TY - JOUR
T1 - Glutamate receptor agonists
T2 - stereochemical aspects
AU - Vogensen, Stine Byskov
AU - Greenwood, Jeremy R
AU - Bunch, Lennart
AU - Clausen, Rasmus Prætorius
N1 - Keywords: agonist, glutamate, ionotropic, metabotropic, stereochemistry, selectivity, X-ray structures
PY - 2011/4
Y1 - 2011/4
N2 - The neurotransmitter (S)-glutamate [(S)-Glu] is responsible for most of the excitatory neurotransmission in the central nervous system. The effect of (S)-Glu is mediated by both ionotropic and metabotropic receptors. Glutamate receptor agonists are generally α-amino acids with one or more stereogenic centers due to strict requirements in the agonist binding pocket of the activated state of the receptor. By contrast, there are many examples of achiral competitive antagonists. The present review addresses how stereochemistry affects the activity of glutamate receptor ligands. The review focuses mainly on agonists and discusses stereochemical and conformational considerations as well as biostructural knowledge of the agonist binding pockets, which is useful in the design of glutamate receptor agonists. Examples are chosen to demonstrate how stereochemistry not only determines how the agonist binding pocket is filled, but also how it affects the conformational space of the ligand and in this way restricts the recognition of various glutamate receptors, ultimately leading to selectivity.
AB - The neurotransmitter (S)-glutamate [(S)-Glu] is responsible for most of the excitatory neurotransmission in the central nervous system. The effect of (S)-Glu is mediated by both ionotropic and metabotropic receptors. Glutamate receptor agonists are generally α-amino acids with one or more stereogenic centers due to strict requirements in the agonist binding pocket of the activated state of the receptor. By contrast, there are many examples of achiral competitive antagonists. The present review addresses how stereochemistry affects the activity of glutamate receptor ligands. The review focuses mainly on agonists and discusses stereochemical and conformational considerations as well as biostructural knowledge of the agonist binding pockets, which is useful in the design of glutamate receptor agonists. Examples are chosen to demonstrate how stereochemistry not only determines how the agonist binding pocket is filled, but also how it affects the conformational space of the ligand and in this way restricts the recognition of various glutamate receptors, ultimately leading to selectivity.
KW - Former Faculty of Pharmaceutical Sciences
U2 - 10.2174/156802611795164990
DO - 10.2174/156802611795164990
M3 - Review
C2 - 21291400
SN - 1568-0266
VL - 11
SP - 887
EP - 906
JO - Current Topics in Medicinal Chemistry
JF - Current Topics in Medicinal Chemistry
IS - 7
ER -