A transfectant cell model was used to examine the structure-activity relationships of serotonin (5-hydroxytryptamine, 5-HT) transport. The findings suggest that 5-HT interacts largely with nonpolar and sterically-confining environments on the transport system, and that a particular spatial coordination of the amino and phenyl groups (separated by an alkyl backbone) is important for transport interaction. Molecular modelling analyses revealed that this motif is also present in the structures of several nontricyclic antidepressants and specific inhibitors of 5-HT transport, as well as adrenergic agents which also possess 5-HT transport-inhibitory activities. While this amino-phenyl coordination motif seems to be a necessary structural requisite for transport interaction, and therefore likely to be part of the transport pharmacophore, additional phenyl rings present in some of the nontricyclic antidepressants may help to account for their relatively higher affinities in 5-HT transport interaction.