STRUCTURE-ACTIVITY-RELATIONSHIPS OF SEROTONIN TRANSPORT - RELEVANCE TO NONTRICYCLIC ANTIDEPRESSANT INTERACTIONS

A transfectant cell model was used to examine the structure-activity r elationships of serotonin (5-hydroxytryptamine, 5-HT) transport. The f indings suggest that 5-HT interacts largely with nonpolar and sterical ly-confining environments on the transport system, and that a particul ar spatial coordination of the amino and phenyl groups (separated by a n alkyl backbone) is important for transport interaction. Molecular mo delling analyses revealed that this motif is also present in the struc tures of several nontricyclic antidepressants and specific inhibitors of 5-HT transport, as well as adrenergic agents which also possess 5-H T transport-inhibitory activities. While this amino-phenyl coordinatio n motif seems to be a necessary structural requisite for transport int eraction, and therefore likely to be part of the transport pharmacopho re, additional phenyl rings present in some of the nontricyclic antide pressants may help to account for their relatively higher affinities i n 5-HT transport interaction.