Preclinical pharmacological profile of the selective 5-HT<sub>1F</sub> receptor agonist lasmiditan

Nelson, David L.; Phebus, Lee A.; Johnson, Kirk W.; Wainscott, David B.; Cohen, Marlene L.; Calligaro, David O.; Xu, Yao‐Chang

doi:10.1177/0333102410370873

Cited by 181 publications

(193 citation statements)

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“…Previous studies have reported only a few exceptions to this pharmacological overlap; these ligands are: sumatriptan (46) (Adham et al, 1993) (Nelson et al, 2010). All five drugs have substantially higher affinity at 5-HT 1F receptors versus 5-HT 1E receptors.…”

Section: Discussionmentioning

confidence: 91%

Toward Selective Drug Development for the Human 5-Hydroxytryptamine 1E Receptor: A Comparison of 5-Hydroxytryptamine 1E and 1F Receptor Structure-Affinity Relationships

Klein

Dukat²,

Glennon³

et al. 2011

J Pharmacol Exp Ther

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The 5-hydroxytryptamine (5-HT) 1E receptor is highly expressed in the human frontal cortex and hippocampus, and this distribution suggests the function of 5-HT 1E receptors might be linked to memory. To test this hypothesis, behavioral experiments are needed. Because rats and mice lack a 5-HT 1E receptor gene, knockout strategies cannot be used to elucidate this receptor's functions. Thus, selective pharmacological tools must be developed. The tryptamine-related agonist BRL54443 [5-hydroxy-3-(1-methylpiperidin-4-yl)-1H-indole] is one of the few agents that binds 5-HT 1E receptors with high affinity and some selectively; unfortunately, it binds equally well to 5-HT 1F receptors (K i Ϸ 1 nM). The differences between tryptamine binding requirements of these two receptor populations have never been extensively explored; this must be done to guide the design of analogs with greater selectivity for 5-HT 1E receptors versus 5-HT 1F receptors. Previously, we determined the receptor binding affinities of a large series of tryptamine analogs at the 5-HT 1E receptor; we now examine the affinities of this same series of compounds at 5-HT 1F receptors. The affinities of these compounds at 5-HT 1E and 5-HT 1F receptors were found to be highly correlated (r ϭ 0.81). All high-affinity compounds were full agonists at both receptor populations. We identified 5-Nbutyryloxy-N,N-dimethyltryptamine as a novel 5-HT 1F receptor agonist with Ͼ60-fold selectivity versus 5-HT 1E receptors. There is significant overlap between 5-HT 1E and 5-HT 1F receptor orthosteric binding properties; thus, identification of 5-HT 1E -selective orthosteric ligands will be difficult. The insights generated from this study will inform future drug development and molecular modeling studies for both 5-HT 1E and 5-HT 1F receptors.

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Section: Discussionmentioning

confidence: 91%

Toward Selective Drug Development for the Human 5-Hydroxytryptamine 1E Receptor: A Comparison of 5-Hydroxytryptamine 1E and 1F Receptor Structure-Affinity Relationships

Klein

Dukat²,

Glennon³

et al. 2011

J Pharmacol Exp Ther

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“…The substance does not cause constriction of the saphenous vein of the rabbit in concentrations up to 10 Ϫ4 M. COL-144 also inhibits stimulus-induced c-fos expression in the trigeminal nucleus caudalis of the rat and reduces dural plasma protein extravasation in a standard experimental setup in experimental animals 1 h after oral dosing. 45 The efficacy and an improved tolerability of COL-144 in migraine headaches was demonstrated in a first placebo-controlled study. The study involved 130 patients who were not on prophylaxis and who had moderate to severe migraine headaches.…”

Section: -Ht 1f Receptor Agonists In Migrainementioning

confidence: 99%

“…44 The latest synthesized 5-HT 1F receptor agonist that has been proposed to be effective in migraine is COL-144. 45 Some of these substances have been tested in experimental migraine models.…”

Section: Ly344864mentioning

confidence: 99%

5-HT1F Receptor Agonists: A New Treatment Option for Migraine Attacks?

2010

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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-HT 1F 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-HT 1F receptor-mediated effects, in part by comparing them to triptans, and we also summarize data from basic research and clinical trials. Key Words: 5-HT 1F , serotonin receptor, migraine, treatment, triptans. CURRENT TREATMENT OPTIONSMigraine attacks can be treated effectively with nonsteroidal anti-inflammatory drugs, pain killers, the first generation triptan (sumatriptan), and newer triptans such as rizatriptan or almotriptan. To date, these 5-HT 1B/1D agonists represent the gold standard for the treatment of migraine attacks. A meta-analysis showed that 59% of all patients achieve a headache response with 100 mg sumatriptan orally. Approximately 29% of subjects are pain-free after 2 h, and 20% of subjects show sustained pain freedom (pain-free by 2 h after dosing and no headache recurrence or use of rescue medication through 24 h). With some of the newer triptans, higher success rates of as much as 40% for the 2 h pain-free endpoint can be seen.1 Despite the good efficacy of triptans, it has been estimated that approximately 25% of all migraine patients do not respond to triptan treatment, even when the drug is used correctly (i.e, according to prescribed dose, time, and route of administration).2 The reasons for treatment failure remain obscure.Triptans are supposed to have three important mechanisms of action: 1) vasoconstriction, 2) inhibition of neuropeptide release, and 3) inhibition of signal transmission to second order neurons within the trigeminal nucleus complex. 3 The inhibition of calcitonin generelated peptide and substance P release attenuates peripheral consequences of trigeminal stimulation (e.g., neurogenic inflammation) and also central pain transmission. However, it is still an unsolved question as to whether neuronal or vascular or both mechanisms are responsible for the anti-migraine effect of these compounds. 5-HT 1 RECEPTORS AND MIGRAINETriptans exert their function mainly through binding at the 5-HT 1B and 5-HT 1D receptor. The 5-HT 1B receptor can be found on smooth muscle cells in cerebral and coronary vessels, and this receptor mediates triptan induced vasoconstriction.4 -8 Experimentally, various isolated blood vessels from several species contract in response to triptans. The vascular effects of 5-HT 1B/1D agonists are more pronounced in cranial vessels than in peripheral arteries, probably ...

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“…For 5-HT 1F receptor agonists it has Table 1. Binding affinity of lasmiditan (n > 5) at human 5-HT receptors [Nelson et al 2010]; Ki (nM). Johnson et al 1997].…”

Section: -Ht 1f Receptor Agonistsmentioning

confidence: 99%

The pharmacological profile and clinical prospects of the oral 5-HT1F receptor agonist lasmiditan in the acute treatment of migraine

Reuter

Israel

Neeb

2014

Ther Adv Neurol Disord

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More than 20 years have passed without the launch of a new substance class for acute migraine therapy. Triptans were the latest class of substances which successfully passed all developmental stages with a significant antimigraine efficacy and a sufficient safety profile. New drugs with a better adverse event profile and at least similar efficacy are needed for migraine subjects who cannot tolerate triptans for attack treatment. Lasmiditan is a novel highly specific 5-HT 1F receptor agonist currently in clinical trials for acute migraine therapy and devoid of vasoconstriction in coronary arteries as determined in a surrogate assay. In both phase II randomized, placebo-controlled trials in acute migraine the primary endpoint was met. For the intravenous formulation a clear dose-dependent effect on headaches could be determined. Lasmiditan tablets in doses of 50-400 mg show significant headache relief after 2 hours compared with placebo and improved accompanying symptoms. This substance is chemically clearly different from other antimigraine drugs, which is also reflected by its dose-dependent adverse event profile chiefly including dizziness, vertigo, paresthesia and fatigue. Adverse events are usually linked to the central nervous system. Future phase III clinical trials with an active triptan comparator or in a preferential trial design will allow a better comparison of lasmiditan and triptans. They will also determine whether lasmiditan will become available to the migraine patient.

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Preclinical pharmacological profile of the selective 5-HT_1F receptor agonist lasmiditan

Cited by 181 publications

References 29 publications

Toward Selective Drug Development for the Human 5-Hydroxytryptamine 1E Receptor: A Comparison of 5-Hydroxytryptamine 1E and 1F Receptor Structure-Affinity Relationships

Toward Selective Drug Development for the Human 5-Hydroxytryptamine 1E Receptor: A Comparison of 5-Hydroxytryptamine 1E and 1F Receptor Structure-Affinity Relationships

5-HT1F Receptor Agonists: A New Treatment Option for Migraine Attacks?

The pharmacological profile and clinical prospects of the oral 5-HT1F receptor agonist lasmiditan in the acute treatment of migraine

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Preclinical pharmacological profile of the selective 5-HT1F receptor agonist lasmiditan

Cited by 181 publications

References 29 publications

Toward Selective Drug Development for the Human 5-Hydroxytryptamine 1E Receptor: A Comparison of 5-Hydroxytryptamine 1E and 1F Receptor Structure-Affinity Relationships

Toward Selective Drug Development for the Human 5-Hydroxytryptamine 1E Receptor: A Comparison of 5-Hydroxytryptamine 1E and 1F Receptor Structure-Affinity Relationships

5-HT1F Receptor Agonists: A New Treatment Option for Migraine Attacks?

The pharmacological profile and clinical prospects of the oral 5-HT1F receptor agonist lasmiditan in the acute treatment of migraine

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Preclinical pharmacological profile of the selective 5-HT_1F receptor agonist lasmiditan