Structure-affinity requirements for the binding of serotonin (5-HT) analogs at human 5-HT1E receptors were investigated by examining the affinities of >40 tryptamine-related compounds. No tryptamine analog was found to bind with substantially higher affinity than 5-HT. The results indicate that hydrogen bonding plays a key role in the 5-HT1E/receptor interaction. This finding was supported using quantitative structure-activity analysis (QSAR) techniques such as comparative molecular field analysis (CoMFA) and the program QsarIS.