, Volume 7, Issue 2, pp 176–182 | Cite as

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

  • Lars Neeb
  • Jannis Meents
  • Uwe Reuter
Review Article


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 


  1. 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.CrossRefPubMedGoogle Scholar
  2. 2.
    Diener HC, Limmroth V. Advances in pharmacological treatment of migraine. Expert Opin Investig Drugs 2001;10: 1831–1845.CrossRefPubMedGoogle Scholar
  3. 3.
    Goadsby PJ. The pharmacology of headache. Prog Neurobiol 2000;62: 509–525.CrossRefPubMedGoogle Scholar
  4. 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.PubMedGoogle Scholar
  5. 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.PubMedGoogle Scholar
  6. 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.PubMedGoogle Scholar
  7. 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.CrossRefPubMedGoogle Scholar
  8. 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.CrossRefPubMedGoogle Scholar
  9. 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.CrossRefPubMedGoogle Scholar
  10. 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.CrossRefPubMedGoogle Scholar
  11. 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.PubMedGoogle Scholar
  12. 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.CrossRefPubMedGoogle Scholar
  13. 13.
    Jayamaha JE, Street MK. Fatal cerebellar infarction in a migraine sufferer whilst receiving sumatriptan. Intensive Care Med 1995;21: 82–83.CrossRefPubMedGoogle Scholar
  14. 14.
    O’Connor P, Gladstone P. Oral sumatriptan-associated transmural myocardial infarction. Neurology 1995;45: 2274–2276.PubMedGoogle Scholar
  15. 15.
    Mueller L, Gallagher RM, Ciervo CA. Vasospasm-induced myocardial infarction with sumatriptan. Headache 1996;36: 329–331.CrossRefPubMedGoogle Scholar
  16. 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.PubMedGoogle Scholar
  17. 17.
    Laine K, Raasakka T, Mantynen J, Saukko P. Fatal cardiac arrhythmia after oral sumatriptan. Headache 1999;39: 511–512.CrossRefPubMedGoogle Scholar
  18. 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.CrossRefGoogle Scholar
  19. 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.CrossRefPubMedGoogle Scholar
  20. 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.CrossRefPubMedGoogle Scholar
  21. 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.CrossRefPubMedGoogle Scholar
  22. 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.CrossRefPubMedGoogle Scholar
  23. 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.CrossRefPubMedGoogle Scholar
  24. 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.CrossRefPubMedGoogle Scholar
  25. 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.CrossRefPubMedGoogle Scholar
  26. 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.CrossRefPubMedGoogle Scholar
  27. 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.CrossRefPubMedGoogle Scholar
  28. 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.CrossRefPubMedGoogle Scholar
  29. 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.CrossRefPubMedGoogle Scholar
  30. 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.CrossRefPubMedGoogle Scholar
  31. 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.CrossRefPubMedGoogle Scholar
  32. 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.CrossRefPubMedGoogle Scholar
  33. 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.CrossRefPubMedGoogle Scholar
  34. 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.CrossRefPubMedGoogle Scholar
  35. 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.PubMedGoogle Scholar
  36. 36.
    Ma QP. Co-localization of 5-HT(1B/1D/1F) receptors and glutamate in trigeminal ganglia in rats. Neuroreport 2001;12: 1589–1591.CrossRefPubMedGoogle Scholar
  37. 37.
    Moskowitz MA, Macfarlane R. Neurovascular and molecular mechanisms in migraine headaches. Cerebrovasc Brain Metab Rev 1993;5: 159–177.PubMedGoogle Scholar
  38. 38.
    Ramadan NM. The link between glutamate and migraine. CNS Spectr 2003;8: 446–449.PubMedGoogle Scholar
  39. 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.CrossRefPubMedGoogle Scholar
  40. 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.CrossRefPubMedGoogle Scholar
  41. 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.CrossRefPubMedGoogle Scholar
  42. 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.Google Scholar
  43. 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.CrossRefPubMedGoogle Scholar
  44. 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.CrossRefPubMedGoogle Scholar
  45. 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.Google Scholar
  46. 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.PubMedGoogle Scholar
  47. 47.
    Goldstein DJ, Offen WW, Klein EG, et al. Lanepitant, an NK-1 antagonist, in migraine prevention. Cephalalgia 2001;21: 102–106.CrossRefPubMedGoogle Scholar
  48. 48.
    Peroutka SJ. Neurogenic inflammation and migraine: implications for the therapeutics. Mol Interv 2005;5: 304–311.CrossRefPubMedGoogle Scholar
  49. 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.CrossRefPubMedGoogle Scholar
  50. 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.CrossRefPubMedGoogle Scholar
  51. 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.PubMedGoogle Scholar
  52. 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.CrossRefPubMedGoogle Scholar
  53. 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.PubMedGoogle Scholar
  54. 54.
    Edvinsson L, Tfelt-Hansen P. The blood-brain barrier in migraine treatment. Cephalalgia 2008;28: 1245–1258.CrossRefPubMedGoogle Scholar
  55. 55.
    Tfelt-Hansen PC. Does sumatriptan cross the blood-brain barrier in animals and man? J Headache Pain 2010;11: 5–12.CrossRefPubMedGoogle Scholar
  56. 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. 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.CrossRefPubMedGoogle Scholar
  58. 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.PubMedGoogle Scholar
  59. 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.CrossRefPubMedGoogle Scholar
  60. 60.
    Ullmer C, Schmuck K, Kalkman HO, Lubbert H. Expression of serotonin receptor mRNAs in blood vessels. FEBS Lett 1995;370: 215–221.CrossRefPubMedGoogle Scholar
  61. 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.CrossRefPubMedGoogle Scholar
  62. 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(abstract).Google Scholar
  63. 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.CrossRefPubMedGoogle Scholar
  64. 64.
    Gossen D, de Surray JM, Onkelinx C. First human dose study with LY334370, a selective 5HT1f agonst. 12th Mgraine Trust International Symposium, 1998.Google Scholar
  65. 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.CrossRefPubMedGoogle Scholar
  66. 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.Google Scholar
  67. 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. 68.
    Ramadan NM, Skljarevski V, Phebus LA, Johnson KW. 5-HT1F receptor agonists in acute migraine treatment: a hypothesis. Cephalalgia 2003;23: 776–785.CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2010

Authors and Affiliations

  1. 1.Department of NeurologyCharité Universitätsmedizin BerlinBerlinGermany

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