REGIOISOMERIC 3-AMINOMETHYL, 4-AMINOMETHYL AND 5-AMINOMETHYL ISOXAZOLES - SYNTHESIS AND MUSCARINIC ACTIVITY

A series of 3-, 4- and 5-aminomethyl isoxazoles and isoxazoles with on e or two additional methyl groups at the heterocycle were synthesized in order to investigate the structural requirements, ie heterocyclic m oiety, regiochemistry and length of an aminoalkyl unit, for muscarinic activity. This was assayed on isolated rabbit vas deferens (M(1) rece ptor subtype) and isolated guinea-pig atrium (M(2) receptor subtype) a nd ileum (M(3) receptor subtype). The isoxazoles tested are one to thr ee orders of magnitude less active than furane or oxadiazole derivativ es, having similar structural characteristics except for the heterocyc le. Thus, the differences in molecular point charges and charge distri bution contribute to the muscarinic activity of these compounds more t han small differences in molecular shape and conformational energies.