br Experimental procedure br Introduction Migraine is a debi

Experimental procedure
Introduction Migraine is a debilitating neurovascular disorder characterized by recurring unilateral pulsating headaches of moderate to severe intensity, associated with nausea, photophobia and/or phonophobia, lasting from 4 to 72 h (Headache Classification Committee of the International Headache Society, 2013). In the Global Burden of Disease Study, migraine was ranked as the third disabler in women, sixth disabler when taking both genders into account, and the most disabling of all neurological disorders, affecting approximately 15% of the world population (Steiner, Stovner, & Birbeck, 2013), with a profound negative effect on the patient's quality of life (Ruiz de Velasco, González, Etxeberria, & Garcia-Monco, 2003). Furthermore, this neurovascular disorder represents an economic loss of €20 billion in Europe every year (Gustavsson et al., 2011). Thus, migraine is a public health problem that affects both the individual and society.
Triptans As mentioned in the above section, the role of serotoninergic neurotransmission in migraine led to the design of antimigraine drugs that targeted the 5-HT receptors (Kimball et al., 1960; Sicuteri et al., 1961; Somerville, 1976); however, the exact 5-HT receptors involved in the relief of migraine attacks were unknown. Indeed, intravenous infusion of 5-HT was able to abort migraine attacks, but considering that there are fourteen 5-HT receptors (Villalón & MaassenVanDenBrink, 2017), and they were all activated, numerous side effects were observed (Kimball et al., 1960). After several studies using selective agonists and antagonists, it was demonstrated that the therapeutic action of 5-HT was mediated by “5-HT1-like receptors” that constricted cranial blood vessels (Apperley et al., 1980; Feniuk & Humphrey, 1992; Humphrey et al., 1988), and the first triptan was developed: sumatriptan (Humphrey, 2007). In the early 1990s, sumatriptan was officially introduced to the market (The Subcutaneous Sumatriptan International Study Group, 1991). In view of the low oral bioavailability and lipophilicity of sumatriptan (Fowler et al., 1991), as well as the vast market potential, “second generation” triptans (zolmitriptan, naratriptan, rizatriptan, almotriptan, eletriptan, frovatriptan, donitriptan and avitriptan) were developed, with a chemical structure similar to sumatriptan (see Fig. 1), but in general with higher oral availability and lipophilicity (see Table 1), as well as a longer Methylprednisolone Sodium Succinate synthesis half-life (de Vries, Villalón, & Saxena, 1999; Tfelt-Hansen, De Vries, & Saxena, 2000; Villalón & MaassenVanDenBrink, 2017).
Triptan monotherapy is ineffective for approximately 25% of migraineurs and in 40% of acute migraine attacks (Diener & Limmroth, 2001). Several studies have tried to elucidate the lack of efficacy in some migraineurs, but were unable to explain why some patients are responders to the triptans while others are nonresponders. Whereas a difference in efficacy could be due to pharmacokinetic factors for some of the oral triptans, pharmacokinetics did not seem to be responsible for differences in efficacy in response to subcutaneous sumatriptan (Visser et al., 1996), nor polymorphisms in the 5-HT1B and 5-HT1F receptor genes were able to explain differences in clinical responses to sumatriptan (MaassenVanDenBrink et al., 1998; MaassenVanDenBrink, Vergouwe, Ophoff, Naylor, et al., 1998; Mehrotra, Vergouwe, Ophoff, Saxena, et al., 2007). Moreover, as previously discussed, migraine patients are known to have an increased cardiovascular risk; therefore, it is important to develop novel effective antimigraine drugs that are devoid of cardiovascular side effects. Several triptans bind to the 5-HT1F receptor (see Table 2). Also, as will be discussed later, 5­HT1F receptors are expressed in several structures associated with migraine pathophysiology and with the (neuronal) therapeutic actions of triptans. This led to the development of selective 5-HT1F receptor agonists as possible option for migraine treatment. Several selective 5-HT1F receptor agonists have been developed (see Fig. 1), including LY344864, an aminocarbazole, LY334370, a 4-(3-indolyl)piperidine (Glennon & Dukat, 2002) and lasmiditan (COL-144, LY573144), a piridinoyl-piperidine (Nelson et al., 2010). While the selective 5-HT1F receptor agonists were referred to as SSOFRAs (Selective Serotonin One F Receptor Agonists) for some time, in the last years the term “ditan” has been accepted as a synonymous of selective 5-HT1F receptor agonist (Hoffmann & Goadsby, 2014). In this context, it is important to consider alniditan, a 5-HT1A/1B/1D receptor agonist with only low 5-HT1F receptor affinity (see Table 2), suggesting that the suffix “ditan” is merely to distinguish novel acutely acting (5-HT1 receptor agonists) antimigraine drugs from triptans, without any structural (see Fig. 2) and/or pharmacological criteria (see Table 2). As the following paragraph is only focused on 5-HT1F receptor agonists, alniditan will not be further discussed when ditans are mentioned.