Effect of 4-substitution on psychotomimetic activity of 2,5-dimethoxy amphetamines as studied by means of different substituent parameter scales.

Electron-withdrawing substituents at position 4 of 2,5-dimethoxy-substituted amphetamines increase, whereas electron-donating substituents decrease the psychotomimetic activity. The origin of this clearly localized effect is discussed. The uses of modified Hammett substituent scales (sigma(-) and sigma(+)), and especially the good sigma(+) correlation, strongly suggest that electron-donating substituents decrease the biological activity through a specific effect relating to the extent of the conjugative electron release from the 5-methoxy group to the phenyl ring.