Lasmiditan mechanism of action – review of a selective 5-HT1F agonist

Abstract

Migraine is a leading cause of disability worldwide, but it is still underdiagnosed and undertreated. Research on the pathophysiology of this neurological disease led to the discovery that calcitonin gene-related peptide (CGRP) is a key neuropeptide involved in pain signaling during a migraine attack. CGRP-mediated neuronal sensitization and glutamate-based second-and third-order neuronal signaling may be an important component involved in migraine pain. The activation of several serotonergic receptor subtypes can block the release of CGRP, other neuropeptides, and neurotransmitters, and can relieve the symptoms of migraine. Triptans were the first therapeutics developed for the treatment of migraine, working through serotonin 5-HT 1B/1D receptors. The discovery that the serotonin 1F (5-HT 1F) receptor was expressed in the human trigeminal ganglion suggested that this receptor subtype may have a role in the treatment of migraine. The 5-HT 1F receptor is found on terminals and cell bodies of trigeminal ganglion neurons and can modulate the release of CGRP from these nerves. Unlike 5-HT 1B receptors, the activation of 5-HT 1F receptors does not cause vasoconstriction. The potency of different serotonergic agonists towards 5-HT 1F was correlated in an animal model of migraine (dural plasma protein extravasation model) leading to the development of lasmiditan. Lasmiditan is a newly approved acute treatment for migraine in the United States and is a lipophilic, highly selective 5-HT 1F agonist that can cross the blood-brain barrier and act at peripheral nervous system (PNS) and central nervous system (CNS) sites. Lasmiditan activation of CNS-located 5-HT 1F receptors (e.g., in the trigeminal nucleus caudalis) could potentially block the release of CGRP and the neurotransmitter glutamate, thus preventing and possibly reversing the development of central sensitization. Activation of 5-HT 1F receptors in the thalamus can block secondary central sensitization of this region, which is associated with progression of migraine and extracephalic cutaneous allodynia. The 5-HT 1F receptors are also elements of descending pain modulation, presenting another site where lasmiditan may alleviate migraine. There is emerging evidence that mitochondrial dysfunction might be implicated in the pathophysiology of migraine, and that 5-HT 1F receptors can promote mitochondrial biogenesis. While the exact mechanism is unknown, evidence suggests that lasmiditan can alleviate migraine through 5-HT 1F agonist activity that leads to inhibition of neuropeptide and neurotransmitter release and inhibition of PNS trigeminovascular and CNS pain signaling pathways.

Lasmiditan in patients with common migraine comorbidities: apost hocefficacy and safety analysis of two phase 3 randomized clinical trials

“…The current results suggest the presence of any of the comorbid conditions studied will not significantly influence the efficacy and safety of lasmiditan, although the potential for fatigue to effect lasmiditan efficacy should be considered. The lack of lasmiditan driven safety effects in the Cardiac and Vascular groups is congruent with the lack of vasoconstrictive properties, which is of concern for triptans [20][21][22][23][24][25][26] . The basis for this difference is the selectivity lasmiditan has for the 5-HT 1F receptor.…”

“…The mechanism of action of lasmiditan seems to be inhibition of the peripheral and central nervous system and pain pathways, including the trigeminal nerve. This inhibition results in decreased release of neuropeptides and neurotransmitters such as calcitonin gene-related peptide and glutamate which attenuates their local activity and neuronal firing 22 . Thus, it is important to note patients in both the central nervous system-related Anxiety and Depression Comorbidity "Yes" Subgroups actually had improved odds of becoming pain and MBS free at 2 h post dosing with lasmiditan compared to those patients without these comorbidities (Figures 1 and 2).…”

Pharmacokinetics, Pharmacodynamics and Drug–Drug Interactions of New Anti-Migraine Drugs—Lasmiditan, Gepants, and Calcitonin-Gene-Related Peptide (CGRP) Receptor Monoclonal Antibodies

“…The chemical name of lasmiditan is 2,4,6-trifluoro-N- [6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl]benzamide. The chemical structure is presented in Figure 1 [21]. Lasmiditan is a 5-HT agonist with an over 440 times more potent binding affinity for 5-HT 1F than 5-HT 1B and 5-HT 1D receptors [21] and which potently inhibits markers of electrical stimulation in the trigeminal ganglion [14].…”

“…The chemical structure is presented in Figure 1 [21]. Lasmiditan is a 5-HT agonist with an over 440 times more potent binding affinity for 5-HT 1F than 5-HT 1B and 5-HT 1D receptors [21] and which potently inhibits markers of electrical stimulation in the trigeminal ganglion [14]. This inhibits release of neuropeptides and neurotransmitters such as CGRP and glutamate, thereby inhibiting their local activity and migraine attack pain pathways [21].…”

“…Lasmiditan is a 5-HT agonist with an over 440 times more potent binding affinity for 5-HT 1F than 5-HT 1B and 5-HT 1D receptors [21] and which potently inhibits markers of electrical stimulation in the trigeminal ganglion [14]. This inhibits release of neuropeptides and neurotransmitters such as CGRP and glutamate, thereby inhibiting their local activity and migraine attack pain pathways [21]. Efficacy and safety of lasmiditan in stopping migraine attacks were confirmed compared to a placebo in randomized phase III clinical trials , also in patients with vascular risk factors [27].…”