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. 2010 Apr;7(2):176–182. doi: 10.1016/j.nurt.2010.03.003

5-HT1F receptor agonists: A new treatment option for migraine attacks?

Lars Neeb 1, Jannis Meents 1, Uwe Reuter 1,✉
PMCID: PMC5084098  PMID: 20430316

Summary

Migraine is a debilitating disorder of the CNS. Although therapeutic options for migraine attacks have tremendously advanced with the development of triptans more than a decade ago, several conditions (such as vascular disease) restrict their use. Moreover, some patients do not respond to triptans and other currently available medications. Therefore, treatment alternatives are needed. Study data show that 5-HT1F receptor agonists successfully abort migraine attacks. These data also suggest a favorable vascular side-effect profile of these substances, which could be beneficial for migraine treatment in subjects with cardiac or vascular disease. We discuss the current knowledge of 5-HT1F receptor-mediated effects, in part by comparing them to triptans, and we also summarize data from basic research and clinical trials.

Key Words: 5-HT1F, serotonin receptor, migraine, treatment, triptans

References

  • 1.Ferrari MD, Goadsby PJ, Roon KI, Lipton RB. Triptans (serotonin, 5-HT1B/1D agonists) in migraine: detailed results and methods of a meta-analysis of 53 trials. Cephalalgia. 2002;22:633–658. doi: 10.1046/j.1468-2982.2002.00404.x. [DOI] [PubMed] [Google Scholar]
  • 2.Diener HC, Limmroth V. Advances in pharmacological treatment of migraine. Expert Opin Investig Drugs. 2001;10:1831–1845. doi: 10.1517/13543784.10.10.1831. [DOI] [PubMed] [Google Scholar]
  • 3.Goadsby PJ. The pharmacology of headache. Prog Neurobiol. 2000;62:509–525. doi: 10.1016/S0301-0082(00)00010-1. [DOI] [PubMed] [Google Scholar]
  • 4.Bouchelet I, Cohen Z, Case B, Seguela P, Hamel E. Differential expression of sumatriptan-sensitive 5-hydroxytryptamine receptors in human trigeminal ganglia and cerebral blood vessels. Mol Pharmacol. 1996;50:219–223. [PubMed] [Google Scholar]
  • 5.Longmore J, Hargreaves RJ, Boulanger CM, et al. Comparison of the vasoconstrictor properties of the 5-HT1D-receptor agonists rizatriptan (MK-462) and sumatriptan in human isolated coronary artery: outcome of two independent studies using different experimental protocols. Funct Neurol. 1997;12:3–9. [PubMed] [Google Scholar]
  • 6.Hamel E, Fan E, Linville D, Ting V, Villemure JG, Chia LS. Expression of mRNA for the serotonin 5-hydroxytryptamine 1D beta receptor subtype in human and bovine cerebral arteries. Mol Pharmacol. 1993;44:242–246. [PubMed] [Google Scholar]
  • 7.Nilsson T, Longmore J, Shaw D, Olesen IJ, Edvinsson L. Contractile 5-HT1B receptors in human cerebral arteries: pharmacological characterization and localization with immunocytochemistry. Br J Pharmacol. 1999;128:1133–1140. doi: 10.1038/sj.bjp.0702773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.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. doi: 10.1097/00004647-199908000-00010. [DOI] [PubMed] [Google Scholar]
  • 9.Longmore J, Razzaque Z, Shaw D, et al. Comparison of the vasoconstrictor effects of rizatriptan and sumatriptan in human isolated cranial arteries: immunohistological demonstration of the involvement of 5-HT1B-receptors. Br J Clin Pharmacol. 1998;46:577–582. doi: 10.1046/j.1365-2125.1998.00821.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Connor HE, Feniuk W, Humphrey PP. 5-Hydroxytryptamine contracts human coronary arteries predominantly via 5-HT2 receptor activation. Eur J Pharmacol. 1989;161:91–94. doi: 10.1016/0014-2999(89)90184-2. [DOI] [PubMed] [Google Scholar]
  • 11.MaassenVanDenBrink A, Reekers M, Bax WA, Ferrari MD, Saxena PR. Coronary side-effect potential of current and prospective antimigraine drugs. Circulation. 1998;98:25–30. doi: 10.1161/01.cir.98.1.25. [DOI] [PubMed] [Google Scholar]
  • 12.Cavazos JE, Caress JB, Chilukuri VR, Devlin T, Gray L, Hurwitz BJ. Sumatriptan-induced stroke in sagittal sinus thrombosis. Lancet. 1994;343:1105–1106. doi: 10.1016/S0140-6736(94)90220-8. [DOI] [PubMed] [Google Scholar]
  • 13.Jayamaha JE, Street MK. Fatal cerebellar infarction in a migraine sufferer whilst receiving sumatriptan. Intensive Care Med. 1995;21:82–83. doi: 10.1007/BF02425161. [DOI] [PubMed] [Google Scholar]
  • 14.O’Connor P, Gladstone P. Oral sumatriptan-associated transmural myocardial infarction. Neurology. 1995;45:2274–2276. doi: 10.1212/wnl.45.12.2274. [DOI] [PubMed] [Google Scholar]
  • 15.Mueller L, Gallagher RM, Ciervo CA. Vasospasm-induced myocardial infarction with sumatriptan. Headache. 1996;36:329–331. doi: 10.1046/j.1526-4610.1996.3605329.x. [DOI] [PubMed] [Google Scholar]
  • 16.Abbrescia VD, Pearlstein L, Kotler M. Sumatriptan-associated myocardial infarction: report of case with attention to potential risk factors. J Am Osteopath Assoc. 1997;97:162–164. doi: 10.7556/jaoa.1997.97.3.162. [DOI] [PubMed] [Google Scholar]
  • 17.Laine K, Raasakka T, Mantynen J, Saukko P. Fatal cardiac arrhythmia after oral sumatriptan. Headache. 1999;39:511–512. doi: 10.1046/j.1526-4610.1999.3907511.x. [DOI] [PubMed] [Google Scholar]
  • 18.Bonaventura P, Voorn P, Luyten WH, Leysen JE. 5HT1B and 5HT1D receptor mRNA differential co-localization with peptide mRNA in the guinea pig trigeminal ganglion. Neuroreport. 1998;9:641–645. doi: 10.1097/00001756-199803090-00015. [DOI] [PubMed] [Google Scholar]
  • 19.Rebeck GW, Maynard KI, Hyman BT, Moskowitz MA. Selective 5-HT1D alpha serotonin receptor gene expression in trigeminal ganglia: implications for antimigraine drug development. Proc Natl Acad Sci U S A. 1994;91:3666–3669. doi: 10.1073/pnas.91.9.3666. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Smith D, Hill RG, Edvinsson L, Longmore J. An immunocytochemical investigation of human trigeminal nucleus caudalis: CGRP, substance P and 5-HT1D-receptor immunoreactivities are expressed by trigeminal sensory fibres. Cephalalgia. 2002;22:424–431. doi: 10.1046/j.1468-2982.2002.00378.x. [DOI] [PubMed] [Google Scholar]
  • 21.Fanciullacci M, Alessandri M, Figini M, Geppetti P, Michelacci S. Increase in plasma calcitonin gene-related peptide from the extra-cerebral circulation during nitroglycerin-induced cluster headache attack. Pain. 1995;60:119–123. doi: 10.1016/0304-3959(94)00097-X. [DOI] [PubMed] [Google Scholar]
  • 22.Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. 1990;28:183–187. doi: 10.1002/ana.410280213. [DOI] [PubMed] [Google Scholar]
  • 23.Juhasz G, Zsombok T, Modos EA, et al. NO-induced migraine attack: strong increase in plasma calcitonin gene-related peptide (CGRP) concentration and negative correlation with platelet serotonin release. Pain. 2003;106:461–470. doi: 10.1016/j.pain.2003.09.008. [DOI] [PubMed] [Google Scholar]
  • 24.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. doi: 10.1046/j.1468-2982.2001.00208.x. [DOI] [PubMed] [Google Scholar]
  • 25.Johnson KW, Schaus JM, Durkin MM, et al. 5-HT1F receptor agonists inhibit neurogenic dural inflammation in guinea pigs. Neuroreport. 1997;8:2237–2240. doi: 10.1097/00001756-199707070-00029. [DOI] [PubMed] [Google Scholar]
  • 26.Razzaque Z, Heald MA, Pickard JD, et al. Vasoconstriction in human isolated middle meningeal arteries: determining the contribution of 5-HT1b- and 5-HT1f-receptor activation. Br J Clin Pharmacol. 1999;47:75–82. doi: 10.1046/j.1365-2125.1999.00851.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Adham N, Kao HT, Schecter LE, et al. Cloning of another human serotonin receptor (5-HT1F): a fifth 5-HT1 receptor subtype coupled to the inhibition of adenylate cyclase. Proc Natl Acad Sci U S A. 1993;90:408–412. doi: 10.1073/pnas.90.2.408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Adham N, Borden LA, Schechter LE, et al. Cell-specific coupling of the cloned human 5-HT1F receptor to multiple signal transduction pathways. Naunyn Schmiedebergs Arch Pharmacol. 1993;348:566–575. doi: 10.1007/BF00167231. [DOI] [PubMed] [Google Scholar]
  • 29.Waeber C, Moskowitz MA. [3H]sumatriptan labels both 5-HT1D and 5-HT1F receptor binding sites in the guinea pig brain: an autoradiographic study. Naunyn Schmiedebergs Arch Pharmacol. 1995;352:263–275. doi: 10.1007/BF00168556. [DOI] [PubMed] [Google Scholar]
  • 30.Pascual J, del Arco C, Romon T, del Olmo E, Castro E, Pazos A. Autoradiographic distribution of [3H]sumatriptan-binding sites in post-mortem human brain. Cephalalgia. 1996;16:317–322. doi: 10.1046/j.1468-2982.1996.1605317.x. [DOI] [PubMed] [Google Scholar]
  • 31.Bruinvels AT, Landwehrmeyer B, Gustafson EL, et al. Localization of 5-HT1B, 5-HT1D alpha, 5-HT1E and 5-HT1F receptor messenger RNA in rodent and primate brain. Neuropharmacology. 1994;33:367–386. doi: 10.1016/0028-3908(94)90067-1. [DOI] [PubMed] [Google Scholar]
  • 32.Hirst WD, Cheung NY, Rattray M, Rice GW, Wilkin GP. Cultured astrocytes express messenger RNA for multiple serotonin receptor subtypes, without functional coupling of 5-HT1 receptor subtypes to adenylyl cyclase. Brain Res Mol Brain Res. 1998;61:90–99. doi: 10.1016/S0169-328X(98)00206-X. [DOI] [PubMed] [Google Scholar]
  • 33.Bouchelet I, Case B, Olivier A, Hamel E. No contractile effect for 5-HT1D and 5-HT1F receptor agonists in human and bovine cerebral arteries: similarity with human coronary artery. Br J Pharmacol. 2000;129:501–508. doi: 10.1038/sj.bjp.0703081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Centurion D, Ortiz MI, Sanchez-Lopez A, De Vries P, Saxena PR, Villalon CM. Evidence for 5-HT(1B/1D) and 5-HT(2A) receptors mediating constriction of the canine internal carotid circulation. Br J Pharmacol. 2001;132:983–990. doi: 10.1038/sj.bjp.0703914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Cohen ML, Schenck K. 5-Hydroxytryptamine(1F) receptors do not participate in vasoconstriction: lack of vasoconstriction to LY344864, a selective serotonin(1F) receptor agonist in rabbit saphenous vein. J Pharmacol Exp Ther. 1999;290:935–939. [PubMed] [Google Scholar]
  • 36.Ma QP. Co-localization of 5-HT(1B/1D/1F) receptors and glutamate in trigeminal ganglia in rats. Neuroreport. 2001;12:1589–1591. doi: 10.1097/00001756-200106130-00015. [DOI] [PubMed] [Google Scholar]
  • 37.Moskowitz MA, Macfarlane R. Neurovascular and molecular mechanisms in migraine headaches. Cerebrovasc Brain Metab Rev. 1993;5:159–177. [PubMed] [Google Scholar]
  • 38.Ramadan NM. The link between glutamate and migraine. CNS Spectr. 2003;8:446–449. doi: 10.1017/s1092852900018757. [DOI] [PubMed] [Google Scholar]
  • 39.Ferrari A, Spaccapelo L, Pinetti D, Tacchi R, Bertolini A. Effective prophylactic treatments of migraine lower plasma glutamate levels. Cephalalgia. 2009;29:423–429. doi: 10.1111/j.1468-2982.2008.01749.x. [DOI] [PubMed] [Google Scholar]
  • 40.Shepheard S, Edvinsson L, Cumberbatch M, et al. Possible anti-migraine mechanisms of action of the 5HT1F receptor agonist LY334370. Cephalalgia. 1999;19:851–858. doi: 10.1046/j.1468-2982.1999.1910851.x. [DOI] [PubMed] [Google Scholar]
  • 41.Granados-Soto V, Arguelles CF, Rocha-Gonzalez HI, Godinez-Chaparro B, Flores-Murrieta FJ, Villalon CM. The role of peripheral 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F serotonergic receptors in the reduction of nociception in rats. Neuroscience. 2010;165:561–568. doi: 10.1016/j.neuroscience.2009.10.020. [DOI] [PubMed] [Google Scholar]
  • 42.Overshiner CC, Adham N, Zgombick JM, Branchek TA, Calligaro DO, Phebus LA. LY334370 is selective for the cloned 5-HT1f receptor. Paper presented at: 26th Annual Meeting of the Society for Neuroscience; 1996.
  • 43.Phebus LA, Johnson KW, Zgombick JM, et al. Characterization of LY344864 as a pharmacological tool to study 5-HT1F receptors: binding affinities, brain penetration and activity in the neurogenic durai inflammation model of migraine. Life Sci. 1997;61:2117–2126. doi: 10.1016/S0024-3205(97)00885-0. [DOI] [PubMed] [Google Scholar]
  • 44.Xu YC, Johnson KW, Phebus LA, et al. N-[3-(2-Dimethylaminoethyl)-2-methyl-lH-indol-5-yl]-4-fluorobenzamide: a potent, selective, and orally active 5-HT(1F) receptor agonist potentially useful for migraine therapy. J Med Chem. 2001;44:4031–4034. doi: 10.1021/jm0155190. [DOI] [PubMed] [Google Scholar]
  • 45.Nelson DL, Phebus LA, Johnson KW, Wainscott DB, Cohen ML, Xu YC. COL-144: Preclinical profile of a selective 5-HT1F receptor agonist for migraine. Cephalalgia. 2009;29:122–123. doi: 10.1177/0333102410370873. [DOI] [PubMed] [Google Scholar]
  • 46.Markowitz S, Saito K, Moskowitz MA. Neurogenically mediated leakage of plasma protein occurs from blood vessels in dura mater but not brain. J Neurosci. 1987;7:4129–4136. doi: 10.1523/JNEUROSCI.07-12-04129.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Goldstein DJ, Offen WW, Klein EG, et al. Lanepitant, an NK-1 antagonist, in migraine prevention. Cephalalgia. 2001;21:102–106. doi: 10.1046/j.1468-2982.2001.00161.x. [DOI] [PubMed] [Google Scholar]
  • 48.Peroutka SJ. Neurogenic inflammation and migraine: implications for the therapeutics. Mol Interv. 2005;5:304–311. doi: 10.1124/mi.5.5.10. [DOI] [PubMed] [Google Scholar]
  • 49.Wainscott DB, Johnson KW, Phebus LA, Schaus JM, Nelson DL. Human 5-HT1F receptor-stimulated [35S]GTPgammaS binding: correlation with inhibition of guinea pig durai plasma protein extravasation. Eur J Pharmacol. 1998;352:117–124. doi: 10.1016/S0014-2999(98)00336-7. [DOI] [PubMed] [Google Scholar]
  • 50.Mitsikostas DD, Sanchez del Rio M. Receptor systems mediating c-fos expression within trigeminal nucleus caudalis in animal models of migraine. Brain Res Brain Res Rev. 2001;35:20–35. doi: 10.1016/S0165-0173(00)00048-5. [DOI] [PubMed] [Google Scholar]
  • 51.Nozaki K, Moskowitz MA, Boccalini P. CP-93,129, sumatriptan, dihydroergotamine block c-fos expression within rat trigeminal nucleus caudalis caused by chemical stimulation of the meninges. Br J Pharmacol. 1992;106:409–415. doi: 10.1111/j.1476-5381.1992.tb14348.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Mitsikostas DD, Sanchez del Rio M, Moskowitz MA, Waeber C. Both 5-HT1B and 5-HT1F receptors modulate c-fos expression within rat trigeminal nucleus caudalis. Eur J Pharmacol. 1999;369:271–277. doi: 10.1016/S0014-2999(99)00067-9. [DOI] [PubMed] [Google Scholar]
  • 53.Dixon CM, Saynor DA, Andrew PD, Oxford J, Bradbury A, Tarbit MH. Disposition of sumatriptan in laboratory animals and humans. Drug Metab Dispos. 1993;21:761–769. [PubMed] [Google Scholar]
  • 54.Edvinsson L, Tfelt-Hansen P. The blood-brain barrier in migraine treatment. Cephalalgia. 2008;28:1245–1258. doi: 10.1111/j.1468-2982.2008.01675.x. [DOI] [PubMed] [Google Scholar]
  • 55.Tfelt-Hansen PC. Does sumatriptan cross the blood-brain barrier in animals and man? J Headache Pain. 2010;11:5–12. doi: 10.1007/s10194-009-0170-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Katofiasc M, Johnson KW, Phebus LA. The selective 5-HT1F agonists, LY334370 and LY397584, inhibit both central and peripheral branches of trigeminal sensory afferents in rats. Cephalalgia. 2000;20:419–420. [Google Scholar]
  • 57.Shepheard SL, Williamson DJ, Williams J, Hill RG, Hargreaves RJ. Comparison of the effects of sumatriptan and the NK1 antagonist CP-99,994 on plasma extravasation in Dura mater and c-fos mRNA expression in trigeminal nucleus caudalis of rats. Neuropharmacology. 1995;34:255–261. doi: 10.1016/0028-3908(94)00153-J. [DOI] [PubMed] [Google Scholar]
  • 58.Humphrey PP, Feniuk W, Perren MJ, et al. GR43175, a selective agonist for the 5-HTl-like receptor in dog isolated saphenous vein. Br J Pharmacol. 1988;94:1123–1132. doi: 10.1111/j.1476-5381.1988.tb11630.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Cohen ML, Johnson KW, Schenck KW, Phebus LA. Migraine therapy: relationship between serotonergic contractile receptors in canine and rabbit saphenous veins to human cerebral and coronary arteries. Cephalalgia. 1997;17:631–638. doi: 10.1046/j.1468-2982.1997.1706631.x. [DOI] [PubMed] [Google Scholar]
  • 60.Ullmer C, Schmuck K, Kalkman HO, Lubbert H. Expression of serotonin receptor mRNAs in blood vessels. FEBS Lett. 1995;370:215–221. doi: 10.1016/0014-5793(95)00828-W. [DOI] [PubMed] [Google Scholar]
  • 61.Wurch T, Palmier C, Colpaert FC, Pauwels PJ. Recombinant saphenous vein 5-HT1B receptors of the rabbit: comparative pharmacology with human 5-HT1B receptors. Br J Pharmacol. 1997;120:153–159. doi: 10.1038/sj.bjp.0700868. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Bard JA, Kucharewicz SA, Zgombick JM, Weinshank RL, Branchek TA. Cloning and characterization of rabbit and dog 5-HFIF receptor subtypes: a comparison of the pharmacological profile to the human species homologue. Soc Neurosci Absts. 1996;22:528.8–528.8. [Google Scholar]
  • 63.Cohen ML, Schenck K. Contractile responses to sumatriptan and ergotamine in the rabbit saphenous vein: effect of selective 5-HT(1F) receptor agonists and PGF(2alpha) Br J Pharmacol. 2000;131:562–568. doi: 10.1038/sj.bjp.0703587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Gossen D, de Surray JM, Onkelinx C. First human dose study with LY334370, a selective 5HT1f agonst. 12th Mgraine Trust International Symposium, 1998.
  • 65.Goldstein DJ, Roon KI, Offen WW, et al. Selective seratonin 1F (5-HT(1F)) receptor agonist LY334370 for acute migraine: a randomised controlled trial. Lancet. 2001;358:1230–1234. doi: 10.1016/S0140-6736(01)06347-4. [DOI] [PubMed] [Google Scholar]
  • 66.Reuter U, Pilgrim AJ, Diener HC, Färkkilä M, Ferrari M. COL-144: a selective 5-HT1F agonist for the treatment of migraine attacks. Cephalalgia. 2009;29:122–122. [Google Scholar]
  • 67.Pilgrim AJ, Dussault B, Rupniak NMJ, White J, Mazur D, DiSanto AR. COL-144, an orally bioavailable selective 5-HT1F receptor agonist for acute migraine therapy. Cephalalgia. 2009;29(Suppl 1):24–25. [Google Scholar]
  • 68.Ramadan NM, Skljarevski V, Phebus LA, Johnson KW. 5-HT1F receptor agonists in acute migraine treatment: a hypothesis. Cephalalgia. 2003;23:776–785. doi: 10.1046/j.1468-2982.2003.00525.x. [DOI] [PubMed] [Google Scholar]

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