serotonin 5-HT1F receptors


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(Updated 7/19/04)

N Adham, H Kao, LE Schechter, J Bard, M Olsen, D Urquhart, M Durkin, PR Hartig, RL Weinshak, and TA Branchek
Cloning of Another Human Serotonin Receptor (5-HT1F): A Fifth 5-HT1 Receptor Subtype Coupled to the Inhibition of Adenylate Cyclase
PNAS 90: 408-412, 1993.
"An intronless gene encoding an additional human serotonin (5-HT) 5-HT1-like receptor subtype was isolated from a human genomic library with probes obtained from degenerate PCR primers used to amplify 5-HT-receptor-specific sequences. The highest degree of homology was found with the 5-HT1E subtype (70%) and the 5-HT1D (63%) and 5-HT1Dß (60%) receptors. RNA for this gene was detected in the human brain but was not detected in kidney, liver, spleen, heart, pancreas, and testes. High-affinity (Kd = 9.2 nM) 3H-labeled 5-HT binding was detected. Competition studies revealed the following rank order of potencies for serotonergic ligands: 5-HT > sumatriptan >> 5-carboxyamidotryptamine > 8-hydroxy-2(di-1-propylamino)tetralin > spiperone. 5-HT produced a dose-dependent inhibition of forskolin-stimulated cAMP accumulation (EC50 = 7.9 nM) in transfected cells. These properties distinguish this receptor from any previously characterized and establish a fifth 5-HT1-like receptor subtype (5-HT1F) coupled to the inhibition of adenylate cyclase." [Abstract/Full Text]

Adham N, Borden LA, Schechter LE, Gustafson EL, Cochran TL, Vaysse PJ, Weinshank RL, Branchek TA.
Cell-specific coupling of the cloned human 5-HT1F receptor to multiple signal transduction pathways.
Naunyn Schmiedebergs Arch Pharmacol 1993 Dec;348(6):566-75
"We recently described the cloning of a fifth member of the 5-hydroxytryptamine (5-HT)1 (serotonin1) receptor class that inhibits adenylyl cyclase, namely the human 5-HT1F receptor (Adham et al. 1993a). In the present study we have examined in greater detail the functional coupling of the 5-HT1F receptor in two different cell lines, NIH-3T3 and LM(tk-) fibroblasts (receptor densities of 1.7 and 4.4 pmol/mg protein, respectively). The maximal inhibitory response elicited by 5-HT was significantly greater in NIH-3T3 as compared to LM(tk-) cells, whereas the EC50 values were comparable. To investigate the relationship between receptor occupancy and inhibition of cAMP accumulation mediated by 5-HT1F receptors in NIH-3T3 cells (and hence the degree of receptor reserve), we used the irreversible receptor antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). The half-maximal response required only about 10% receptor occupancy, consistent with a receptor reserve of 90% (88 +/- 2.1%, n = 4) for 5-HT-induced inhibition of FSCA. Despite the presence of such a high degree of receptor reserve, a range of intrinsic activities was displayed by structurally diverse classes of compounds. For example, sumatriptan and lysergol were as efficacious as 5-HT itself and thus acted as full agonists, whereas metergoline and 1-NP behaved as partial agonists and as shown previously (Adham et al. 1993a), methiothepin was a silent antagonist (Kb = 438 nM). We have also investigated activation of additional signal transduction pathways by the 5-HT1F receptor and found that the responses differ in the two cell lines with respect to stimulation of phospholipase C. For example, in NIH-3T3 cells no elevation of inositol phosphates (IP) of [Ca2+]i was observed even at very high agonist concentrations (100 microM). In contrast, in LM(tk-) cells concentrations of 5-HT as low as 10 nM induced stimulation of IP and a rapid increase of [Ca2+]i. The 5-HT1F receptor failed to alter arachidonic acid release in either cell line. The maximal increase in IP accumulation in LM(tk-) cells was modest, averaging about 100% above basal. The increases of IP and [Ca2+]i required 5-HT concentrations less than one order of magnitude greater than those inhibiting FSCA (EC50 = 17, 55 and 8 nM, respectively), and both responses were blocked by 100 microM methiothepin. All three responses (cAMP, IP, and [Ca2+]i) were sensitive to pertussis toxin pre-treatment, suggesting the involvement of Gi/Go protein(s) in these signal transduction pathways." [Abstract]

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 Mar 26;369(3):271-7
"A possible mechanism of action of antimigraine drugs such as sumatriptan is inhibition of the trigeminovascular pathway. Sumatriptan's effects might be mediated by 5-HT1B, 5-HT1D or 5-HT1F receptors. To establish the relative importance of these subtypes, we compared the effects of sumatriptan with those of a selective 5-HT1F receptor agonist (LY 344864) on c-fos protein expression in the trigeminal nucleus caudalis. c-fos expression was induced in urethane-anaesthetized rats by intracisternal capsaicin administration. Sumatriptan and LY 344864 decreased the number of capsaicin-induced c-fos-like immunoreactive cells within trigeminal nucleus caudalis (ID50 = 0.04 and 0.6 mg kg(-1)). The effect of sumatriptan, but not of LY 344864, was prevented by pretreatment with the antagonist SDZ 21-009, which displays high affinity for rat 5-HT1B receptors. LY 344864 appears to attenuate c-fos-like immunoreactivity via 5-HT1F receptors, while sumatriptan acts via 5-HT1B receptors. The fact that activation of 5-HT1F receptors is sufficient to modulate the activity of the trigeminal system suggests that this receptor may be a target for antimigraine drugs with improved safety profile." [Abstract]

Bouchelet, Isabelle, Case, Bruce, Olivier, Andre, Hamel, Edith
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
"The present results demonstrate that the triptan-induced contraction in brain vessels is mediated exclusively by the 5-HT1B receptor, which is also present in a majority of human coronary arteries. These results suggest that selective 5-HT1D and 5-HT1F receptor agonists might represent new antimigraine drugs devoid of cerebro- and cardiovascular effects." [Abstract]

Nilsson T, Longmore J, Shaw D, Pantev E, Bard JA, Branchek T, Edvinsson L.
Characterisation of 5-HT receptors in human coronary arteries by molecular and pharmacological techniques.
Eur J Pharmacol 1999 May 7;372(1):49-56
"In human coronary arteries, atrium. ventricle and epicardium. RT-PCR products corresponding to the human 5-HT2A, 5-HT1B and 5-HT1F receptors were expressed in high levels, mRNAs coding for 5-HT7, 5-HT1A and 5-HT1D receptors were only weakly expressed. No 5-HT1F receptor mRNA was detected. In coronary arteries there was a differential expression of 5-HT1B versus 5-HT1D receptor mRNAs, with 5-HT1B mRNAs being found in greater abundance. Dense 5-HT1B-immunoreactivity was detected on smooth muscle layer within coronary artery, however, 5-HT1D-immunoreactivity was not detected. It is concluded that 5-HT-evoked contraction of human coronary arteries is most probably mediated via the activation of both 5-HT1B and 5-HT2A receptors." [Abstract]

Dupuis, DS, Colpaert, FC, Pauwels, PJ
G-protein activation at 5-HT1A receptors by the 5-ht1F ligand LY334370 in guinea-pig brain sections and recombinant cell lines
Br. J. Pharmacol. 1998 124: 283-290
"1. G-protein activation by the 5-ht1F receptor agonist 5-(4- fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole fumarate (LY334370) was investigated by use of autoradiography of receptor- activated G-proteins in guinea-pig brain sections and [35S]-GTPgammaS binding responses in cell lines stably expressing human 5-HT1A (h 5- HT1A) receptors. 2. LY334370 (10 microM) caused little or no stimulation of [35S]-GTPgammaS binding in guinea-pig brain regions enriched in 5-ht1F binding sites (e.g., claustrum, caudate/putamen and thalamic nuclei), as identified by labelling with 10 nM [3H]- sumatriptan plus 10 nM 5-carboxamidotryptamine (5-CT). 3. Application of LY334370 (10 microM) to guinea-pig brain sections resulted in an increase of [35S]-GTPgammaS binding in hippocampus (123+/-17%), lateral septum (58+/-14%), dorsal raphe (57+/-10%), entorhinal (37+/-11%) and cingulate cortex (28+/-10%). This distribution fits with the G-protein activation mediated by 5-HT1A receptors as found with lisuride (10 microM), and labelling of 5-HT1A receptors by 140 pM [125I]-4-(2'- methoxy-phenyl)- -[2'-(n-2"-pyridinyl)-p-iodobenzamido]-ethyl- piperazine (p-MPPI). 4. The LY334370-mediated [35S]-GTPgammaS response was antagonized by the selective, silent 5-HT1A receptor antagonist N- [2-[4-(2-methoxyphenyl)1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohex anecarboxa-mide (WAY100635, 1 microM) in each of the brain structures investigated. The distribution pattern of the [35S]-GTPgammaS binding response and the antagonist profile suggest that the LY334370-induced response in guinea-pig brain is mediated by 5-HT1A receptors. 5. The maximal LY334370-induced [35S]-GTPgammaS binding response (83 to 94%) in membranes of recombinant C6-glial/h 5-HT1A and HeLa/h 5-HT1A cells was close to that of 5-HT, suggesting LY334370 to exert high intrinsic activity at h 5-HT1A receptors. 6. In conclusion, in guinea-pig brain sections and recombinant cell lines the 5-ht1F receptor agonist LY334370 causes G-protein activation that is mediated by 5-HT1A receptors. Caution should be taken when employing this ligand as a putative selective 5-ht1F agonist." [Abstract]

Chen, Joanne J., Vasko, Michael R., Wu, Xiaoping, Staeva, Theodora P., Baez, Melvyn, Zgombick, John M., Nelson, David L.
Multiple Subtypes of Serotonin Receptors Are Expressed in Rat Sensory Neurons in Culture
J Pharmacol Exp Ther 1998 287: 1119-1127
"RT-PCR analysis of RNA isolated from embryonic sensory neurons in culture confirmed the expression of 5-HT1B, 5-HT1D and 5-HT2A receptor mRNA. It also demonstrated the presence of 5-HT1F, 5-HT2C, 5-HT3, 5-HT4, 5-HT5A and 5-HT5B receptor mRNA and the absence of 5-HT1A, 5-HT1E, 5-HT2B, 5-HT6 and 5-HT7 mRNA. The identification of multiple subtypes of serotonin receptors expressed in cultured embryonic sensory neurons suggests that DRG neuronal cultures may be an excellent model to examine the direct effects of serotonin on the activity of these sensory neurons." [Full Text]

Shimron-Abarbanell D, Harms H, Erdmann J, Albus M, Maier W, Rietschel M, Korner J, Weigelt B, Franzek E, Sander T, Knapp M, Propping P, Nothen MM.
Systematic screening for mutations in the human serotonin 1F receptor gene in patients with bipolar affective disorder and schizophrenia.
Am J Med Genet 1996 Apr 9;67(2):225-8
"Using single strand conformational analysis we screened the complete coding sequence of the serotonin 1F (5-HT1F) receptor gene for the presence of DNA sequence variation in a sample of 137 unrelated individuals including 45 schizophrenic patients, 46 bipolar patients, as well as 46 healthy controls. We detected only three rare sequence variants which are characterized by single base pair substitutions, namely a silent T-->A transversion in the third position of codon 261 (encoding isoleucine), a silent C-->T transition in the third position of codon 176 (encoding histidine), and an C-->T transition in position -78 upstream from the start codon. The lack of significant mutations in patients suffering from schizophrenia and bipolar affective disorder indicates that the 5-HT1F receptor is not commonly involved in the etiology of these diseases."

Ramadan NM, Skljarevski V, Phebus LA, Johnson KW.
5-HT1F receptor agonists in acute migraine treatment: a hypothesis.
Cephalalgia. 2003 Oct;23(8):776-85.
"Serotonin-1F receptor (5-HT1F) agonists may relieve acute migraine without vasoconstriction. We conducted a review of preclinical and clinical data that assessed the potential link between migraine and 5-HT1F activation. (i) A high correlation exists between the potency of various 5-HT1 receptor agonists in the guinea pig dural plasma protein extravasation assay and their 5-HT1F receptor binding affinity. (ii) 5-HT1F receptors are on the trigeminal system, and may participate in blocking migraine pain transmission through the trigeminal ganglion and nucleus caudalis. (iii) 5-HT1F receptors are located on glutamate-containing neurones and their activation might inhibit glutamate release; glutamate excess may play a role in migraine. (iv) Selective 5-HT1F receptor agonists (LY334370; LY344864) are effective in preclinical migraine models and are non-vasoconstrictive. (v) LY334370 is effective in acute migraine, and does not cause any symptoms/signs of coronary vasoconstriction. Preclinical experiments and clinical observations argue for a role of selective 5-HT1F agonists in migraine." [Abstract]

Phebus LA, Johnson KW, Zgombick JM, Gilbert PJ, Van Belle K, Mancuso V, Nelson DL, Calligaro DO, Kiefer AD Jr, Branchek TA, Flaugh ME.
Characterization of LY344864 as a pharmacological tool to study 5-HT1F receptors: binding affinities, brain penetration and activity in the neurogenic dural inflammation model of migraine.
Life Sci 1997;61(21):2117-26
"LY344864 is a selective receptor agonist with an affinity of 6 nM (Ki) at the recently cloned 5-HT1F receptor. It possesses little affinity for the 56 other serotonergic and non-serotonergic neuronal binding sites examined. When examined for its ability to inhibit forskolin-induced cyclic AMP accumulation in cells stably transfected with human 5-HT1F receptors, LY344864 was shown to be a full agonist producing an effect similar in magnitude to serotonin itself. After an intravenous dose of 1 mg/kg, rat plasma LY344864 levels declined with time whereas brain cortex levels remained relatively constant for the first 6 hours after injection. Oral and intravenous LY344864 administration potently inhibited dural protein extravasation caused by electrical stimulation of the trigeminal ganglion in rats. Taken together, these data demonstrate that LY344864 is a selective 5-HT1F receptor agonist that can be used to explore both the in vitro and in vivo functions of this receptor." [Abstract]

Goadsby PJ, Classey JD.
Evidence for serotonin (5-HT)1B, 5-HT1D and 5-HT1F receptor inhibitory effects on trigeminal neurons with craniovascular input.
Neuroscience. 2003;122(2):491-8.
"Development of serotonin (5HT(1B/1D)) agonists for the acute attack of migraine resulted in considerable interest in their action. The superior sagittal sinus (SSS) was isolated in alpha-chloralose (60 mg/kg, i.p. and 20 mg/kg i.v.i. supplementary 2 hourly) anaesthetised cats. The SSS was stimulated electrically (100 V, 250 micros duration, 0.3 Hz) and neurons of the trigeminocervical complex monitored using electrophysiological methods. To test 5-HT(1B) receptor-mediated activity common carotid blood flow (CCF) was monitored with a transonic flow probe placed around the vessel. Naratriptan (5-HT(1B/1D/1F) receptor agonist) and alniditan (5-HT(1B/1D) receptor agonist) produced reductions in carotid blood flow of 38+/-5% and 42+/-6%, respectively. These effects were attenuated by the 5-HT(1B) receptor antagonist SB224289 (P<0.05). LY344864 (5-HT(1F) receptor agonist) had no effect on CCF. Naratriptan inhibited SSS-evoked activity (61+/-7%), an effect partially inhibited by the 5-HT(1B) receptor antagonist SB224289 (30+/-5%), or by the 5-HT(1D) receptor antagonist BRL-15572 (37+/-6%). There remained an inhibitory effect of naratriptan after both 5-HT(1B) and 5-HT(1D) receptor blockade (22+/-5%). Alniditan inhibited SSS-evoked trigeminal activity (53+/-6%), an effect abolished after 5-HT(1B) and 5-HT(1D) receptor blockade. LY344864 (5-HT(1F) receptor agonist) inhibited SSS-evoked trigeminal activity (28+/-5%), an effect unaltered by either SB224289 or BRL-15572. It can be concluded that there are inhibitory 5-HT(1B), 5-HT(1D) and 5-HT(1F) receptors in the trigeminocervical complex of the cat. 5-HT(1B) receptor-mediated inhibition is the most potent of the three in terms of inhibition of trigeminovascular nociceptive traffic." [Abstract]

Cohen, Marlene L., Schenck, Kathryn
Contractile responses to sumatriptan and ergotamine in the rabbit saphenous vein: effect of selective 5-HT1F receptor agonists and PGF2{alpha}
Br. J. Pharmacol. 2000 131: 562-568
"Thus, activation of 5-HT1F receptors will not induce vascular contraction (either alone or following modest tone with PGF2) or augment contraction to other contractile agonists in the rabbit saphenous vein." [Abstract]

Razzaque Z, Heald MA, Pickard JD, Maskell L, Beer MS, Hill RG, Longmore J.
Vasoconstriction in human isolated middle meningeal arteries: determining the contribution of 5-HT1B- and 5-HT1F-receptor activation.
Br J Clin Pharmacol 1999 Jan;47(1):75-82
"These experiments show that in human middle meningeal artery vasoconstriction to sumatriptan-like agents is 5-HT1B-receptor mediated with little if any contribution from 5-HT1F-receptor activation." [Abstract]

Maassen VanDenBrink A, Vergouwe MN, Ophoff RA, Naylor SL, Dauwerse HG, Saxena PR, Ferrari MD, Frants RR.
Chromosomal localization of the 5-HT1F receptor gene: no evidence for involvement in response to sumatriptan in migraine patients.
Am J Med Genet 1998 Jun 5;77(5):415-20
"The 5-HT1F receptor, which is present in both human vascular and neuronal tissue, may mediate the therapeutic effect and/or side-effects of sumatriptan. We investigated the chromosomal localization of the 5-HT1F receptor gene and the relation between eventually existing polymorphisms and the clinical response to sumatriptan in migraine patients. The 5-HT1F receptor gene was localized using a monochromosomal mapping panel, followed by a radiation-reduced hybrid mapping and fluorescent in situ hybridization. The results of these techniques show that the 5-HT1F receptor gene is localized at 3p12. We investigated the presence of polymorphisms by single strand conformation polymorphism analysis in 14 migraine patients who consistently responded well to sumatriptan, 12 patients who consistently experienced recurrence of the headache after initial relief, 12 patients with no response to sumatriptan, and in 13 patients who consistently experienced chest symptoms after use of sumatriptan. No polymorphisms were detected in any of the patients. We therefore conclude that genetic diversity of the 5-HT1F receptor gene is most probably not responsible for the variable clinical response to sumatriptan." [Abstract]

Erdmann J, Shimron-Abarbanell D, Shridhar V, Smith DI, Propping P, Nothen MM.
Assignment of the human serotonin 1F receptor gene (HTR1F) to the short arm of chromosome 3 (3p13-p14.1).
Mol Membr Biol 1997 Jul-Sep;14(3):133-5
"In the present study, we report the chromosomal localization of the human 5-HT1F receptor gene (HTR1F) by the analysis of somatic cell hybrids. Based upon the HTR1F cDNA sequence, a primer set that reacted with human genomic DNA but not mouse or hamster genomic DNA was derived from the relatively nonconserved 5'-untranslated and coding region. Using monochromosomal hybrid cell lines of the NIGMS Mapping Panel 2 we localized the HTR1F to human chromosome 3. To confirm the localization on chromosome 3 and to further sublocalize the HTR1F gene, a set of human cell hybrids regionally separating chromosome 3 into 7 regions was similarly analysed. Analysis of this regional panel showed that the HTR1F gene was located proximal to the 3p14.1 breakpoint in hybrid APH14 and distal to the breakpoint in 3p13 in hybrid APH13. This localizes the HTR1F gene to human chromosome 3p13-p14.1." [Abstract]

Guptan P, Dhingra A, Panicker MM.
Multiple transcripts encode the 5-HT1F receptor in rodent brain.
Neuroreport 1997 Oct 20;8(15):3317-21
"The mouse serotonin 1F (5-HT1F) receptor is encoded by at least three transcripts in mouse brain. These transcripts are expressed predominantly in cortex and hippocampus. Similar transcripts are seen in Northern analysis of rat brain mRNA. 5' RACE showed a predominant transcription start site around 350 bp upstream of the translational start present in mouse cDNA. Our results suggest that the heterogeneity seen in transcript size is due to differences in the 3' untranslated region, which could play a critical role in mRNA targeting and localization. The mouse 5-HT1F genomic clone shows the coding region to be intronless and an intron splice junction is seen in the 5' untranslated region which is conserved in both rat and mouse." [Abstract]

Adham N, Bard JA, Zgombick JM, Durkin MM, Kucharewicz S, Weinshank RL, Branchek TA.
Cloning and characterization of the guinea pig 5-HT1F receptor subtype: a comparison of the pharmacological profile to the human species homolog.
Neuropharmacology 1997 Apr-May;36(4-5):569-76
"The anti-migraine compound, sumatriptan, has been shown to have substantial affinity for the cloned human 5-HT1F receptor suggesting that, in addition to 5-HT1B/5-HT1D receptor subtypes, the 5-HT1F receptor may be a therapeutic target for the treatment of migraine. Several investigators have used the guinea pig plasma extravasation model to evaluate potential anti-migraine drugs. Since species differences in the pharmacology of serotonin receptors are well known, we compared the pharmacological profiles of the cloned human and guinea pig 5-HT1F receptors in order to validate the usefulness of the in vivo model in predicting anti-migraine activity of compounds targeted for humans. We have cloned the guinea pig 5-HT1F by homology to the human 5-HT1F receptor and evaluated its pharmacological profile using radioligand binding assays. The cloned guinea pig 5-HT1F gene exhibited 94% amino acid identity to the corresponding human homolog. High affinity (Kd approximately 10 nM) [3H]5-HT binding was detected to membranes obtained from Cos-7 cells transiently expressing the guinea pig 5-HT1F receptor. The cloned guinea pig receptor displayed typical 5-HT1F receptor pharmacology with the following rank order of binding affinities: 5-HT > sumatriptan > 1-NP = DHE > alpha-methyl 5-HT > metergoline > methiothepin > 5-CT. The pharmacological profiles of the cloned guinea pig and human 5-HT1F receptors were very similar as reflected by the high correlation (r2 = 0.72, slope = 0.76) observed between the binding affinities of compounds for these two species homologs. In situ hybridization studies in guinea pig tissue revealed 5-HT1F receptor mRNA expression in the neurons of the trigeminal ganglion, suggesting that the 5-HT1F receptor may play a role in the presynaptic inhibition of neuropeptide release at the level of the intracranial vasculature, thereby blocking the development of neurogenic inflammation. Dorsal root ganglion cells also moderately expressed the 5-HT1F transcripts. The localization of the 5-HT1F receptor to areas involved in the mediation and transfer of nociceptive information implies a role for this receptor in pain processing. These findings indicate that a selective 5-HT1F agonist may be a novel approach to treat migraine." [Abstract]

Bhalla P, Sharma HS, Wurch T, Pauwels PJ, Saxena PR.
Molecular cloning and expression of the porcine trigeminal ganglion cDNA encoding a 5-ht(1F) receptor.
Eur J Pharmacol. 2002 Feb 1;436(1-2):23-33.
"Using a combination of reverse transcription polymerase chain reaction (RT-PCR) and inverse-PCR techniques, we amplified, cloned and sequenced a full-length porcine 5-hydroxytryptamine 1F (5-ht(1F)) receptor complementary DNA (cDNA) derived from porcine trigeminal ganglion. Sequence analysis revealed 1101 base pairs (bp) encoding an open reading frame of 366 amino acids showing a high similarity (>90%) with the 5-ht(1F) receptor sequences from other species, including human. The recombinant porcine 5-ht(1F) receptor was expressed in African green monkey kidney cell lines (COS-7 cells) and its ligand binding profile was determined using [3H]5-HT. The affinities of several agonists (LY334370 (5-(4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole fumarate)>CP122638 (N-methyl-3 [pyrrolidin 2(R)-yl methyl]-1H-indol-5-ylmethyl sulphonamide)=naratriptan =5HT>eletriptan>sumatriptan>frovatriptan =avitriptan>dihydroergotamine>zolmitriptan>5-carboxamidotryptamine>rizatriptan>alniditan=donitriptan>L694247 (2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl]-1H-indole-3-yl] ethylamine) and putative antagonists (methiothepin>GR127935 (N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl 4'-(5-methyl-1,2,4-oxadiazol-3-yl) [1,1-biphenyl]-4-carboxamide hydrochloride)>ritanserin>SB224289 (2,3,6,7-tetrahydro-1'-methyl-5-[2'-methyl-4'(5-methyl-1,2,4-oxadiazol-3-yl) biphenyl-4-carbonyl] furo [2,3-f] indole-3-spiro-4'-piperidine hydrochloride)>BRL155572 ([1-(3-chlorophenyl)-4-[3,3-diphenyl (2-(S,R) hydroxypropanyl)piperazine] hydrochloride)>ketanserin=pindolol) correlated highly with those described for the recombinant human 5-ht(1F) receptor (Spearman correlation coefficient; r(s)=0.942). Nevertheless, as compared to the human homologue, some triptans (i.e. sumatriptan, zolmitriptan and rizatriptan) displayed a 10- to 15-fold lower affinity for the porcine 5-ht(1F) receptor. Using RT-PCR technique, the expression of porcine 5-ht(1F) receptor mRNA was observed in cerebral cortex, trigeminal ganglion and several blood vessels, but not in skeletal muscles. In conclusion, we have cloned and established the amino acid sequence and ligand binding profile of the porcine 5-ht(1F) receptor as well as the distribution of its mRNA. This information may be helpful in exploring the role of 5-ht(1F) receptor in physiological processes and diseases, such as migraine." [Abstract]

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 Aug;50(2):219-23
"The efficacy of sumatriptan in migraine relief has been attributed to its interaction with 5-hydroxytryptamine1D (5-HT1D) receptors in cerebral blood vessels and/or on nerve endings of the trigeminovascular system in the dura mater. Using the high sensitivity of polymerase chain reaction (PCR) amplification, we investigated the expression of the sumatriptan-sensitive 5-HT receptors, namely, the 5-HT1D alpha, 5-HT1D beta, and 5-HT1F subtypes in human trigeminal ganglia (10 experiments) and cerebral blood vessels (seven experiments) obtained postmortem. Messages for the 5-HT1D alpha and 5-HT1D beta receptors were expressed in all except one of the 10 trigeminal ganglia studied. Expression of the 5-HT1F receptor was detected by gel electrophoresis of the PCR products in six ganglia and by Southern blot hybridization in two additional cases. In human brain vessels, message for the 5-HT1D beta receptor was present in all samples, whereas specific PCR products corresponding to the 5-HT1D alpha receptor could hardly be detected in only two preparations. PCR products indicative of the 5-HT1F receptor message were detected by gel electrophoresis in three brain vessel preparations and confirmed in the other four by Southern blot hybridization. Restriction mapping and sequence analysis of all PCR products identified the expected human 5-HT receptor DNA sequences. The data confirm that the 5-HT1D beta receptor is the dominant species in human cerebral blood vessels and further show that this receptor and the 5-HT1F are expressed in both neural and vascular tissues. In contrast, the data point to a preferential expression of 5-HT1D alpha receptors in neural versus vascular tissues and strongly reemphasize the need for selective 5-HT1D alpha agonists in the identification of the target tissue(s) for antimigraine drugs. Moreover, the data stress the importance to better understand the role of 5-HT1F receptors in cerebrovascular functions and dural inflammation and further raise interest regarding their possible involvement in migraine therapy."

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Recent 5-HT1F Receptor Research

1) Rapoport AM
The therapeutic future in headache.
Neurol Sci. 2012 May;33 Suppl 1:S119-25.
There are many categories and individual types of headache and most have a variety of treatment protocols, while a few are best treated by just one medication. This paper will concentrate on acute care medications for migraine and discuss some new and future acute care treatments. There is not much to discuss about prevention, except that onabotulinumtoxinA has been approved for prevention of chronic migraine. Cluster headache will also be discussed, as there are some future treatments for acute care and prevention being studied at present. For the acute care of migraine in the US, we have seven triptans by tablet plus other routes and one non steroidal anti-inflammatory medication approved by the FDA that is currently available (Cambia brand of buffered diclofenac potassium for oral solution). There are several other acute care medications in various stages of development and there are three new methods of administering a triptan and others under investigation. The optimal acute care therapy for migraine should be faster, easier to use and more efficient with fewer adverse events than what is currently available. What follows is a brief review of the status in development for five of the many new acute care medications being investigated: the CGRP antagonist tablet telcagepant, the sumatriptan iontophoretic patch Zelrix, sumatriptan powder for use in the OptiNose apparatus, dihydroergotamine for oral inhalation (Levadex), civamide nasal solution for prevention of episodic cluster headache (Civanex) and sphenopalatine ganglion stimulation for acute cluster attacks in chronic cluster headaches. Other future treatments that will not be discussed include transcranial magnetic stimulation, a 5-HT(1F) agonist named alniditan, large conductance calcium-activated potassium channel openers, glial modulators or other medications and devices in early stages of development. [PubMed Citation] [Order full text from Infotrieve]

2) Färkkilä M, Diener HC, Géraud G, Láinez M, Schoenen J, Harner N, Pilgrim A, Reuter U
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 May;11(5):405-13.
[PubMed Citation] [Order full text from Infotrieve]

3) Dahlöf C, Maassen Van Den Brink A
Dihydroergotamine, ergotamine, methysergide and sumatriptan - basic science in relation to migraine treatment.
Headache. 2012 Apr;52(4):707-14.
The 5-hydroxytryptamine (5-HT) receptor family mediates the effects of several drugs highly effective in migraine primarily by activating 5-HT(1B) , 5-HT(1D) , and 5-HT(1F) receptors. Ergotamine, dihydroergotamine, and methysergide, as well as the "triptan" sumatriptan, are all agonists for these receptors. The receptor profile and degree of selectivity of these four drugs differ, which is reflected by their side effects that limit their use in the acute and prophylactic treatment of migraine. The acute antimigraine efficacy of these remedies is very much dependent on the formulation used where, in general, parenteral formulations are more effective in reliving the symptoms of a migraine attack. [PubMed Citation] [Order full text from Infotrieve]

4) Tfelt-Hansen PC, Olesen J
The 5-HT1F receptor agonist lasmiditan as a potential treatment of migraine attacks: a review of two placebo-controlled phase II trials.
J Headache Pain. 2012 Jun;13(4):271-5.
Lasmiditan is a novel selective 5-HT(1F) receptor agonist. It is both scientifically and clinically relevant to review whether a 5-HT(1F) receptor agonist is effective in the acute treatment of migraine. Two RCTs in the phase II development of lasmiditan was reviewed. In the intravenous placebo-controlled RCT, lasmiditan doses of 2.5-45 mg were used, and there was a linear association between headache relief (HR) rates and dose levels (P < 0.02). For lasmiditan 20 mg, HR was 64 % and for placebo it was 45 % (NS). In the oral placebo-controlled RCT, lasmiditan doses of 50, 100, 200 and 400 mg were used. For HR, all doses of lasmiditan were superior to placebo (P < 0.05). For lasmiditan 400 mg, HR was 64 % and it was 25 % for placebo. Adverse events (AEs) emerging from the treatment were reported by 22 % of the patients receiving placebo and by 65, 73, 87 and 87 % of patients receiving 50, 100, 200 and 400 mg, respectively. The majority of AEs after lasmiditan 100 and 400 mg were moderate or severe. For the understanding of migraine pathophysiology, it is very important to note that a selective 5-HT(1F) receptor agonist like lasmiditan is effective in the acute treatment of migraine. Thus, migraine can be treated with a drug that has no vasoconstrictor ability. While lasmiditan most likely is effective in the treatment of migraine attacks it had, unfortunately, a high incidence of CNS related AEs in the oral RCT. If confirmed in larger studies in phase III, this might adversely limit the use of this highly specific non-vascular acute treatment of migraine. Larger studies including the parameters of patients' preferences are necessary to accurately position this new treatment principle in relation to the triptans. [PubMed Citation] [Order full text from Infotrieve]

5) Peatfield R
Headache currents commentary.
Headache. 2012 Apr;52(4):715.
What Happens to the Old Headache Medicines? Rapoport AM, MD. Old headache medicines never die; they either fade away or come back in disguise. The disguise is often a new route of administration, which may work better, faster, more completely, with fewer adverse events, and/or have certain other advantages. The clinical aspects of 3 of the oldest headache medicines (ergotamine tartrate, dihydroergotamine, and methysergide) will be discussed here. Sumatriptan will then be discussed as the prototype of the newest category of acute care therapy (triptans) for migraine. It will be compared with the older medications, and the new forms being developed will be briefly discussed. Diclofenac potassium for oral solution will be mentioned as the newest drug approved for migraine by the Food and Drug Administration and a possible alternative to triptans in patients with frequent headaches or those with contraindications to vasoconstrictors. Dihydroergotamine, Ergotamine, Methysergide and Sumatriptan - Basic Science in Relation to Migraine Treatment. Dahlöf C, Maassen Van Den Brink A. The 5-hydroxytryptamine (5-HT) receptor family mediates the effects of several drugs highly effective in migraine primarily by activating 5-HT(1B) , 5-HT(1D) , and 5-HT(1F) receptors. Ergotamine, dihydroergotamine and methysergide, as well as the "triptan" sumatriptan, are all agonists for these receptors. The receptor profile and degree of selectivity of these 4 drugs differ, which is reflected by their side effects that limit their use in the acute and prophylactic treatment of migraine. The acute antimigraine efficacy of these remedies is very much dependent on the formulation used where, in general, parenteral formulations are more effective in relieving the symptoms of a migraine attack. [PubMed Citation] [Order full text from Infotrieve]

6) Amrutkar DV, Ploug KB, Hay-Schmidt A, Porreca F, Olesen J, Jansen-Olesen I
mRNA expression of 5-hydroxytryptamine 1B, 1D, and 1F receptors and their role in controlling the release of calcitonin gene-related peptide in the rat trigeminovascular system.
Pain. 2012 Apr;153(4):830-8.
Triptans, a family of 5-hydroxytryptamine (5-HT) 1B, 1D, and 1F receptor agonists, are used in the acute treatment of migraine attacks. The site of action and subtypes of the 5-HT(1) receptor that mediate the antimigraine effect have still to be identified. This study investigated the mRNA expression of these receptors and the role of 5-HT(1) receptor subtypes in controlling the release of calcitonin gene-related peptide (CGRP) in rat dura mater, trigeminal ganglion (TG), and trigeminal nucleus caudalis (TNC). The mRNA for each receptor subtype was quantified by quantitative real-time polymerase chain reaction. A high potassium concentration was used to release CGRP from dura mater, isolated TG, and TNC in vitro. The immunoreactive CGRP (iCGRP) release was measured by enzyme-linked immunoassay. The mRNA transcripts of the 3 5-HT(1) receptor subtypes were detected in the trigeminovascular system. Sumatriptan inhibited iCGRP release by 31% in dura mater, 44% in TG, and 56% in TNC. This effect was reversed by a 5-HT(1B/1D) antagonist (GR127395). The 5-HT(1F) agonist (LY-344864) was effective in the dura mater (26% iCGRP inhibition), and the 5-HT(1D) agonist (PNU-142633) had a significant effect in the TNC (48%), whereas the 5-HT(1B) agonist (CP-94253) was unable to reduce the iCGRP release in all tissues studied. We found that sumatriptan reduced the iCGRP release via activation of 5-HT(1D) and 5-HT(1F) receptor subtypes. The 5-HT(1F) receptor agonist was effective only in peripheral terminals in dura mater, whereas the 5-HT(1D) agonist had a preferential effect on central terminals in the TNC. [PubMed Citation] [Order full text from Infotrieve]

7) Klein M, Teitler M
Distribution of 5-ht(1E) receptors in the mammalian brain and cerebral vasculature: an immunohistochemical and pharmacological study.
Br J Pharmacol. 2012 Jun;166(4):1290-302.
[PubMed Citation] [Order full text from Infotrieve]

8) Jeong HJ, Mitchell VA, Vaughan CW
Role of 5-HT(1) receptor subtypes in the modulation of pain and synaptic transmission in rat spinal superficial dorsal horn.
Br J Pharmacol. 2012 Mar;165(6):1956-65.
[PubMed Citation] [Order full text from Infotrieve]

9) Murray KC, Stephens MJ, Rank M, D'Amico J, Gorassini MA, Bennett DJ
Polysynaptic excitatory postsynaptic potentials that trigger spasms after spinal cord injury in rats are inhibited by 5-HT1B and 5-HT1F receptors.
J Neurophysiol. 2011 Aug;106(2):925-43.
Sensory afferent transmission and associated spinal reflexes are normally inhibited by serotonin (5-HT) derived from the brain stem. Spinal cord injury (SCI) that eliminates this 5-HT innervation leads to a disinhibition of sensory transmission and a consequent emergence of unusually long polysynaptic excitatory postsynaptic potentials (EPSPs) in motoneurons. These EPSPs play a critical role in triggering long polysynaptic reflexes (LPRs) that initiate muscles spasms. In the present study we examined which 5-HT receptors modulate the EPSPs and whether these receptors adapt to a loss of 5-HT after chronic spinal transection in rats. The EPSPs and associated LPRs recorded in vitro in spinal cords from chronic spinal rats were consistently inhibited by 5-HT(1B) or 5-HT(1F) receptor agonists, including zolmitriptan (5-HT(1B/1D/1F)) and LY344864 (5-HT(1F)), with a sigmoidal dose-response relation, from which we computed the 50% inhibition (EC(50)) and potency (-log EC(50)). The potencies of 5-HT receptor agonists were highly correlated with their binding affinity to 5-HT(1B) and 5-HT(1F) receptors, and not to other 5-HT receptors. Zolmitriptan also inhibited the LPRs and general muscle spasms recorded in vivo in the awake chronic spinal rat. The 5-HT(1B) receptor antagonists SB216641 and GR127935 and the inverse agonist SB224289 reduced the inhibition of LPRs by 5-HT(1B) agonists (zolmitriptan). However, when applied alone, SB224289, SB216641, and GR127935 had no effect on the LPRs, indicating that 5-HT(1B) receptors do not adapt to chronic injury, remaining silent, without constitutive activity. The reduction in EPSPs with zolmitriptan unmasked a large glycine-mediated inhibitory postsynaptic current (IPSC) after SCI. This IPSC and associated chloride current reversed at -73 mV, slightly below the resting membrane potential. Zolmitriptan did not change motoneuron properties. Our results demonstrate that 5-HT(1B/1F) agonists, such as zolmitriptan, can restore inhibition of sensory transmission after SCI without affecting general motoneuron function and thus may serve as a novel class of antispastic drugs. [PubMed Citation] [Order full text from Infotrieve]

10) Rapoport A
New frontiers in headache therapy.
Neurol Sci. 2011 May;32 Suppl 1:S105-9.
There are numerous headache therapies available for our patients, more for migraine than for any of the other primary headache disorders. Only four medications have been approved for migraine prevention in the last few decades in the US and onabotulinumtoxinA was recently approved in the UK and the US for chronic migraine. We have been more fortunate in the acute care arena where in the US we have had seven triptans and one nonsteroidal anti-inflammatory medication approved by the FDA and currently available. There are several other acute care medications in various stages of development and there are two new methods of administering a triptan and others under investigation. We are always looking for faster, easier and more efficient administration of medications with fewer adverse events, as optimal migraine therapy requires these characteristics. What follows is a brief review of the progress in development for four of the many new acute care medications being investigated: the CGRP antagonist tablet telcagepant, the sumatriptan iontophoretic patch, sumatriptan powder for use in the OptiNose apparatus and the dihydroergotamine oral inhaler. I will not include transcranial magnetic stimulation, a 5-HT(1F) agonist, large conductance calcium-activated potassium channel openers, glial modulators or other medications and devices in early stages of development [1]. [PubMed Citation] [Order full text from Infotrieve]

11) Maggioni F, Pini LA, Zanchin G
Preclinical pharmacological profile of the selective 5-HT1F receptor agonist lasmiditan. A comment.
Cephalalgia. 2011 Jul;31(9):1061.
[PubMed Citation] [Order full text from Infotrieve]

12) González-Hernández A, Manrique-Maldonado G, Lozano-Cuenca J, Muńoz-Islas E, Centurión D, Maassen VanDenBrink A, Villalón CM
The 5-HT(1) receptors inhibiting the rat vasodepressor sensory CGRPergic outflow: further involvement of 5-HT(1F), but not 5-HT(1A) or 5-HT(1D), subtypes.
Eur J Pharmacol. 2011 Jun 1;659(2-3):233-43.
We have previously shown that 5-HT(1B) receptors inhibit prejunctionally the rat vasodepressor CGRPergic sensory outflow. Since 5-HT(1) receptors comprise 5-HT(1A), 5-HT(1B), 5-HT(1D) and 5-HT(1F) functional subtypes, this study has further investigated the role of 5-HT(1A), 5-HT(1D) and 5-HT(1F) receptor subtypes in the inhibition of the above vasodepressor sensory outflow. Pithed rats were pretreated with i.v. continuous infusions of hexamethonium and methoxamine, followed by 5-HT(1) receptor agonists. Then electrical spinal stimulation (T(9)-T(12)) or i.v. bolus injections of exogenous ?-CGRP produced frequency-dependent or dose-dependent vasodepressor responses. The electrically-induced vasodepressor responses remained unchanged during infusions of the 5-HT(1A) receptor agonists 8-OH-DPAT and NN-DP-5-CT. In contrast, these responses were inhibited by the agonists sumatriptan (5-HT(1A/1B/1D/1F)), indorenate (5-HT(1A)), PNU-142633 (5-HT(1D)) or LY344864 (5-HT(1F)), which did not affect the vasodepressor responses to exogenous CGRP (implying a prejunctional sensory-inhibition). When analysing the effects of antagonists: (i) 310 ?g/kg (but not 100 ?g/kg) GR127935 (5-HT(1A/1B/1D/1F)) abolished the inhibition to sumatriptan, indorenate, PNU-142633 or LY344864; (ii) 310 ?g/kg SB224289 (5-HT(1B)) or BRL15572 (5-HT(1D)) failed to block the inhibition to sumatriptan or PNU-142633, whereas SB224289+BRL15572 partly blocked the inhibition to sumatriptan; and (iii) 10 ?g/kg WAY100635 (5-HT(1A)) failed to block the inhibition to indorenate. These results suggest that 5-HT(1F), but not 5-HT(1A) or 5-HT(1D), receptor subtypes inhibit the vasodepressor sensory CGRPergic outflow although, admittedly, no selective 5-HT(1F) receptor agonist is available yet. The pharmacological profile of these receptors resembles that shown in rat dorsal root ganglia by molecular biology techniques. [PubMed Citation] [Order full text from Infotrieve]

13) Olesen J, Ashina M
Emerging migraine treatments and drug targets.
Trends Pharmacol Sci. 2011 Jun;32(6):352-9.
Migraine has a 1-year prevalence of 10% and high socioeconomic costs. Despite recent drug developments, there is a huge unmet need for better pharmacotherapy. In this review we discuss promising anti-migraine strategies such as calcitonin gene-related peptide (CGRP) receptor antagonists and 5-hydroxytrypamine (5-HT)(1F) receptor agonists, which are in late-stage development. Nitric oxide antagonists are also in development. New forms of administration of sumatriptan might improve efficacy and reduce side effects. Botulinum toxin A has recently been approved for the prophylaxis of chronic migraine. Tonabersat, a cortical spreading depression inhibitor, has shown efficacy in the prophylaxis of migraine with aura. Several new drug targets such as nitric oxide synthase, the 5-HT(1D) receptor, the prostanoid receptors EP(2) and EP(4), and the pituitary adenylate cyclase receptor PAC1 await development. The greatest need is for new prophylactic drugs, and it seems likely that such compounds will be developed in the coming decade. [PubMed Citation] [Order full text from Infotrieve]

14) Klein MT, Dukat M, Glennon RA, Teitler M
Toward selective drug development for the human 5-hydroxytryptamine 1E receptor: a comparison of 5-hydroxytryptamine 1E and 1F receptor structure-affinity relationships.
J Pharmacol Exp Ther. 2011 Jun;337(3):860-7.
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) ? 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 = 0.81). All high-affinity compounds were full agonists at both receptor populations. We identified 5-N-butyryloxy-N,N-dimethyltryptamine as a novel 5-HT(1F) receptor agonist with >60-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. [PubMed Citation] [Order full text from Infotrieve]

15) Chan KY, Vermeersch S, de Hoon J, Villalón CM, Maassenvandenbrink A
Potential mechanisms of prospective antimigraine drugs: a focus on vascular (side) effects.
Pharmacol Ther. 2011 Mar;129(3):332-51.
Currently available drugs for the acute treatment of migraine, i.e. ergot alkaloids and triptans, are cranial vasoconstrictors. Although cranial vasoconstriction is likely to mediate-at least a part of-their therapeutic effects, this property also causes vascular side-effects. Indeed, the ergot alkaloids and the triptans have been reported to induce myocardial ischemia and stroke, albeit in extremely rare cases, and are contraindicated in patients with known cardiovascular risk factors. In view of these limitations, novel antimigraine drugs devoid of vascular (side) effects are being explored. Currently, calcitonin gene-related peptide (CGRP) receptor antagonists, which do not have direct vasoconstrictor effects, are under clinical development. Other classes of drugs, such as 5-HT(1F) receptor agonists, glutamate receptor antagonists, nitric oxide synthase inhibitors, VPAC/PAC receptor antagonists and gap junction modulators, have also been proposed as potential targets for acute antimigraine drugs. Although these prospective drugs do not directly induce vasoconstriction, they may well induce indirect vascular effects by inhibiting or otherwise modulating the responses to endogenous vasoactive substances. These indirect vascular effects might contribute to the therapeutic efficacy of the previously mentioned compounds, but may alternatively also lead to vascular side-effects. As described in the current review, some of the prospective antimigraine drugs with a proposed non-vascular mechanism of action may still have direct or indirect vascular effects. [PubMed Citation] [Order full text from Infotrieve]

16) Monteith TS, Goadsby PJ
Acute migraine therapy: new drugs and new approaches.
Curr Treat Options Neurol. 2011 Feb;13(1):1-14.
OPINION STATEMENT: The conceptual shift of our understanding of migraine from a vascular disorder to a brain disorder has dramatically altered the approach to the development of new medicines in the field. Current pharmacologic treatments of acute migraine consist of nonspecific and relatively specific agents. Migraine-specific drugs comprise two classes, the ergot alkaloid derivatives and the triptans, serotonin 5-HT(1B/1D) receptor agonists. The ergots, consisting of ergotamine and dihydroergotamine (DHE), are the oldest specific antimigraine drugs available and are considered relatively safe and effective. Ergotamine has been used less extensively because of its adverse effects; DHE is better tolerated. The triptan era, beginning in the 1990s, was a period of considerable change, although these medicines retained vasoconstrictor actions. New methods of delivering older drugs include orally inhaled DHE and the transdermal formulation of sumatriptan, both currently under study. Novel medicines being developed are targeted at neural sites of action. Serotonin 5-HT(1F) receptor agonists have proven effective in phase II studies and have no vascular actions. Calcitonin gene-related peptide (CGRP) receptor antagonists are another promising nonvasoconstrictor approach to treating acute migraine. Olcegepant (BIBN4096BS) and telcagepant (MK-0974) have been shown to be safe and effective in phase I, II, and (for telcagepant) phase III clinical trials. Other targets under investigation include glutamate (AMPA/kainate), TRPV1, prostanoid EP4, and nitric oxide synthase. With new neural targets and the potential for therapeutic advances, the next era of antimigraine medications is near. [PubMed Citation] [Order full text from Infotrieve]

17) Ferrari MD, Färkkilä M, Reuter U, Pilgrim A, Davis C, Krauss M, Diener HC
Acute treatment of migraine with the selective 5-HT1F receptor agonist lasmiditan--a randomised proof-of-concept trial.
Cephalalgia. 2010 Oct;30(10):1170-8.
[PubMed Citation] [Order full text from Infotrieve]

18) Nelson DL, Phebus LA, Johnson KW, Wainscott DB, Cohen ML, Calligaro DO, Xu YC
Preclinical pharmacological profile of the selective 5-HT1F receptor agonist lasmiditan.
Cephalalgia. 2010 Oct;30(10):1159-69.
[PubMed Citation] [Order full text from Infotrieve]

19) Olesen J
5-Hydroxyptryptamine 1F (5-HT1F) receptor agonism. A possible new treatment principle for acute migraine attacks.
Cephalalgia. 2010 Oct;30(10):1157-8.
[PubMed Citation] [Order full text from Infotrieve]

20) Classey JD, Bartsch T, Goadsby PJ
Distribution of 5-HT(1B), 5-HT(1D) and 5-HT(1F) receptor expression in rat trigeminal and dorsal root ganglia neurons: relevance to the selective anti-migraine effect of triptans.
Brain Res. 2010 Nov 18;1361:76-85.
Triptans, acting as serotonin, 5-HT(1B/1D/1F), receptor agonists, provide an effective and established treatment option in migraine and cluster headache. Clinical observations suggest a relatively specific effect of these compounds on primary headache disorders, but not in other pain syndromes. The mechanism of this specificity, however, is not well understood. Hence, we systematically studied primary sensory ganglia in rat to determine if the peripheral distribution of 5HT(1B/1D/1F) receptors showed any anatomical difference that would account for the specificity of clinical effect. Rat primary afferent and sensory ganglia neurons--trigeminal ganglia (Vg), and dorsal root ganglia (DRG): C(2), C(5), T(5), L(5)--were examined using paraffin-embedded, slide-bound tissue sections reacted with specific primary antibodies for rat 5-HT(1B, 1D) and (1F) receptors in a peroxidase-based immunohistochemical method. Immunoreactivity specific for all three serotonergic receptor subtypes was demonstrated in the five peripheral nervous system regions examined and quantitated. There was a good agreement for 5-HT(1B) and 5-HT(1D) receptors to that previously demonstrated in Vg and DRG L(5), while this was the first characterisation for 5-HT(1F) receptor in any of the five regions, as well as for 5-HT(1B) and 5HT(1D) receptors in DRG C(2), C(5) and T(5). In summary, all three 5-HT receptors are equally represented in Vg and the DRGs examined. We conclude that the triptans are theoretically able to bind to receptors at each level of the peripheral neuraxis without any apparent anatomical preference for the head. [PubMed Citation] [Order full text from Infotrieve]