[Structure-activity relationship in ring-opened serotonin analogs: 3-(2-aminophenyl)-propanamine and...

The complete reduction of the carbonyl group of the 5-HT agonist 3-(2-amino-5-hydroxy-phenyl)-3-oxo-propanamine results in a drastic loss of activity: as investigations on the isolated gastric fundus of the rat showed, the affinity to the D receptor of serotonin is reduced by a factor of 100 whereas the relative intrinsic activity also decreases from 0.83 to values less than 0.3. The additional suppression of the phenolic hydroxyl group causes only a relatively unimportant decrease of the affinity while the relative intrinsic activity increases again up to 0.65. These results support the postulate according to which the active conformation of serotonin shows a stretched side chain, as its logical interpretation is only possible under this assumption. Inside the 1-(N-piperidino)-3-(2-amino-phenyl)-3-oxo-propanes the derivative methoxylated at C-5 of the benzene nucleus with a pA2 value of 7.39 proved to be the most effective 5-HT antagonist the mechanism being a purely competitive one.