All triptans have an
indole structure identical to the
neurotransmitter 5-HT. Classic triptan structure contain side chain on the indole ring, and a basic nitrogen in a similar distance from the indole structure. The main structural difference of the triptans is the position of the sulfonamide and the side chain attached to it (see figure 1 and table 1). Rizatriptan and zolmitriptan have instead of a sulfonamide a
triazole and
2-oxazolidone respectively. Another exception to the classic structure is seen on eletriptan where the nitrogen-alkyl chain connected to the indole ring is replaced with a dimethyl-pyrrolidine, and in naratriptan where the nitrogen-alkyl chain is replaced with a 1-methyl-piperidine ring. One of the frovatriptan side chains forms an additional ring with the indole, resulting in a
carbazole ring system.
Structures of the triptans File:Triptan - indole structure.svg|Fig 1.
Indole structure of triptans File:Carbazole.png|Fig 1a.
Carbazole structure of frovatriptan
The 5-HT1B/D pharmacophore 5-HT1B and 5-HT1D receptors are considered very similar, they share amino acid
homology and their
ligands expose similar binding properties thus they have similar
pharmacophore. The pharmacophore model for these receptors ligands is qualitative and defines the relative positions of important groups. It is defined with following five main features: an aromatic group (usually the indole), protonated amine (
a donor of hydrogen bond),
acceptor of hydrogen bond, additional hydrogen bond site (both donor and acceptor) and hydrophobic region located between both
hydrogen bond sites, see figure 2. The pharmacophore can be characterized as
amphipathic, that means that the structure has both
hydrophobic and
hydrophilic groups.
Relevant structural features of triptans and binding to the receptor 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 C3 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-HT1D receptor. The uptake rate of the agonist is different depending on whether the
amine in R2 is primary, secondary or tertiary but the latter seem to give the best results. For the R1 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 R1 substituent is necessary to maintain the rapid oral bioavailability of triptans. By placing an electron-withdrawing group or large group on position C2 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. ==Triptan drugs==