Enantioselectivity in Drug-Receptor Interactions
G protein-coupled receptors (GPCRs) constitute one of the largest superfamilies of proteins in the human genome. It is estimated that there are at least 600 and probably over 1000 receptor species. The known ones are the target for approximately 60% of to
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Enantioselectivity in Drug-Receptor Interactions W.
SOUDIJN, I. VAN WUNGAARDEN, and A.P.
IJzERMAN
A. Introduction G protein-coupled receptors (GPCRs) constitute one of the largest superfamilies of proteins in the human genome. It is estimated that there are at least 600 and probably over 1000 receptor species. The known ones are the target for approximately 60% of today's medicines for such diverse disease states as high blood pressure (,B-adrenoceptor and angiotensin receptor antagonists), asthma (,B-adrenoceptor agonists), and acid overproduction in the stomach (histamine H2 receptor antagonists). Each member shares structural and/or sequence motifs and operates by common transduction mechanisms to mediate the transmission of extracellular signals into biochemical or electrophysiological responses within a cell. The signalling species is a specific endogenous molecule (e.g., neurotransmitter or hormone) which binds to the receptor. This results in activation of receptor and intracellularly located G proteins and propagation of the signal to effector molecules such as adenylyl cyclase. This enzyme converts ATP into cyclic AMP, the classical "second" messenger. Many neurotransmitters and hormones are chiral compounds. Among them are proteins and peptides, such as FSH (follicle stimulating hormone) and the endorphins, respectively. They are composed of natural amino acids, which, except for glycine, are all chiral. The translation machinery for peptide and protein synthesis has evolved to utilize only one of the chiral forms of amino acids, the L-form. The reason for this is not clear. Amino acids themselves may also act as endogenous signalling molecules for GPCRs. Examples are GABA (r-aminobutyric acid) acting on GABA B receptors, and metabotropic glutamate receptors for which L-glutamate and L-aspartate serve as signalling molecules. Other small endogenous molecules may serve a similar purpose. Among them are the classical biogenic amines, such as (nor)adrenaline, histamine, and serotonin, and numerous other examples, such as leukotrienes, adenosine, and ATP. This group hosts both nonchiral and chiral substances. Dopamine, serotonin, acetylcholine and histamine do not have a chiral center in their structure, whereas others possess one (adrenaline and noradrenaline) or more (adenosine and ATP). Interestingly, for a large
M. Eichelbaum et al. (eds.), Stereochemical Aspects of Drug Action and Disposition © Springer-Verlag Berlin Heidelberg 2003
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number of cloned ("orphan") receptors, the endogenous ligand is not known (yet). An important effort to keep track of the latest information on receptors is the G protein-coupled receptor database which is maintained on the Internet (www.gpcr.org!7tm/). The earliest evidence for stereoselective receptor recognition was reported by PIUTII (1886) who pointed out that D-asparagine has a sweet taste, while the natural L-isomer is insipid. Interestingly, PASTEUR (1886) ascribed this finding to the presence of an optically active substance in the nervou
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