Allosteric modulation of G protein-coupled receptors.
Allosteric modulation of G protein-coupled receptors has recently been recognized as an alternative approach for selectivity in drug action. Allosteric modulators that enhance or diminish the effects of (endogenous) agonists or antagonists on a variety of G protein-coupled receptors are described in this review, with emphasis on the latest developments in this research area. Specific examples include allosteric ligands for adenosine A1 and A3 receptors, Ca(2+)-sensing receptors, metabotropic glutamate receptor subtypes, gamma-aminobutyric acid type B and muscarinic receptors. It appears that all three major classes of G protein-coupled receptors (A, B and C) are amenable to allosteric modulation by small molecules. This constitutes an attractive and novel means to identify new leads in the drug discovery process. However, it requires a reengineering of most current assays.
Soudijn
Willem
W
Leiden/Amsterdam Center for Drug Research, Leiden University, Division of Medicinal Chemistry, PO Box 9502, 2300RA Leiden, The Netherlands.
van Wijngaarden
Ineke
I
IJzerman
Ad P
AP
D000818:Animals; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D008968:Molecular Conformation; D011955:Receptors, Drug / Q000737:chemistry / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000737:chemistry / Q000187:drug effects; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry / Q000187:drug effects; D011976:Receptors, Muscarinic / Q000737:chemistry / Q000187:drug effects; D018047:Receptors, Purinergic P1 / Q000737:chemistry / Q000187:drug effects
D002135:Calcium-Binding Proteins; D011955:Receptors, Drug; D018080:Receptors, GABA-B; D018094:Receptors, Metabotropic Glutamate; D011976:Receptors, Muscarinic; D018047:Receptors, Purinergic P1; D019204:GTP-Binding Proteins