Excitatory amino-acid receptor agonists. Synthesis and pharmacology of analogues of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid

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

“…In addition to the mutagenesis approach to characterize the interaction between the ligand and the residue at the 708 R2 position, we determined the potencies of other AMPA analogs with different aliphatic substituents at the 5-position (Sløk et al, 1997). Extending the side chain from a methyl (in AMPA) to a propyl group reduced the potency on GluR1 from 3.4 (Vogensen et al, 2000) to 7.9 M, and introduction of larger substituents reduced the potency even further, with ATPA as the least potent (Table 3).…”

“…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.…”

“…The selectivity is even more pronounced (1000-fold) compared with the peak current in the AMPA receptors observed after fast application (Clarke et al, 1997). Studies performed on cortical wedges, which mainly reflect activation of the AMPA receptors, showed that the 5-ethyl analog of AMPA was more potent than AMPA, whereas the propyl and butyl analogs showed decreased potencies (Sløk et al, 1997). These observations and studies of willardiine analogs (Wong et al, 1994;Jane et al, 1997;Swanson et al, 1998) have resulted in a hypothesis proposing that the AMPA and kainate receptors might contain a hydrophobic cavity that can accommodate hydrophobic substituents to a certain size at the 5-position of the isoxazole ring of the AMPA molecule (Krogsgaard-Larsen et al, 1996).…”

Resolution, absolute stereochemistry, and enantiopharmacology of the GluR1-4 and GluR5 antagonist 2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid

“…13,14 The weak AMPA agonist effect of (RS)-2-amino-3-(5-tert-butyl-3-hydroxy-4-isoxazolyl)propionic acid (ATPA) 15 ( Fig. 1) and the inactivity of analogs of AMPA containing slightly larger alkyl groups have been inter-preted in terms of a limited volume of this proposed cavity.…”

“…1) and the inactivity of analogs of AMPA containing slightly larger alkyl groups have been inter-preted in terms of a limited volume of this proposed cavity. 14 Conversion of the 3-hydroxy group of AMPA into a carboxymethoxy group provided the relatively weak AMPA antagonist, (RS)-2-amino-3-[3-(carboxymethoxy)-5-methyl-4-isoxazolyl]propionic acid (AMOA) (Fig. 1), showing limited selectivity.…”