The structure-based design of novel AMPA bioisosteres

The reaction of 4-acetyl-5-methyl-3-isoxazolyl carboxylate with a variety o f hydrazines and semicarbazides yielded molecules which are viable antagoni st candidates for the AMPA receptor. Molecular modeling studies used in con junction with the x-ray crystal structures of these derivatives show a clos e correlation between the hydrogen bonding characteristics of AMPA with tha t of the hydrazone and semicarbazone isoxazole derivatives. Uncyclized hydr azones and semicarbazones (1-5) were formed by using corresponding hydrazin es and semicarbazides containing strong electron withdrawing groups to prev ent cyclization with the ethyl ester. The crystals of 1 are orthorhombic wi th a = 14.2997(3), b = 15.4112(4), c = 16.0153(4) Angstrom, Z = 8, and spac e group Pbca; 2 monoclinic with a = 19.738(2), b = 10.4155(7), c = 15.583(1 ) Angstrom, beta = 92.348(2)degrees, Z = 8, and space group C2/c; 3 triclin ic with a = 8.3365(5), b = 8.4930(5), c = 12.2379(7) Angstrom, alpha = 92.5 68(2), beta = 102.229(2), gamma = 104.449(1)degrees, Z = 2, and space group P(1)over bar.