Treatment with sumatriptan during migraine attacks appeared to be associated with a decrease in 5-HT1B receptor binding, a finding that is most likely associated with the binding of sumatriptan to central 5-HT1B receptors, but the contribution of ongoing cerebral serotonin release to the lower binding cannot be excluded; the migraine attack-associated decrease in binding could indicate that migraine attacks are associated with increases in endogenous serotonin.
Almotriptan maleate (ALMT), a highly selective 5-hydroxy tryptamine 1B/1D (5-HT1B/1D) receptor agonist used in the treatment of migraine headache was subjected to various ICH (Q1A (R2)) specified guidelines.
Indeed, the development of sumatriptan and second generation triptans in the 1990's led to discover that these drugs produce selective cranial extracerebral vasoconstriction (via 5-HT1B receptors) and inhibition of the trigeminovascular system responses implicated in migraine (via 5-HT1D/5-HT1F receptors).
The development of the triptan class of serotonin 5-HT1B/1D/1F receptor agonists has advanced our understanding of the neurobiology of migraine pain, which subsequently resulted in the development of calcitonin gene-related peptide (CGRP) modulators that are now showing promise as acute and preventative anti-migraine agents.
Among the 36 central nervous system (CNS) marketed drugs tested, hydrophilic triptans, 5-HT(1B/1D) receptor agonists for the treatment of migraine attacks, were identified as OATP1A2 substrates.
Two polymorphisms in the promoter region of the 5-HT(1B) receptor (T-261G and A-161T) and the synonymous variation G861C in the coding region were genotyped by restriction fragment length polymorphism in 105 migraine patients.
Genomic DNA of a relatively small but very well-characterized set of migraine patients with consistently good response to sumatriptan (n = 14), with no response (n = 12), with recurrence of the headache (n = 12), with chest symptoms (n = 13), and patients without chest symptoms (n = 27) was available for the genetic analyses and screened for the F124C variant and the A-161T polymorphism in the human 5-HT(1B) receptor gene.
Although selective serotonin (5-HT) receptor agonists (i.e., 5-HT(1B/1D)) are successful in alleviating migrainous symptoms in < or = 70% of known sufferers, for the remaining 30%, additional migraine abortive medications remain unsuccessful, not tested or yet to be identified.
These genetic differences could be explained by various genes, the HTR1B, encoding the 5-HT(1) receptor subtype, MAOA gene that encodes the monoamino-oxidase, the main metabolic enzyme of this triptan, SLC6A4 (gene encoding the serotonin transporter) and DRD(2) (gene encoding the D(2) receptor), both involved in the pathogenesis of migraine.
Although very efficient for migraine relief, activation of 5-HT(1B) receptor may also cause vasoconstriction outside brain, within the heart arteries for example.
Only about 70% of migraine and cluster headache (CH) patients report significant treatment responses to triptans, which are agonists at 5-HT(1B/D) receptors belonging to the family of G protein-coupled receptors.
Serotonin [5-hydroxytryptamine (5-HT)] has been implicated in the pathophysiology of migraine, and the clinical efficacy of the 5-HT1B/5-HT1D receptor agonist sumatriptan points to neural and/or vascular 5-HT1D receptors as relevant targets in migraine therapy.