Design, synthesis, and structure – Activity relationship studies of novel tryptamine derivatives as 5‑HT1B receptor agonists

Abstract

Migraine is a prevalent disabling primary headache disorder that accompanies characteristic depletion of endogenous 5-hydroxytryptamine (5-HT; serotonin). The 5-HT1B receptor (5-HT1BR) is a Gi class G protein-coupled receptor, and it is a target for the treatment of migraine, depression, anxiety and other diseases related to serotonergic neurotransmission. Triptans have replaced ergotamines in clinical usage and are currently the first-line antimigraine therapy for attacks of moderate to severe intensity. In this study, a series of novel tryptamine derivatives were designed based on the binding mode of FDA-approved triptans with 5-HT1BR by molecular docking, synthesized, and evaluated for 5-HT1BR activation. Among the compounds examined, 6k (EC50 =8.57 nM; Ki =16.56 nM), 6f (EC50 =10.77 nM;Ki =36.95 nM), and 6m (EC50 =24.32 nM; Ki =22.20 nM) were found to be more potent 5-HT1BR activators than the FDA-approved drug sumatriptan (EC50 =37.71 nM;Ki =130.62 nM). Molecular docking results showed that the common tryptamine skeleton of the compounds maintained hydrogen bonding with Thr134 and ionic interactions with Asp129 of 5-HT1BR. A fluorine atom was introduced at position 7 of the indole ring to improve the drug-like properties of the compounds and binding affinity by forming a new hydrogen bond. The different substituents incorporated at position 5 may also form CH-π interactions with Val201 of 5-HT1BR. In addition, the substituents of the affinity-improved compounds 6k and 6f formed additional hydrogen bonds with Thr203 in the model system. Druggability and pharmacokinetic predictions suggest that the synthesized compounds could offer some improvements over the drug, sumatriptan. These results provide some insights for further medicinal chemistry efforts toward developing novel 5-HT1BR agonists for migraine therapy.