Heteroaryl Analogues of AMPA. Synthesis and Quantitative Structure−Activity Relationships

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Abstract
A number of 3-isoxazolol bioisosteres, 7a−i, of (S)-glutamic acid (Glu), in which the methyl group of (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA, 1) was replaced by different 5-membered heterocyclic rings, were synthesized. Comparative in vitro pharmacological studies on this series of AMPA analogues were performed using receptor binding assays (IC50 values) and the electrophysiological rat cortical slice model (EC50 values). None of these compounds showed detectable affinity for the N-methyl-d-aspartic acid subtype of Glu receptors. Some of the compounds were weak inhibitors of [3H]kainic acid binding. The inhibitory effects on [3H]AMPA binding and agonist potencies at AMPA receptors of 7a−i were strictly dependent on the structure, electrostatic potential, and methyl substitution of the heterocyclic 5-substituent. Thus, while 7a (IC50 = 0.094 μM; EC50 = 2.3 μM) was approximately equipotent with AMPA (IC50 = 0.023 μM; EC50 = 5.4 μM), (RS)-2-amino-3-[3-hydroxy-5-(1H-imidazol-2-yl)isoxazol-4-yl]propionic acid (7b) (IC50 = 48 μM; EC50 = 550 μM) was some 2 orders of magnitude weaker than AMPA, and (RS)-2-amino-3-[3-hydroxy-5-(1-methyl-1H-imidazol-2-yl)isoxazol-4-yl]propionic acid (7c) (IC50 > 100 μM; EC50 > 1000 μM) was inactive. Furthermore, (RS)-2-amino-3-[3-hydroxy-5-(2-methyl-2H-tetrazol-5-yl)isoxazol-4-yl]propionic acid (7i) (IC50 = 0.030 μM; EC50 = 0.92 μM) was more potent than AMPA, whereas its N-1 methyl isomer, (RS)-2-amino-3-[3-hydroxy-5-(1-methyl-1H-tetrazol-5-yl)isoxazol-4-yl]propionic acid (7h) (IC50 = 54 μM; EC50 > 1000 μM) was inactive as an AMPA agonist. A quantitative structure−activity relationship (QSAR) analysis revealed a positive correlation between receptor affinity, electrostatic potential near the nitrogen atom at the “ortho” position of the heterocyclic 5-substituent, and the rotational energy barrier around the bond connecting the two rings. We envisage that a hydrogen bond between the protonated amino group and an ortho-positioned heteroatom of the ring substituent at the 5-position stabilize receptor-active conformations of these AMPA analogues.