Molecular pharmacology of homologues of ibotenic acid at cloned metabotropic glutamic acid receptors
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Molecular pharmacology of homologues of ibotenic acid at cloned metabotropic glutamic acid receptors. / Bräuner-Osborne, Hans; Nielsen, B; Krogsgaard-Larsen, P.
In: European Journal of Pharmacology, Vol. 350, No. 2-3, 05.06.1998, p. 311-6.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Molecular pharmacology of homologues of ibotenic acid at cloned metabotropic glutamic acid receptors
AU - Bräuner-Osborne, Hans
AU - Nielsen, B
AU - Krogsgaard-Larsen, P
PY - 1998/6/5
Y1 - 1998/6/5
N2 - We have studied the effects of the enantiomers of 2-amino-3-(3-hydroxyisoxazol-5-yl)propionic acid (homoibotenic acid, HIBO) and analogues substituted with a methyl, bromo or butyl group in the four position of the ring at cloned metabotropic glutamate (mGlu) receptors expressed in Chinese hamster ovary (CHO) cells. In contrast to the parent compound ibotenic acid, which is a potent group I and II agonist, the (S)-forms of homoibotenic acid and its analogues are selective and potent group I antagonists whereas the (R)-forms are inactive both as agonists and antagonists at group I, II, and III mGlu receptors. Interestingly, (S)-homoibotenic acid and the analogues display equal potency at both mGlu1alpha and mGlu5a with Ki values in the range of 97 to 490 microM, (S)-homoibotenic acid and (S)-2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid [(S)-4-butylhomoibotenic acid] displaying the lowest and highest potency, respectively. The homoibotenic acid analogues thereby differ from mGlu receptor antagonists derived from phenylglycine such as (S)-4-carboxyphenylglycine which only antagonizes mGlu1alpha (Ki = 18 microM) showing no effect at mGlu5a (Ki > 300 microM).
AB - We have studied the effects of the enantiomers of 2-amino-3-(3-hydroxyisoxazol-5-yl)propionic acid (homoibotenic acid, HIBO) and analogues substituted with a methyl, bromo or butyl group in the four position of the ring at cloned metabotropic glutamate (mGlu) receptors expressed in Chinese hamster ovary (CHO) cells. In contrast to the parent compound ibotenic acid, which is a potent group I and II agonist, the (S)-forms of homoibotenic acid and its analogues are selective and potent group I antagonists whereas the (R)-forms are inactive both as agonists and antagonists at group I, II, and III mGlu receptors. Interestingly, (S)-homoibotenic acid and the analogues display equal potency at both mGlu1alpha and mGlu5a with Ki values in the range of 97 to 490 microM, (S)-homoibotenic acid and (S)-2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid [(S)-4-butylhomoibotenic acid] displaying the lowest and highest potency, respectively. The homoibotenic acid analogues thereby differ from mGlu receptor antagonists derived from phenylglycine such as (S)-4-carboxyphenylglycine which only antagonizes mGlu1alpha (Ki = 18 microM) showing no effect at mGlu5a (Ki > 300 microM).
KW - Animals
KW - CHO Cells
KW - Cricetinae
KW - Excitatory Amino Acid Agonists
KW - Ibotenic Acid
KW - Ligands
KW - Receptors, Metabotropic Glutamate
KW - Second Messenger Systems
KW - Stereoisomerism
KW - Structure-Activity Relationship
M3 - Journal article
C2 - 9696422
VL - 350
SP - 311
EP - 316
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 2-3
ER -
ID: 45613957