Regioisomeric 3-, 4- and 5-aminomethyl isoxazoles: Synthesis and muscarinic activity

Article abstract of DOI:10.1016/0223-5234(96)88303-6

A series of 3-, 4- and 5-aminomethyl isoxazoles and isoxazoles with one or two additional methyl groups at the heterocycle were synthesized in order to investigate the structural requirements, ie heterocyclic moiety, regiochemistry and length of an aminoalkyl unit, for muscarinic activity. This was assayed on isolated rabbit vas deferens (M₁ receptor subtype) and isolated guinea-pig atrium (M₂ receptor subtype) and ileum (M₃ receptor subtype). The isoxazoles tested are one to three orders of magnitude less active than furane or oxadiazole derivatives, having similar structural characteristics except for the heterocycle. Thus, the differences in molecular point charges and charge distribution contribute to the muscarinic activity of these compounds more than small differences in molecular shape and conformational energies.