Serotonin receptor targeted therapy for migraine treatment: an overview of drugs in phase I and II clinical development

References

• Hamel E. Serotonin and migraine: biology and clinical implications. Cephalalgia. 2007;11:1293–1330.
   Google Scholar
• Dahlöf C, Maassen Van Den Brink A. Dihydroergotamine, ergotamine, methysergide and sumatriptan - basic science in relation to migraine treatment. Headache. 2012;52:707–714.
   PubMed Web of Science ®Google Scholar
• Ramírez Rosas MB, Labruijere S, Villalón CM, et al. Activation of 5-hydroxytryptamine1B/1D/1F receptors as a mechanism of action of antimigraine drugs. Expert Opin Pharmacother. 2013;14:1599–1610.
   PubMed Web of Science ®Google Scholar
• Sicuteri F, Testi A, Anselmi B. Biochemical investigations in headache: increase in hydroxyindole acid excretion during migraine attacks. Int Arch Allergy Immunol. 1961;19:55–58.
   Web of Science ®Google Scholar
• Somerville BW. Platelet-bound and free serotonin levels in jugular and forearm venous blood during migraine. Neurology. 1976;26:41–45.
   PubMed Web of Science ®Google Scholar
• Ferrari MD, Saxena PR. On serotonin and migraine: a clinical and pharmacological review. Cephalalgia. 1993;13:151–165.
   PubMed Web of Science ®Google Scholar
• Ferrari MD, Odink J, Tapparelli C, et al. Serotonin metabolism in migraine. Neurology. 1989;39:1239–1242.
   PubMed Web of Science ®Google Scholar
• Humphrey PPA. 5-Hydroxytryptamine and the pathophysiology of migraine. J Neurol. 1991;238:S38–S44.
   PubMed Web of Science ®Google Scholar
• Leone M, Attanasio A, Croci D, et al. The serotonergic agent m-chlorophenylpiperazine induces migraine attacks: A controlled study. Neurology. 2000;55:136–139.
   PubMed Web of Science ®Google Scholar
• Panconesi A, Sicuteri R. Headache induced by serotonergic agonists—a key to the interpretation of migraine pathogenesis? Cephalalgia. 1997;17:3–14.
   PubMed Web of Science ®Google Scholar
• Chugani DC, Niimura K, Chaturvedi S, et al. Increased brain serotonin synthesis in migraine. Neurology. 1999;53:1473–1479.
   PubMed Web of Science ®Google Scholar
• Sakai Y, Dobson C, Diksic M, et al. Sumatriptan normalizes the migraine attack-related increase in brain serotonin synthesis. Neurology. 2008;70:431–439.
   PubMed Web of Science ®Google Scholar
• Sakai Y, Nishikawa M, Diksic M, et al. α-[11C] methyl-L tryptophan-PET as a surrogate for interictal cerebral serotonin synthesis in migraine without aura. Cephalalgia. 2014;34:165–173.
   PubMed Web of Science ®Google Scholar
• Hegerl U, Juckel G. Intensity dependence of auditory evoked potentials as an indicator of central serotonergic neurotransmission: a new hypothesis. Biol Psychiatry. 1993;33:173–187.
   PubMed Web of Science ®Google Scholar
• Coppola G, Vandenheede M, Di Clemente L, et al. Somatosensory evoked high-frequency oscillations reflecting thalamo-cortical activity are decreased in migraine patients between attacks. Brain. 2005;128:98–103.
   PubMed Web of Science ®Google Scholar
• Proietti-Cecchini A, Schoenen JAJ. Intensity dependence of the cortical auditory evoked potentials as a surrogate marker of central nervous system serotonin transmission in man: demonstration of a central effect for the 5-HT1B/1D agonist zolmitriptan (311C90, Zomig). Cephalalgia. 1997;17:849–854.
   PubMed Web of Science ®Google Scholar
• Liu H, Liu M, Wang Y, et al. Association of 5-HTT gene polymorphisms with migraine: a systematic review and meta-analysis. J Neurol Sci. 2011;305:57–66.
   PubMed Web of Science ®Google Scholar
• Schurks M, Rist PM, Kurth T. STin2 VNTR polymorphism in the serotonin transporter gene and migraine: pooled and meta-analyses. J Headache Pain. 2010;11:317–326.
   PubMed Web of Science ®Google Scholar
• Thompson MD, Noble-Topham S, Percy ME, et al. Chromosome 1p36 in migraine with aura: association study of the 5-HT(1D) locus. Neuroreport. 2012;23:45–48.
   PubMed Web of Science ®Google Scholar
• Marziniak M, Mossner R, Schmitt A, et al. A functional serotonin transporter gene polymorphism is associated with migraine with aura. Neurology. 2005;64:157–159.
   PubMed Web of Science ®Google Scholar
• Oterino A, Castillo J, Pascual J, et al. Genetic association study and meta-analysis of the HTR2C Cys23Ser polymorphism and migraine. J Headache Pain. 2007;8:231–235.
   PubMed Web of Science ®Google Scholar
• Joshi G, Pradhan S, Mittal B. No direct association of serotonin transporter (STin2 VNTR) and receptor (HT 102T>C) gene variants in genetic susceptibility to migraine. Dis Markers. 2010;29:223–229.
   PubMed Web of Science ®Google Scholar
• Ates O, Karakus N, Sezer S, et al. Genetic association of 5-HT1A and 5-HT1B gene polymorphisms with migraine in a Turkish population. J Neurol Sci. 2013;326:64–67.
   PubMed Web of Science ®Google Scholar
• Sharif NA, Senchyna M. Serotonin receptor subtype mRNA expression in human ocular tissues, determined by RT-PCR. Mol Vis. 2006;12:1040–1047.
   PubMed Web of Science ®Google Scholar
• Balaban CD. Migraine, vertigo and migrainous vertigo: links between vestibular and pain mechanisms. J Vestib Res. 2011;21:315–321.
   PubMed Web of Science ®Google Scholar
• Barnes NM, Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology. 1999;38:1083–1152.
   PubMed Web of Science ®Google Scholar
• Hannon J, Hoye D. Molecular biology of 5-HT receptors. Behav Brain Res. 2008;195:198–213.
   PubMed Web of Science ®Google Scholar
• Villalón CM, VanDenBrink AM. The role of 5-hydroxytryptamine in the pathophysiology of migraine and its relevance to the design of novel treatments. Mini Rev Med Chem. 2016 Jul 28. DOI:10.2174/1389557516666160728121050. [ Epub ahead of print].
   PubMedGoogle Scholar
• Hou M, Kanje M, Longmore J, et al. 5-HT(1B) and 5-HT(1D) receptors in the human trigeminal ganglion: colocalization with calcitonin gene-related peptide, substance P and nitric oxide synthase. Brain Res. 2001;909:112–120.
   PubMed Web of Science ®Google Scholar
• Nilsson T, Longmore J, Shaw D, et al. Characterisation of 5-HT receptors in human coronary arteries by molecular and pharmacological techniques. Eur J Pharmacol. 1999;372:49–56.
   PubMed Web of Science ®Google Scholar
• Morecroft I, Heeley RP, Prentice HM, et al. 5-Hydroxytryptamine receptors mediating contraction in human small muscular pulmonary arteries: importance of the 5-HT1B receptor. Br J Pharmacol. 1999;128:730–734.
   PubMed Web of Science ®Google Scholar
• Castro E, Pascual J, Romon T, et al. Differential distribution of [3H] sumatriptan binding sites (5-HT1B, 5-HT1D and 5-HT1F) in human brain: focus on brain stem and spinal cord. Neuropharmacology. 1997;36:535–542.
   PubMed Web of Science ®Google Scholar
• Fink K, Zentner J, Goethert M. Subclassification of presynaptic 5-HT autoreceptors in the human cerebral cortex as 5-HT1Dβ receptors. Naunyn-Schmiedeberg’s Arch Pharmacol. 1995;352:451–454.
   Google Scholar
• Maura G, Marcoli M, Tortarolo M, et al. Glutamate release in human cerebral cortex and its modulation by 5-hydroxytryptamine acting at h5-HT1D receptors. Br J Pharmacol. 1998;123:45–50.
   PubMed Web of Science ®Google Scholar
• Feuerstein TJ, Huring H, Van Velthoven V, et al. 5-HT1Dlike receptors inhibit the release of endogenously formed [3H]GABA in human, but not in rabbit, neocortex. Neurosci Lett. 1996;209:210–214.
   PubMed Web of Science ®Google Scholar
• Ma Q-P. Co-localization of 5-HT(1B/1D/1F) receptors and glutamate in trigeminal ganglia in rats. Neuroreport. 2001;12:1589–1591.
   PubMed Web of Science ®Google Scholar
• Lucaites VL, Krushinski JH, Schaus JM, et al. [3H]LY334370, a novel radioligand for the 5-HT1F receptor II. Autoradiographic localization in rat, guinea pig, monkey and human brain. Naunyn Schmiedebergs Arch Pharmacol. 2005;371(3):178–184.
   PubMed Web of Science ®Google Scholar
• Cohen Z, Bouchelet I, Olivier A, et al. Multiple microvascular and astroglial 5-hydroxytryptamine receptor subtypes in human brain: molecular and pharmacologic characterization. J Cereb Blood Flow Metab. 1999;19:908–917.
   PubMed Web of Science ®Google Scholar
• Ramadan NM, Skljarevski V, Phebus LA, et al. 5-HT1F receptor agonists in acute migraine treatment: a hypothesis. Cephalalgia. 2003;23:776–785.
   PubMed Web of Science ®Google Scholar
• Amlaiky N, Ramboz S, Boschert U, et al. Isolation of a mouse “5-HT1E-like” serotonin receptor expressed predominantly in hippocampus. J Biol Chem. 1992;267:19761–19764.
   PubMed Web of Science ®Google Scholar
• Roberto G, Piccinni C, D’Alessandro R, et al. Triptans and serious adverse vascular events: data mining of the FDA Adverse Event Reporting System database. Cephalalgia. 2014;34:5–13.
   PubMed Web of Science ®Google Scholar
• Tepper SJ, Millson D. Safety profile of the triptans. Expert Opin Drug Saf. 2003;2:123–132.
   PubMedGoogle Scholar
• Florian JA, Watts SW. Integration of mitogen activated protein kinase activation in vascular 5-hydroxytryptamine2A receptor signal transduction. J Pharmacol Exp Ther. 1998;284:346–355.
   PubMed Web of Science ®Google Scholar
• Schmitz B, Ullmer C, Segelcke D, et al. BF-1—A novel selective 5-HT2B receptor antagonist blocking neurogenic dural plasma protein extravasation in guinea pigs. Eur J Pharmacol. 2015;751:73–80.
   PubMed Web of Science ®Google Scholar
• Bonhaus DW, Chang LK, Cao Z, et al. RS-127445, a selective 5-HT2B receptor antagonist, blocks a mCPP induced plasma protein extravasation in dura mater and capsaicin-evoked c-fos expression in trigeminal nucleus cauadalis. In: Olesen J, Goadsby PJeds. Cluster headache and related headaches. New York: Oxford University Press; 1999. p. 278–286.
   Google Scholar
• Johnson KW, Nelson DL, Dieckman DK, et al. Neurogenic dural protein extravasation induced by metachlorophenylpiperazine (mCPP) involves nitric oxide and 5-HT2B receptor activation. Cephalalgia. 2003;23:117–123.
   PubMed Web of Science ®Google Scholar
• Martin RS, Martin GR. Investigations into migraine pathogenesis: time course for effects of m-CPP, BW723C86 or glyceryl trinitrate on appearance of Fos-like immunoreactivity in rat trigeminal nucleus caudalis (TNC). Cephalalgia. 2001;21:46–52.
   PubMed Web of Science ®Google Scholar
• Schmuck K, Ullmer C, Kalkman HO, et al. Activation of meningeal 5-HT2B receptors: an early step in the generation of migraine headache? Eur J Neurosci. 1996;8:959–967.
   PubMed Web of Science ®Google Scholar
• Segelcke D, Messlinger K. Putative role of 5-HT2B receptors in migraine pathophysiology. Cephalalgia. 2016 Apr 28. 0333102416646760. Epub ahead of print
   Google Scholar
• Gustafson EL, Durkin MM, Bard JA, et al. A receptor autoradiographic and in situ hybridisation analysis of the distribution of the 5-HT7 receptor in rat brain. Br J Pharmacol. 1996;117:657–666.
   PubMed Web of Science ®Google Scholar
• Stowe RL, Barnes NM. Selective labelling of 5-HT7 receptor recognition sites in rat brain using [3H]5-carboxamidotryptamine. Neuropharmacology. 1998;37(12):1611–1619.
   Google Scholar
• To ZP, Bonhaus DW, Eglen RM, et al. Characterization and distribution of putative 5-HT7 receptors in guinea-pig brain. Br J Pharmacol. 1995;115:107–116.
   PubMed Web of Science ®Google Scholar
• Terrón JA, Martínez-García E. 5-HT7 receptor mediated dilatation in the middle meningeal artery of anesthetized rats. Eur J Pharmacol. 2007;560:56–60.
   PubMed Web of Science ®Google Scholar
• Terrón JA. Is the 5-HT(7) receptor involved in the pathogenesis and prophylactic treatment of migraine? Eur J Pharmacol. 2002;439:1–11.
   PubMed Web of Science ®Google Scholar
• Martín-Cora FJ, Pazos A. Autoradiographic distribution of 5-HT7 receptors in the human brain using [3H] mesulergine: comparison to other mammalian species. Br J Pharmacol. 2004;141:92–104.
   PubMed Web of Science ®Google Scholar
• Cardenas CG, Del Mar LP, Vysokanov AV, et al. Serotonergic modulation of hyperpolarization-activated current in isolated rat dorsal root ganglion neurons. J Physiol. 1999;518:507–523.
   PubMed Web of Science ®Google Scholar
• Lionetto L, Negro A, Casolla B, et al. Sumatriptan succinate: pharmacokinetics of different formulations in clinical practice. Expert Opin Pharmacother. 2012;13:2369–2380.
   PubMed Web of Science ®Google Scholar
• Vikelis M, Mitsikostas DD, Rapoport AM. Sumatriptan transdermal iontophoretic patch (NP101-ZelrixTM): review of pharmacology, clinical efficacy, and safety in the acute treatment of migraine. Neuropsychiatr Dis Treat. 2012;8:429–434.
   PubMed Web of Science ®Google Scholar
• Gutman D, Hellriegel E, Aycardi E, et al. A Phase I, open-label, single-dose safety, pharmacokinetic, and tolerability study of the sumatriptan iontophoretic transdermal system in adolescent migraine patients. Headache. 2016;56:1300–1309.
   PubMed Web of Science ®Google Scholar
• Center for Drug Evaluation and Research. Application number: 202278Orig1s000. 2012. http://www. accessdata.fda.gov/drugsatfda_docs/nda/2013/202278 Orig1s000ClinPharmR.pdf. Accessed August 25, 2015
   Google Scholar
• McCall RB, Huff R, Chio CL, et al. Preclinical studies characterizing the anti-migraine and cardiovascular effects of the selective 5-HT1D receptor agonist PNU-142633. Cephalalgia. 2002;22:799–806.
   PubMed Web of Science ®Google Scholar
• Gomez-Mancilla B, Cutler NR, Leibowitz MT, et al. Safety and efficacy of PNU-142633, a selective 5-HT1D agonist, in patients with acute migraine. Cephalalgia. 2001;21:727–732.
   PubMed Web of Science ®Google Scholar
• Ferrari MD. Re: Gomez-Mancilla et al. Safety and efficacy of PNU-142633, a selective 5-HT(1D) agonist, in patients with acute migraine. Cephalalgia. 2001;21:727–732.
   PubMed Web of Science ®Google Scholar
• Vaughan D, Speed J, Medve R, et al. Safety and pharmacokinetics of NXN-188 after single and multiple doses in five phase I, randomized, double-blind, parallel studies in healthy adult volunteers. Clin Ther. 2010;32:146–160.
   PubMed Web of Science ®Google Scholar
• Medve RA, Lategan TW. A phase 2 multicenter, randomized, double-blind, parallel-group, placebo-controlled study of NXN-188 dihydrochloride in acute migraine without aura. J Headache Pain. 2010;11:S38.
   Web of Science ®Google Scholar
• Bhatt DK, Gupta S, Jansen-Olesen I, et al. NXN-188, a selective nNOS inhibitor and a 5-HT1B/1D receptor agonist, inhibits CGRP release in preclinical migraine models. Cephalalgia. 2013;33:87–100.
   PubMed Web of Science ®Google Scholar
• Johnson KW, Schaus JM, Durkin MM, et al. 5-HT1F receptor agonists inhibit neurogenic inflammation in guinea pigs. Neuroreport. 1997;8:2237–2240.
   PubMed Web of Science ®Google Scholar
• Cohen ML, Schenck K. Contractile responses to sumatriptan and ergotamine in the rabbit saphenous vein: effect of selective 5-HT1F receptor agonists and PGF2α. Br J Pharmacol. 2000;131:562–568.
   PubMed Web of Science ®Google Scholar
• Shepheard S, Edvinsson L, Cumberbatch M, et al. Possible antimigraine mechanisms of action of the 5-HT1F receptor agonist LY334370. Cephalalgia. 1999;19:851–858.
   PubMed Web of Science ®Google Scholar
• Goldstein DJ, Roon KI, Offen WW, et al. Selective serotonin 1F (5-HT(1F)) receptor agonist LY334370 for acute migraine: a randomised controlled trial. Lancet. 2001;358:1230–1234.
   PubMed Web of Science ®Google Scholar
• Nelson DL, Phebus LA, Johnson KW, et al. Preclinical pharmacological profile of the selective 5-HT1F receptor agonist lasmiditan. Cephalalgia. 2010;30:1159–1169.
   PubMed Web of Science ®Google Scholar
• Ferrari MD, Färkkilä M, Reuter U, et al. Acute treatment of migraine with the selective 5-HT1F receptor agonist lasmiditan–a randomised proof-of-concept trial. Cephalalgia. 2010;30:1170–1178.
   PubMed Web of Science ®Google Scholar
• Färkkilä M, Diener HC, Géraud G, et al. Efficacy and tolerability of lasmiditan, an oral 5-HT(1F) receptor agonist, for the acute treatment of migraine: a phase 2 randomised, placebo-controlled, parallel-group, dose-ranging study. Lancet Neurol. 2012;11:405–413.
   PubMed Web of Science ®Google Scholar
• Cameron C, Kelly S, Hsieh SC, et al. Triptans in the acute treatment of migraine: a systematic review and network meta-analysis. Headache. 2015;55(Suppl 4):221–235.
   PubMed Web of Science ®Google Scholar
• Wells RE, Markowitz SY, Baron EP, et al. Identifying the factors underlying discontinuation of triptans. Headache. 2014;54:278–289.
   PubMed Web of Science ®Google Scholar
• Albieri V, Olsen TS, Andersen KK. Risk of stroke in migraineurs using triptans. Associations with age, sex, stroke severity and subtype. Ebio Medicine. 2016;6:199–205.
   PubMed Web of Science ®Google Scholar
• Kurth T, Winter AC, Eliassen AH, et al. Migraine and risk of cardiovascular disease in women: prospective cohort study. Bmj. 2016;353:i2610. DOI:10.1136/bmj.i2610
   PubMed Web of Science ®Google Scholar
• https://clinicaltrials.gov/ct2/show/NCT02605174?term=col-144&rank=2
   Google Scholar
• https://clinicaltrials.gov/ct2/show/NCT02439320?term=col-144&rank=4
   Google Scholar
• https://clinicaltrials.gov/ct2/show/NCT02565186?term=col-144&rank=5
   Google Scholar
• Burstein R, Collins B, Jakubowski M. Defeating migraine pain with triptans: a race against the development of cutaneous allodynia. Ann Neurol. 2004;55:19–26.
   PubMed Web of Science ®Google Scholar
• Barbanti P, Egeo G. Pharmacological trials in migraine: it’s time to reappraise where the headache is and what the pain is like. Headache. 2015;55:439–441.
   PubMed Web of Science ®Google Scholar
• Barbanti P, Egeo G, Aurilia C, et al. Drugs targeting nitric oxide synthase for migraine treatment. Expert Opin Investig Drugs. 2014;23:1141–1148.
   PubMed Web of Science ®Google Scholar
• MacGregor EA, Evers S, International Headache Society. The role of methysergide in migraine and cluster headache treatment worldwide - A survey in members of the International Headache Society. Cephalalgia. 2016;1–3. 0333102416660551
   Google Scholar
• Wang X, Fang Y, Liang J, et al. 5-HT7 receptors are involved in neurogenic dural vasodilatation in an experimental model of migraine. J Mol Neurosci. 2014;54:164–170.
   PubMed Web of Science ®Google Scholar
• Wang X, Fang Y, Liang J, et al. Selective inhibition of 5-HT7 receptor reduces CGRP release in an experimental model for migraine. Headache. 2010;50:579–587.
   PubMed Web of Science ®Google Scholar
• Wang X, Hu R, Liang J, et al. 5-HT7 receptors are not involved in neuropeptide release in primary cultured rat trigeminal ganglion neurons. J Mol Neurosci. 2016;59:251–259.
   PubMed Web of Science ®Google Scholar