Triptan structures were designed from the structure of 5-HT to attain affinity to 5-HT receptors, hence the identical indole structure. The hydroxyl group (-OH) on the hexane of the indole core and the alkyl-amine side chain on position C on 5-HT have been replaced with other compounds, such as sulfonamides or azol-ring structured derivatives and different amine-alkyl side chains. An electro-negative group can form a hydrogen bond with Thr in the pocket of the receptor. Sulfonamide derivatives attached to the hexane ring of the indole structure have electro-negative properties, as well as the triazole and 2-oxazolidone on rizatriptan and zolmitriptan respectively. This can increase binding ability of the compound and the efficacy, especially with the 5-HT receptor.
A schematic drawing of the binding of sumatriptan to 5-HT receptor can be seen in figure 4. One study  showed that sumatriptan fits better in the binding site of the receptor when the side chain with the protonated nitrogen atom is folded back over the indole structure. This alignment contributes to the hydrogen bonding between the nitrogen in the sulfonamine and the Ser138 in the binding site. It is also favorable to the formation of the hydrogen bond between the oxygen of the sulfonamine and Thr202. Other binding in the pocket of the binding site occurs with the nitrogen atom in the pentene ring of the indole structure of the triptan and the amino acid Ser352. This energetically favorable position of the agonist makes it possible for additional binding of the ligand to other Ser in the binding site, along with additional anchoring between Phe in the pocket of the binding site and the indole of the agonist. The binding of Phe and the triptan is caused by π stacking interactions of the indole and amino acid and an additional effect on this interaction is because of dispersive effect of amino acid leucine (Leu; not shown in figure 4). The amino acids Trp343 and Tyr346 both have electron rich π-systems in their aromatic structures. With their position in the binding site they create a sort of aromatic cage around the protonated nitrogen atom of the side chain on position C on the triptans (this nitrogen atom is protonated at physiological condition), and thereby stabilizes the ion bond the nitrogen atom has formed with a carboxylate on aspartic acid. Side chains of the surrounding amino acids can have an effect on the binding of the nitrogen atom, mainly three Phe can affect the methyl groups bound to the nitrogen atom (not shown in figure 4).
Eletriptan has higher affinity for the receptor, which is probably a result of the bulky substituents of the structure. The amine is protonated at physiological pH condition, triggering better uptake. The uptake rate of the agonist is different depending on whether the amine in R is primary, secondary or tertiary but the latter seem to give the best results. For the R substituent an electron rich sulfonamide groups and amide group has shown the best results in receptor binding and activity. It has been observed that a relationship is between absorption and molecular size hence larger hydrophilic molecules tended to have poor absorption. A small R substituent is necessary to maintain the rapid oral bioavailability of triptans.
By placing an electron-withdrawing group or large group on position C on the indole structure the 5-HT agonist is conversed into an antagonist. This is thought to be because the indole ring is unable to occupy the aromatic part of the binding site.