5-HT5A SEROTONIN RECEPTOR-BINDING - A PRELIMINARY STRUCTURE-AFFINITY INVESTIGATION

5-HT5A receptors represent one of the newest populations of the seroto nin (5-HT) receptor family, and essentially nothing is known regarding the structure-affinity relationships for 5-HT binding. Beginning with the structure of 5-HT (5-HT: 5-HT5A Ki = 170 nM), minor structural mo difications were examined in a stepwise fashion so that the effect of structural alteration could be related back as much as possible to the structure of 5-HT. Subsequently, more dramatic modifications were exa mined such that a total of about 30 tryptamines and related compounds were investigated. A comparative molecular field analysis (CoMFA) stud y was performed in order to gain further insight into the nature of th e drug-receptor interaction. One of the significant findings of the st udy is that 1-(1-naphthyl)piperazines bind at 5-HT5A receptors; in par ticular, 1-(7-hydroxynaphth-1-yl)piperazine (7-OH 1-NP; Ki = 3 nM) was found to bind with > 50-fold higher affinity than 5-HT itself.