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PubMed1995

Mitogenic effect of serotonin in human small cell lung carcinoma cells via both 5-HT1A and 5-HT1D receptors.

We have recently shown that the mitogenic effect of serotonin (5-hydroxytryptamine, 5-HT) on human small lung carcinoma (SCLC) cells is at least partly due to stimulation of a 5-HT1D receptor type. We now report that the 5-HT1A receptor agonist R(+)-8-hydroxy-2-(di-n- propylamino)tetralin (8-OH-DPAT) is also capable of stimulating [3H]thymidine incorporation into SCLC GLC-8 cells, although with lower efficacy than 5-HT. The simultaneous administration of maximal doses of 8-OH-DPAT and the 5-HT1D receptor agonist sumatriptan reproduced the maximal [3H]thymidine incorporation observed with 5-HT alone. The 5-HT1A receptor antagonists spiperone and SDZ 216-525 completely abolished the effect of 8-OH-DPAT (IC50 30 nM for both drugs) behaving as pure antagonists. Accordingly, the two drugs partially inhibited the mitogenic effect of 5-HT. These data indicate that the mitogenic effect of 5-HT in SCLC cells involves both 5-HT1A and 5-HT1D receptor types.

Carcinoma, Small Cell↗
PubMed1996

Pharmacology of serotonin as related to anesthesia.

Serotonin (5-hydroxytryptamine) is an important biogenic amine that fulfills the role of neurotransmitter and neuromodulator. It has been a focus of interest during the last decade. Its diversity of pharmacologic actions is related to a wide variety of receptors and effector mechanisms. Seven serotonin receptor families have been identified thus far. They are genetically different transmembrane proteins composed of several hundred amino acids. The majority of these are G-protein-coupled, except the 5-HT3 receptors, which are directly ligand gated to fast ion channels. Serotonin is widely distributed in the body within the central and peripheral nervous systems, smooth muscles, and platelets, in particular. Consequently, its effects manifest mainly in these organs and influence a wide variety of neural, vascular, smooth muscle, and platelet functions. (Melatonin, a physiologically active metabolite of serotonin, is also instrumental in affecting many neural and hormonal functions.) Several selective agonists and particularly many selective antagonists have been developed for serotonin, which helped the serotonin receptor subtype classification. Some of these drugs are also used therapeutically in the treatment of migraine (eg, sumatriptan, which is a 5-HT1 receptor agonist), vascular disorders (5-HT2 antagonists), and nausea and vomiting (5-HT3 antagonists, eg, dolasetron, granisetron, ondansetron, and tropisetron), and have been investigated in gastrointestinal motility disorders (5-HT4 antagonists) and behavioral psychopathologies (5-HT1 agonists and 5-HT2-4 antagonists). Serotonin reuptake inhibitors are of particular clinical importance in the treatment of psychological illness. Future use of these drugs is also envisioned in the treatment of certain types of pain syndromes. Awareness of the serotonergic drugs and the recognition of possible drug interactions among drugs that influence serotonergic mechanisms in humans are becoming increasingly important in the practice of anesthesiology.

Anesthetics↗
PubMed2004

Functional dyspepsia: drugs for new (and old) therapeutic targets.

The therapeutic management of functional dyspepsia remains a major challenge for the gastroenterologist. Current therapies available are based on putative underlying pathophysiologic mechanisms, including gastric acid sensitivity, slow gastric emptying and Helicobacter pylori infection, but only a small proportion of patients achieve symptomatic benefit from these therapeutic approaches. Relatively novel mechanistic concepts under testing include impaired gastric accomodation, visceral hypersensitivity, and central nervous system dysfunction. Serotonergic modulators (e.g. the 5-HT4 agonist tegaserod, the 5-HT3 antagonist alosetron and the 5-HT1P agonist sumatriptan), CCK-1 antagonists (e.g. dexloxiglumide), opioid agonists (e.g. asimadoline), N-methyl-D-aspartate (NMDA) receptor antagonists (e.g dextromethorphan), neurokinin antagonists (e.g. talnetant), capsaicin-like agents and antidepressants are among the agents currently under investigation. It seems unlikely, however, that targeting a single mechanism with an individual drug will result in complete symptom remission in most cases.

Dyspepsia↗
PubMed2004

Priorities for triptan treatment attributes and the implications for selecting an oral triptan for acute migraine: a study of US primary care physicians (the TRIPSTAR Project).

BACKGROUND: Physicians treating patients with migraine can now choose from among 7 triptans, which differ on a range of attributes that may be important for treatment selection. OBJECTIVE: The aims of this study were to determine the relative importance of treatment attributes of the available triptans and assess their impact on deciding the most appropriate treatment for a particular patient with migraine. METHODS: As part of the TRIPSTAR project, US primary care physicians were surveyed to elicit their views on the relative importance of a prespecified set of treatment attributes for making treatment choices in clinical practice. The treatment attributes assessed were those for which data from controlled clinical trials were available for subsequent comparison. The resulting attribute-importance weights were then combined with data on the performance of individual triptans across these attributes in a multiattribute decision model to assist selection of an oral triptan. RESULTS: Efficacy attributes were considered more important than tolerability or consistency of effect in selecting an oral triptan. For triptan-naive but not triptan-experienced patients, tolerability was considered significantly more important than consistency (30% [95% CI, 27%-34%] vs 21% [19%-24%]). Sustained pain-free status and freedom from cardiovascular (chest) adverse events were the most important efficacy and tolerability attributes for both patient categories. When the relative importance of the treatment attributes was combined in a multiattribute decision model with meta-analysis data from controlled trials, almotriptan, eletriptan, and rizatriptan were significantly closer to the hypothetical ideal triptan than the reference product, sumatriptan 100 mg. CONCLUSION: Multiattribute decision-making models (such as that used in the TRIPSTAR project) that determine and apply the relative importance of treatment attributes to drug selection have considerable potential value as a decision support tool in the treatment of acute migraine.

Acute Disease↗
PubMed2006

Spinal cord injury-specific depression of monosynaptic spinal reflex transmission by l-5-hydroxytryptophan results from loss of the 5-HT uptake system and not 5-HT receptor supersensitivity.

We studied changes in the spinal segmental reflex and serotonergic (5-HT) responses in rats after spinal cord injury (SCI) produced by the weight-dropping method at the T8 level. The spinal monosynaptic reflex amplitude (MSR) was recorded from the L5 ventral root following stimulation of the ipsilateral L5 dorsal root. The 5-HT precursor l-5-hydroxytryptophan (L-5-HTP) depressed MSR in the spinal cord injured rats but not in normal rats. We investigated whether the SCI-specific depression of MSR by L-5-HTP was attributable to postsynaptic supersensitivity of 5-HT receptors or presynaptic loss of the 5-HT uptake system. Sumatriptan, a selective 5-HT(1B/1D) receptor agonist that is not taken up by 5-HT transporters, depressed the MSR similarly in both SCI and normal rats, suggesting that SCI resulted in the loss of 5-HT terminals and not postsynaptic supersensitivity of 5-HT receptors.

5-Hydroxytryptophan↗
PubMed2005

Evidence for a spinal serotonergic control of the peripheral inflammation in the rat.

We investigated the effect of serotonergic agonists and antagonists injected intrathecally by direct punction of the spinal cord at the lumbar level (between L5-L6) on peripheral inflammatory edema. Edema was induced by carrageenan injected subcutaneously in one hindpaw 30 min after spinal treatments. Serotonin (0.1, 1, 10 pmol) caused a graded-inhibition of the inflammatory paw edema. The corticosteroid inhibitor aminoglutethimide (100 mg/kg, p.o. 1.5 h before spinal treatment) did not modify this effect. The 5-HT1A agonist buspirone and the 5-HT1B/1D agonist sumatriptan (0.1, 1.0 and 10 nmol) also inhibited paw edema. The 5-HT1,2 antagonist methysergide (10 and 100 pmol) enhanced edema, but higher doses ( 4 and 8 nmol) diminished edema. NAN-190 (5-HT1 antagonist; 1 and 10 nmol) increased paw edema, while ritanserin (5-HT2 antagonist; 1 nmol) inhibited paw edema. Ondansetron (5-HT3 antagonist; up to 10 nmol) did not affect edema, but metoclopramide (5-HT3 antagonist / 5-HT4 agonist; 5, 10 and 30 pmol) inhibited edema. These data suggest that a tonic release of serotonin in the spinal cord may occurs during ongoing peripheral inflammation, modulating the neurogenic component of edema either by an inhibitory action on 5-HT1 receptors or by a stimulatory action on 5-HT2 receptors. A disfunction in such mechanism may be involved in the pathophysiology of certain types of headaches or migraine, which seem to depend on neurogenic vasodilation, and may also help to explain the therapeuthic effectiveness of some serotonergic agents in these conditions.

Animals↗
PubMed2006

The pharmacological treatment options for pediatric migraine: an evidence-based appraisal.

The treatment of children and adolescents who suffer from migraine headaches must be individually tailored, flexible, and balanced with a blend of bio-behavioral measures, agents for acute treatment and, if needed, daily preventive medicines. While controlled data is limited, there is now enough evidence available to provide a rational framework to build treatment plans appropriate for the pediatric population. Essentially, the pharmacological management of pediatric migraine divides into agents for the acute attacks and agents used daily to prevent or reduce the frequency of attacks. For the acute treatment, the most rigorously studied agents are ibuprofen, acetaminophen, and the nasal spray forms of sumatriptan and zolmitriptan, all of which have shown both safety and efficacy in controlled trials. For preventive treatment the calcium channel blocker flunarezine has the best efficacy profile in controlled trials, but is not available in the U.S. A growing body of data, mostly uncontrolled, is emerging regarding the use of several anti-epileptic agents (e.g. topiramate, disodium valproate, levateracetam), as well as the antihistamine cyproheptadine and the anti-depressant amitriptyline.

Adolescent↗
PubMed2005

Migraine: current concepts and emerging therapies.

Migraine is a recurrent incapacitating neurovascular disorder characterized by attacks of debilitating pain associated with photophobia, phonophobia, nausea and vomiting. Migraine affects a substantial fraction of world population and is a major cause of disability in the work place. Though the pathophysiology of migraine is still unclear three major theories proposed with regard to the mechanisms of migraine are vascular (due to cerebral vasodilatation), neurological (abnormal neurological firing which causes the spreading depression and migraine) and neurogenic dural inflammation (release of inflammatory neuropeptides). The modern understanding of the pathogenesis of migraine is based on the concept that it is a neurovascular disorder. The drugs used in the treatment of migraine either abolish the acute migraine headache or aim its prevention. The last decade has witnessed the advent of Sumatriptan and the 'triptan' class of 5-HT1B/1D receptor agonists which have well established efficacy in treating migraine. Currently prophylactic treatments for migraine include calcium channel blockers, 5-HT2 receptor antagonists, beta adrenoceptor blockers and gamma-amino butyric acid (GABA) agonists. Unfortunately, many of these treatments are non specific and not always effective. Despite such progress, in view of the complexity of the etiology of migraine, it still remains undiagnosed and available therapies are underused. In this article, the diverse pieces of evidence that have linked the different theories of migraine with its pathophysiology are reviewed. Furthermore, the present therapeutic targets and futuristic approaches for the acute and prophylactic treatment of migraine, with a special emphasis to calcitonin gene-related peptide, are critically evaluated.

Analgesics↗
PubMed1999

Detailed examination of fenfluramine-phentermine users with valve abnormalities identified in Fargo, North Dakota.

Although several studies have reported on valve abnormalities among users of fenfluramine or dexfenfluramine, detailed information on these subjects has not been provided, limiting the ability to understand who may be at risk for valve abnormalities and to generate hypotheses about the etiology and pathogenesis of these abnormalities. This study was a detailed medical record review of 18 previously reported users of fenfluramine and phentermine, all with valve abnormalities on echocardiogram and 2 with surgical pathology. Both clinical characteristics and medication use were recorded by trained abstracters using a standardized data collection form. Two subjects (11%) had other possible etiologies of valve disease: a history of rheumatic fever and prescribed ergotamine. Three subjects (17%) had a history of migraine headaches and 4 (22%) had murmurs noted before using fenfluramine. Use of medications that may affect serotonin receptors was common: ergotamine (1 subject, 5%), selective serotonin reuptake inhibitors (6, 33%), sumatriptan (2, 11%), and mirtazapine (1, 5%). Prior medication and nonmedication allergies were recorded in 6 (33%) and 3 (17%) subjects, respectively. All subjects had symptoms possibly due to fenfluramine or phentermine side effects. This study raises the hypotheses that valvular heart disease among fenfluramine users may be less common than previously estimated, that serotonin excess may play a role in valve pathology, and that a patient's response to anorexigens and other medications may serve as a marker for increased risk. Further study is needed to test these hypotheses.

Adult↗
PubMed1999

Serotonin-induced secretion of von Willebrand factor from human umbilical vein endothelial cells via the cyclic AMP-signaling systems independent of increased cytoplasmic calcium concentration.

Endothelial cells are able to synthesize von Willebrand factor (vWf) protein, which is then either secreted in a constitutive way or stored within specific cellular secretory granules, the Weibel-Palade bodies. Stimulated secretion of vWf from these organelles is thought to be induced by agonists causing a transient increase in cytoplasmic calcium concentrations. Serotonin (5-hydroxytryptamine, 5-HT), a local transmitter substance released by activated platelets, has also recently been shown to induce the secretion of vWf. In experiments with human umbilical vein endothelial cells (HUVEC), we found that the 5-HT-induced secretion occurred without a significant increase in cellular calcium levels. The 5-HT 1(D) subtype-specific receptor agonist sumatriptan also induced the release of vWf without causing a calcium signal in HUVEC. Stimulation of endothelial cells with the adenylate cyclase inhibitor, MDL-12 A330, led to the secretion of vWf as well. Simultaneous addition of submaximal concentrations of histamine and 5-HT to HUVEC potentiated the effects of either agonist. Together, these results suggest that in HUVEC 5-HT-induced secretion of vWf is mediated by a decrease in cyclic AMP levels and is independent of changes in cytoplasmic calcium levels.

Adenylyl Cyclase Inhibitors↗
PubMed2000

Induction of a high-affinity ketanserin binding site at the 5-Hydroxytryptamine(1B) receptor by modification of its carboxy-terminal intracellular portion.

Two chimeric 5-hydroxytryptamine (5-HT) receptors were constructed by exchanging the C-terminal portion of the human (h) 5-HT(1B) receptor with the equivalent domain of the h 5-HT(2A) receptor (5-HT(1B/2A)) or with this domain truncated from its last 44 amino acids (5-HT(1B/2ADelta44)). The equilibrium dissociation constant of the radioligand [(3)H]GR 125743 was similar for both chimera compared to the wild-type (wt) h 5-HT(1B) receptor upon transient expression in COS-7 cells. Ketanserin binding affinity was 21-fold increased from pK(i): 5.79 (wt h 5-HT(1B) receptor) to pK(i): 7.11 at the 5-HT(1B/2A) chimeric receptor, this latter value being close to that of the wt h 5-HT(1D) receptor (pK(i): 7.62). This enhanced ketanserin binding affinity was lost when the last 44 C-terminal amino acids of the 5-HT(2A) receptor were deleted in the chimera 5-HT(1B/2ADelta44) (pK(i): 5.80). The binding affinities of the 5-HT antagonists ritanserin, GR 125743, and SB-224289 were not modified at either chimeric 5-HT receptor. The agonists F 11356, 5-HT, zolmitriptan, and sumatriptan yielded slightly increased (2- to 6-fold) binding affinities at both chimera as compared to the wt h 5-HT(1B) receptor. The present data suggest a role for the C-terminal intracellular receptor domain in modifying ketanserin/5-HT(1B) receptor interactions.

Animals↗
PubMed1998

Cortical spreading depression-associated hyperemia in rats: involvement of serotonin.

We investigated whether the vasoactive neurotransmitter serotonin (5-HT) is involved in cortical spreading depression (CSD)-associated hyperemia in the rat. We focused on the 5-HT2 receptor, which is engaged in 5-HT induced small arteriolar relaxation in cats, as well as on the 5-HT1D/1B receptor, the binding site of the potent antimigraine drug sumatriptan. In male barbiturate anaesthetized Wistar rats (n=25) CSDs were elicited by brain topical application of 1 M KCl, and the DC-potential and regional cerebral blood flow (rCBF, by Laser Doppler flowmetry) were measured over the same hemisphere through dura and thinned bone, respectively. Intravenous application of 8 mg/kg of the 5-HT2A/2C receptor antagonist ritanserin (group I; n=8) significantly reduced the hyperperfusion amplitude during CSD by approximately 44% (p<0.05, from 342+/-124 to 194+/-97%, baseline before CSD=100%), and prolonged its duration by approx. 30%. Vehicle alone (group II; n=4) did not affect CSD hyperperfusion. The highly selective 5-HT1D/1B receptor agonist 311C90 was given in two doses: 100 micrograms/kg i.v. (n=5) had no effect on CSD hyperperfusion, while 800 micrograms/kg (n=5) increased hyperperfusion significantly (p<0.05, from 224+/-86 to 310+/-148%). We conclude that serotonin is, probably via 5-HT2 receptors, involved in the modulation of the regional cerebral blood flow increase during CSD. Novel highly selective receptor antagonists may help to discriminate the differential contribution of various 5-HT receptor subspecies.

Animals↗
PubMed1997

Characterisation of a cloned human 5-HT1A receptor cell line using [35S]GTP gamma S binding.

Compound potencies and efficacies depend upon receptor reserve and hence estimating this parameter in assay systems allows for a more meaningful interpretation of the data generated. This study describes a method whereby the degree of receptor reserve, with respect to 5-hydroxytryptamine (5-HT), was determined for a HeLa cell line expressing the human 5-HT1A receptor using the agonist-induced [35S]guanosine 5'[gamma-thio]triphosphate ([35S]GTP gamma S) binding assay, followed by a comparison of the potencies and relative efficacies of several compounds. Following irreversible antagonism with benextramine 5-HT yielded a pKA of 7.3, compared with a pKobs of 8.4 from saturation analysis, indicating the presence of high and low affinity state receptors. A 20% receptor occupancy elicited a half-maximal functional response consistent with the presence of receptor reserve. 5-HT, 5-carboxamidotryptamine (5-CT), 8-hydoxy-dipropylamino-tetralin (8-OH-DPAT), 5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1 H-indole (RU24969), buspirone, gepirone, mesulergine and sumatriptan were equally efficacious. 1-(2-Methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine (NAN 190) displayed reduced relative efficacy and methiothepin inverse agonism.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1997

The role of 5-HT(1B/1D) receptors in the modulation of 5-hydroxytryptamine levels in the frontal cortex of the conscious guinea pig.

The role of 5-HT(1B/1D) receptors in modulating extracellular 5-hydroxytryptamine (5-HT) levels in the guinea pig was investigated with the non-selective 5-HT(1B/1D) receptor inverse agonist, methiothepin, and the selective 5-HT(1B/1D) receptor partial agonists, GR 127935 (n-[4-methoxy-3-(4-methyl-1-piperizinyl)phenyl]-2'-methyl-4'-(5-me thyl-1,2,4-oxadiazole-3-yl)[1,1'-biphenyl]-4-carboxamide) and GR 125743 (n-[4-methoxy-3-(4-methyl-1-piperizinyl)phenyl]-3-methyl-4-(4-pyri dinyl)benzamide). Extracellular 5-HT levels were measured using the technique of brain microdialysis, in the frontal cortex of the freely moving guinea-pig. Extracellular 5-HT was tetrodotoxin sensitive and calcium dependent, and increased when perfused with a high concentration of K+. In addition, extracellular 5-HT levels were lowered by the 5-HT(1B/1D) receptor agonist, sumatriptan, and the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin, while perfusion of the selective serotonin re-uptake inhibitor, paroxetine, increased 5-HT in a concentration-dependent manner. Perfusion of methiothepin, GR 127935 and GR 125743 into the frontal cortex caused significant but transient increases of extracellular 5-HT. However, systemic administration of methiothepin, GR 127935 and GR 125743, at 0.3 mg/kg i.p., produced significant decreases in extracellular 5-HT, to minima of 27 +/- 3%, 31 +/- 12% and 27 +/- 13% of basal, respectively. The increase of extracellular 5-HT, following 5-HT(1B/1D) receptor inverse and partial agonist perfusion into the frontal cortex, was probably a consequence of attenuation of an endogenous 5-HT tone at terminal 5-HT autoreceptors. The unexpected decrease in 5-HT levels following systemic administration may be a result of additional attenuation of endogenous 5-HT tone at cell body autoreceptors in the raphe. Such an increase in local 5-HT levels could then stimulate 5-HT1A receptors to inhibit cell firing and hence decrease 5-HT levels in the terminal regions. This was confirmed when co-administration of the 5-HT1A receptor antagonist, WAY 100635, significantly attenuated the GR 127935 decrease in 5-HT.

Animals↗
PubMed1997

Binding profile of the novel 5-HT1B/1D receptor antagonist, [3H]GR 125,743, in guinea-pig brain: a comparison with [3H]5-carboxamidotryptamine.

Native brain 5-HT1B/1D) receptors were studied using the novel antagonist, [3H]GR 125,743 (N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl-4-(4-pyri dyl)benzamide). In guinea-pig striatal membranes, [3H]GR 125,743 displayed rapid association (t1/2 = 4.5 min), high (90%) specific binding and high affinity (K(d) = 0.29 nM), although B(max) values (fmol/mg protein) varied according to brain region-striatum: 199; frontal cortex: 89; hippocampus: 79; cerebellum: 26. In frontal cortex, the B(max) determined with [3H]5-CT ([3H]carboxamidotryptamine) was significantly higher (178; P < 0.05), suggesting that it also labels other binding sites. In striatal membranes, guanylylimidodiphosphate (GppNHp) inhibited [3H]5-CT but not [3H]GR 125,743 binding, suggesting that the latter has antagonist properties. Nevertheless, in competition binding experiments, the pK(i) values obtained with [3H]GR 125,743 and [3H]5-CT for 20 serotonergic ligands, including L 694,247 (2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl ]-1H-indole-3-yl]ethylamine), GR46,611 (3-[3-(2-dimethylamino-ethyl)-1H-indol-6-yl]-N-(4-methoxybenzyl)acrylami de), sumatriptan and alniditan, were highly correlated (r = 0.99). Ketanserin and ritanserin showed low affinity for [3H]GR 125,743 binding to guinea-pig striatal sites (K(i) = 12600 and 369 nM), suggesting that 5-HT1B (rather than 5-HT1D) receptors are predominantly labelled in this tissue. The present data indicate that [3H]GR 125,743 is a useful tool for studying native 5-HT1B/1D receptors.

Animals↗
PubMed1998

Site-directed mutagenesis of the human 5-HT1B receptor.

Site-directed mutagenesis was used to investigate the molecular interactions involved in ligand binding to the human 5-HT1B receptor. Six mutants were constructed at four positions and expressed in Chinese hamster ovary cells. Substitution of the amino acid F185 in transmembrane region IV by an alanine increased the affinities of sumatriptan, methysergide and 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) 3-4-fold and substitution by a methionine increased the affinities of methysergide and methiothepin 2- and 3-fold, respectively. Substitution of amino acid S334 in transmembrane region VI by an alanine increased the affinity of 8-OH-DPAT 5-fold. In accordance with this, the EC50 value of 8-OH-DPAT was decreased 7-fold. This suggests that the serine at position 334 causes steric hindrance for 8-OH-DPAT binding that is lost in the S334A mutant. Mutation of F354 in transmembrane region VII, which differs between receptor subtypes, increased the affinity of methiothepin 2-3-fold but the affinities of the other compounds tested were essentially unchanged.

Amino Acid Substitution↗
PubMed1998

The antimigraine agent alniditan selectively constricts porcine carotid arteriovenous anastomoses via 5-HT1B/1D receptors.

In previous studies, we have shown that several 5-HT1B/1D receptor agonists, including sumatriptan, potently constrict porcine carotid arteriovenous anastomoses. This effect seems to be of high predictive value for antimigraine activity. In the present experiments, we studied the effects of a new non-indole 5-HT1B/1D receptor agonist, alniditan, on systemic and carotid haemodynamics in anaesthetised pigs. In control animals, no significant changes in either systemic or carotid haemodynamics were observed after four consecutive i.v. injections of physiological saline (0.5 ml each, every 20 min; n = 4). On the other hand, i.v. doses of alniditan (3, 10, 30 and 100 microg kg(-1) in 0.5 ml saline, every 20 min; n = 6) dose-dependently decreased total carotid conductance (maximum change: -31 +/- 6%) by a selective vasoconstrictor action on arteriovenous anastomoses (maximum change: -72 +/- 5%); the nutrient vascular bed dilated in response to alniditan (maximum change: +103 +/- 39%). The dose of alniditan that decreased arteriovenous anastomotic conductance by 50% was 24 +/- 8 microg kg(-1) (64 +/- 20 nmol kg(-1)). Alniditan produced a slight bradycardia (maximum change: -4 +/- 1%) and a more pronounced hypotensive effect (maximum change: -23 +/- 5%). In six animals pre-treated with the potent and selective 5-HT1B/1D receptor antagonist, GR127935, the alniditan-induced changes in carotid haemodynamics were clearly antagonised, whereas the bradycardia and hypotension remained unaffected. These results suggest that alniditan selectively constricts porcine carotid arteriovenous anastomoses mainly via 5-HT1B/1D receptors and should be able to abort migraine headaches. The latter has indeed been confirmed in initial clinical studies in man.

Analgesics↗
PubMed1998

Human 5-HT1F receptor-stimulated [35S]GTPgammaS binding: correlation with inhibition of guinea pig dural plasma protein extravasation.

To determine the potency and efficacy of 5-HT1F receptor ligands, a [35S]GTPgammaS binding assay was developed and optimized for the human 5-HT1F receptor. Compounds which are known to be effective in the abortive treatment of migraine were tested for efficacy and potency in this assay. Naratriptan, sumatriptan, zolmitriptan, and rizatriptan all had agonist activity. The 5-HT1F receptor ligand LY334370 (4-fluoro-N-[3-(1-methyl-4-piperidinyl)-1H-indol-5-yl]-benzamide) was the most potent compound tested with an EC50 of 2.13 +/- 0.15 nM. LY302148 (5-fluoro-3-[1-[2-(1-methyl-1H-pyrazol-4-yl)ethyl]-4-piperidinyl]-1H-ind ole), methysergide, LY306258 (3-dimethylamino-2,3,4,9-tetrahydro-1H-carbazol-6-ol), dihydroergotamine (DHE), L-694,247 and CP-122,288 were also investigated for potency and efficacy. There was a statistically significant correlation between the pEC50 for the stimulation of [35S]GTPgammaS binding and the pID50 for the inhibition of trigeminal nerve-stimulated dural plasma protein extravasation in the guinea pig. In the course of these studies, it was found that the purportedly selective 5-HT1D receptor antagonist GR127935 inhibited 5-HT1F receptor-stimulated [35S]GTPgammaS binding with a Ki of 39.6 +/- 9.5 nM. These studies demonstrate that 5-HT1F receptor-mediated stimulation of [35S]GTPgammaS binding in a clonal cell system is a reproducible, high throughput assay that is predictive of an in vivo model of 5-HT1F receptor activation.

Animals↗