Ibotenic Acid Analogues. Synthesis, Molecular Flexibility, and in Vitro Activity of Agonists and Antagonists at Central Glutamic Acid Receptors

Abstract

The syntheses of (RS)-alpha-amino-3-hydroxy-5-tert-butyl-4-isoxazolepropionic acid (9, ATPA), (alpha-RS, beta-RS)-alpha-amino-beta-methyl-3-hydroxy-5-isoxazolepropionic acid (8), (RS)-alpha-amino-3-hydroxy-5-isoxazolebutyric acid (15a), and (RS)-alpha-amino-3-hydroxy-5-isoxazolevaleric acid (15b) are described. The compounds were tested in vitro together with (RS)-alpha-amino-3-hydroxy-5-(bromomethyl)-4-isoxazolepropionic acid (ABPA) as inhibitors of the binding of radioactive-labeled (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) to rat brain synaptic membranes. These data were compared with the earlier reported effects of the compounds on single neurons in the feline spinal cord obtained by microelectrophoretic techniques. The three compounds AMPA, ATPA, and ABPA are agonists at the class of receptors assumed to represent a subtype of physiological (S)-glutamic acid (Glu) receptors. Inhibition of [3H]AMPA binding by ATPA was 1 order of magnitude weaker than that of AMPA, in agreement with the relative potency of these compounds in vivo. ABPA proved to be equipotent with AMPA both as an inhibitor of AMPA binding and as a neuronal excitant. The compounds 8, 15a, and 15b have no effect as inhibitors of AMPA binding, in agreement with in vivo studies that have shown that 8 does not affect the firing of central neurons whereas 15a and 15b are antagonists at NMDA receptors, a subpopulation of excitatory receptors not affected by AMPA. Molecular mechanical calculations on AMPA, ATPA, and ABPA using the program MM2 showed that conformations of AMPA, ABPA, and especially ATPA by rotation of the amino acid side chain have energy barriers. A possible receptor-active conformation is suggested.

The Selective Activation of the Glutamate Receptor GluR5 by ATPA Is Controlled by Serine 741

“…The AMPA analogs (S)-ATPA (Lauridsen et al, 1985;Stensbøl et al, 1999), isopropyl-AMPA, (R,S)-2-amino-3-(5-propyl-3-hydroxy-4-isoxazolyl)propionic acid (propyl-AMPA), (R,S)-2-amino-3-(5-isobutyl-3-hydroxy-4-isoxazolyl)propionic acid (isobutyl-AMPA) (Sløk et al, 1997), and (S)-2-amino-3-(5-(2-methyltetrazolyl)-3-hydroxy-4-isoxazolyl)propionic acid [(S)-2-Me-Tet-AMPA] (Vogensen et al, 2000) were synthesized as described previously. All other pharmacological tools and reagents were purchased from regular commercial sources.…”

“…AMPA activates the AMPA receptors expressed in oocytes with an EC 50 in the range of 1.3 to 3.5 M (Vogensen et al, 2000), whereas kainate receptors formed from the GluR5 to GluR7 subunits are either activated with EC 50 Ͼ 1 mM or not at all (Egebjerg et al, 1991;Sommer et al, 1992;Schiffer et al, 1997). Surprisingly, (S)-ATPA, an AMPA analog in which the methyl group at the 5-position in the isoxazole ring is replaced by a tert-butyl group (Lauridsen et al, 1985), exhibits a strong preference for GluR5 compared with the AMPA receptors (Clarke et al, 1997;Stensbøl et al, 1999). Analogs of AMPA with different 5-substitutions of the isoxazole ring have been studied extensively (Krogsgaard-Larsen et al, 1996).…”

In Vitro Characterization of 5-Carboxyl-2,4-di-benzamidobenzoic Acid (NS3763), a Noncompetitive Antagonist of GLUK5 Receptors

“…The 2,3-benzodiazepine class of compounds such as GYKI52466 and GYKI53655 are noncompetitive antagonists showing a relatively high degree of selectivity for AMPA receptors, and these compounds have successfully been used to isolate kainate receptors (Paternain et al, 1995). Through use of these antago-nists and cloned kainate receptors, it became clear that ATPA (Lauridsen et al, 1985) is a GLU K5 -preferring agonist potently activating homomeric GLU K5 receptors and native dorsal root ganglion kainate receptors, but shows only weak activity at AMPA receptors, and no activity at GLU K6 homomers (Clarke et al, 1997;Wilding and Huettner, 2001).…”

Low-affinity kainate receptor agonists induce insult-dependent apoptosis and necrosis in cultured murine cortical neurons

“…The pharmacological profile of KA is well established, but comparatively little is known of the excitotoxic actions of the following glutamate analogues with reported selectivity for GluR5-7: (RS)-2-amino-3-(hydroxy-5-tert-butylisoxazol-4-yl) propanoic acid (ATPA), (S)-5-iodowillardiine (IW), and (2S,4R)-4-methylglutamate (4MG). ATPA, an AMPA analogue (Lauridsen et al, 1985), has been described as a moderately potent AMPA receptor agonist with selectivity for GluR5 but devoid of activity at GluR6 (Clarke et al, 1997;Wahl et al, 1998;Bleakman et al, 1999). Similarly, IW possesses activity at AMPA-preferring receptors in the hippocampus but is more potent than other willardiines at KApreferring receptors in the dorsal root ganglion (Patneau et al, 1992;Wong et al, 1994).…”