Excitatory amino acid agonists and partial agonists
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Excitatory amino acid agonists and partial agonists. / Christensen, I. T.; Reinhardt, A.; Nielsen, B.; Ebert, B.; Madsen, U.; Nielsen, E. O.; Brehm, L.; Krogsgaard-Larsen, P.
In: Drug Design and Delivery, Vol. 5, No. 1, 1989, p. 57-71.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Excitatory amino acid agonists and partial agonists
AU - Christensen, I. T.
AU - Reinhardt, A.
AU - Nielsen, B.
AU - Ebert, B.
AU - Madsen, U.
AU - Nielsen, E. O.
AU - Brehm, L.
AU - Krogsgaard-Larsen, P.
PY - 1989
Y1 - 1989
N2 - The racemic 3-isoxazolol amino acids α-amino-3-hydroxy-5-methyl-4-isoxazolepentanoic acid [(2)homo-AMPA] (12) and α-amino-3-hydroxy-5-phenyl-4-isoxazolepropanoic acid (APPA) (19) were synthesized and tested biologically. The two compounds are structurally related to AMPA, whihc is a potent and highly selective agonist at the QUIS/AMPA subtype of central excitatory amino acid (EAA) receptors. Both were shown to be neuronal excitants, though less potent than the parent compound. The full EAA agonistic effect of (2)homo-AMPA (12) could be blocked by the non-NMDA antagonist CNQX but was insensitive to AP5, an antagonist at the NMDA subtype of EAA receptors. It was an inhibitor of the binding of [3H]AMPA (IC50 49 μM) and of the calcium chloride-dependent binding of [3H]glutamic acid (IC50 3 μM), but did not show significant affinity for kainic acid binding sites or glutamic acid uptake mechanisms. APPA (19) proved to be a relatively selective partial agonist at QUIS/AMPA receptors. Thus, CNQX reduced the excitatory effect of 19 by more than 70%, whereas this effect of 19 was reduced by less than 10% in the presence of AP5. Like (2)homo-AMPA (12), 19 was an inhibitor of [3H]AMPA binding (IC50 50 μM) and did not inhibit [3H]kainic acid binding or glutamic acid uptake. However, in contrast to 12, 19 did not affect the calcium chloride-dependent binding of [3H]glutamic acid.
AB - The racemic 3-isoxazolol amino acids α-amino-3-hydroxy-5-methyl-4-isoxazolepentanoic acid [(2)homo-AMPA] (12) and α-amino-3-hydroxy-5-phenyl-4-isoxazolepropanoic acid (APPA) (19) were synthesized and tested biologically. The two compounds are structurally related to AMPA, whihc is a potent and highly selective agonist at the QUIS/AMPA subtype of central excitatory amino acid (EAA) receptors. Both were shown to be neuronal excitants, though less potent than the parent compound. The full EAA agonistic effect of (2)homo-AMPA (12) could be blocked by the non-NMDA antagonist CNQX but was insensitive to AP5, an antagonist at the NMDA subtype of EAA receptors. It was an inhibitor of the binding of [3H]AMPA (IC50 49 μM) and of the calcium chloride-dependent binding of [3H]glutamic acid (IC50 3 μM), but did not show significant affinity for kainic acid binding sites or glutamic acid uptake mechanisms. APPA (19) proved to be a relatively selective partial agonist at QUIS/AMPA receptors. Thus, CNQX reduced the excitatory effect of 19 by more than 70%, whereas this effect of 19 was reduced by less than 10% in the presence of AP5. Like (2)homo-AMPA (12), 19 was an inhibitor of [3H]AMPA binding (IC50 50 μM) and did not inhibit [3H]kainic acid binding or glutamic acid uptake. However, in contrast to 12, 19 did not affect the calcium chloride-dependent binding of [3H]glutamic acid.
KW - (2)homo-AMPA
KW - agonist
KW - AMPA analogues
KW - AMPA homologues
KW - APPA
KW - excitatory amino acid receptors
KW - partial agonist
KW - QUIS/AMPA agonists
KW - QUIS/AMPA receptors
UR - http://www.scopus.com/inward/record.url?scp=0024849550&partnerID=8YFLogxK
M3 - Journal article
AN - SCOPUS:0024849550
VL - 5
SP - 57
EP - 71
JO - Drug Design and Delivery
JF - Drug Design and Delivery
SN - 0884-2884
IS - 1
ER -
ID: 281988926