed. S.C. Gad, pp. 797-907. New York: Wiley.
 
Search WWH ::




Custom Search