Inhibition of tyrosine hydroxylase in vitro and in vivo by 3-amino-pyrrolo[3,4c]isoxazole and derivatives

Tyrosine hydroxylase was shown to be inhibited in vitro by a series of 3-amino-pyrrolo[3,4c]isoxazoles. Greatest inhibition was observed with ethyl 3-amino-4H-pyrrolo[3,4c]isoxazole-5(6H) carboxylate and other 5-carboxylates. Acylation of the 3-amine group greatly decreased inhibition. Inhibition by ethyl 3-amino-4H-pyrrolo[3,4c]isoxazole carboxylate was noncompetitive with tyrosine or pteridine cofactor, but could be reversed by addition of iron or copper. 3-Amino-pyrroloisoxazoles were found to form metal complexes with Fe 2+, suggesting that their inhibition may be due to chelation. Tyrosine hydroxylase activity of adrenal extracts was decreased in rats treated with ethyl-3-amino-4H-pyrrolo[3,4c]isoxazole carboxylate and its -acetylated derivative.