Excitatory amino acid agonists and partial agonists

I. T. Christensen, A. Reinhardt, B. Nielsen, B. Ebert, U. Madsen, E. O. Nielsen, L. Brehm, P. Krogsgaard-Larsen*

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

33 Citationer (Scopus)

Abstract

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.

OriginalsprogEngelsk
TidsskriftDrug Design and Delivery
Vol/bind5
Udgave nummer1
Sider (fra-til)57-71
Antal sider15
ISSN0884-2884
StatusUdgivet - 1989

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