HETEROARYL ANALOGS OF AMPA - SYNTHESIS AND QUANTITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS

A number of 3-isoxazolol bioisosteres, 7a-i, of (S)-glutamic acid (Glu ), in which the methyl group of amino-3-(3-hydroxy-5-methylisoxazol-4- yl)propionic acid (AMPA, 1) was replaced by different 5-membered heter ocyclic 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 cortica l slice model (EC50 values). None of these compounds showed detectable affinity for the N-methyl-D-aspartic acid subtype of Glu receptors. S ome of the compounds were weak inhibitors of [H-3]kainic acid binding. The inhibitory effects on [3H]AMPA binding and agonist potencies at A MPA receptors of 7a-i were strictly dependent on the structure, electr ostatic potential, and methyl substitution of the heterocyclic 5-subst ituent. Thus, while 7a (IC50 = 0.094 mu M; EC50 = 2.3 mu M) was approx imately equipotent with AMPA (IC50 = 0.023 mu M; EC50 = 5.4 mu M), (RS )-2-amino-3-[3-hydroxy-5-(1H-imidazol-2- yl)isoxazol-4-yl]propionic ac id (7b) (IC50 = 48 mu M; EC50 = 550 mu M) was some 2 orders of magnitu de weaker than AMPA, and -amino-3-[3-hydroxy-5-(1-methyl-1H-imidazol-2 -yl)- isoxazol-4-yl]propionic acid (7c) (IC50 > 100 mu M; EC50 > 1000 mu M) was inactive. Furthermore, (2-methyl-2H-tetrazol-5-yl)isoxazol-4 -yl]propionic acid (7h) (IC50 = 0.030 mu M; EC50 = 0.02 mu M) was more potent than AMPA, whereas its N-1 methyl isomer, (1-methyl-1H-tetrazo l-5-yl)isoxazol-4-yl]propionic acid (7h) (IC50 = 54 mu M; EC50 > 1000 mu M) was inactive as an AMPA agonist. A quantitative structure-activi ty relationship (QSAR) analysis revealed a positive correlation betwee n receptor affinity, electrostatic potential near the nitrogen atom at the ''ortho'' position of the heterocyclic Ei-substituent, and the ro tational energy barrier around the bond connecting the two rings. We e nvisage 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.