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At least 19 recordsLinked to original sources

PubMed1992

Agonist activity of sumatriptan and metergoline at the human 5-HT1D beta receptor: further evidence for a role of the 5-HT1D receptor in the action of sumatriptan.

We have recently cloned a novel human 5-HT1D receptor subtype termed 5-HT1D beta. CHO K1 cells expressing the human serotonin 5-HT1D beta receptor were assayed to determine the second messenger system of this receptor. Cyclic AMP radioimmunoassays revealed that the 5-HT1D beta receptor is negatively coupled to adenylate cyclase in this cell system. A maximum of 50% inhibition of forskolin stimulated cAMP production was obtained with 5-HT1 receptor agonists which was blocked by the non-selective 5-HT receptor antagonist methiothepin (pKB = 100 nM). The novel anti-migraine drug sumatriptan, a putative 5-HT1D selective compound, acted as an agonist at the 5-HT1D beta receptor. Most notably metergoline, a putative 5-HT1 receptor antagonist, did not block the effects of 5-HT and was found to be acting as a full agonist at the 5-HT1D beta receptor. The ability of metergoline to act as an agonist at the 5-HT1D beta receptor may explain why it does not inhibit 5-HT and sumatriptan induced contraction of dog saphenous vein and other large conducting arteries. These results suggest that the 5-HT1D beta receptor may be the site of action of sumatriptan in preventing migraine, and that metergoline's actions on the dog saphenous vein are not contradictory to that hypothesis, as previously reported.

Cells, Cultured↗

PubMed1992

Sumatriptan and 5-benzyloxytryptamine: contractility of two 5-HT1D receptor ligands in canine saphenous veins.

Sumatriptan and 5-benzyloxytryptamine are ligands with high affinity for 5-HT1D receptors in the caudate nucleus. Both compounds contracted canine saphenous veins, in vitro. Benzyloxytryptamine was less potent as a contractile agonist than sumatriptan which was less potent than serotonin. In high concentrations (greater than 10(-5) M) serotonin-induced contraction resulted, in part, from activation of alpha-adrenoceptors as determined by blockade of contraction with prazosin (10(-6) M) and idazoxan (10(-6) M). Likewise, benzyloxytryptamine but not sumatriptan also activated contractile alpha-receptors in the canine saphenous vein. Furthermore, benzyloxytryptamine antagonized contraction to sumatriptan in an apparently non-competitive fashion. Thus, benzyloxytryptamine, although possessing some alpha-receptor agonist activity, like sumatriptan, can interact with serotonin receptors in canine saphenous veins. Although effects of sumatriptan and benzyloxytryptamine quantitatively differed in canine saphenous veins, both agents showed similar affinity and agonist efficacy at 5-HT1D receptors in brain. These studies may reflect potential differences between the 5-HT1D receptor in brain and the 5-HT1-like receptor in canine saphenous veins.

Animals↗

PubMed1992

Direct visualization of serotonin1D receptors in the human brain using a new iodinated radioligand.

The development of the new ligand serotonin-5-O-carboxymethyl-glycyl [125I]tyrosinamide (abbreviated [125I]GTI) allows for the direct visualization of serotonin1B and serotonin1D (5-HT1B/1D) sites. Autoradiographic techniques were used to demonstrate the selective binding of this ligand to 5-HT1D sites in human post-mortem brain materials. The distribution of [125I]GTI binding sites was compared to [3H]5-HT sites in the presence of different displacers. The results show the selective binding of [125I]GTI to sites in the basal ganglia and substantia nigra which corresponds to 5-HT1D receptors.

Aged↗

PubMed1992

An investigation of the 5-HT1D receptor binding affinity of 5-hydroxytryptamine, 5-carboxyamidotryptamine and sumatriptan in the central nervous system of seven species.

The ability of three 5-HT1 receptor agonists, 5-HT (5-hydroxytryptamine), 5-CT (5-carboxyamidotryptamine) and sumatriptan to inhibit the binding of [3H]5-HT, in the presence of cyanopindolol and mesulergine, from cerebral cortical and/or caudate membranes in seven species (dog, guinea-pig, rabbit, pig, human, hamster and calf) has been investigated. Under the experimental conditions used, 5-CT and sumatriptan consistently yielded displacement curves best fit to a two-site model whereas 5-HT always gave a monophasic displacement curve. The pIC50 values obtained with 5-HT displacement gave a mean of 8.1 +/- 0.1 (mean +/- S.E.M.). In contrast the biphasic displacement curves for 5-CT and sumatriptan yielded high and low affinity pIC50 values of 8.3 +/- 0.1, 5.5 +/- 0.1 and 7.6 +/- 0.1, 5.0 +/- 0.1, respectively. These data indicate that under these experimental conditions the high affinity component labelled by [3H]5-HT is the same receptor subtype, previously denoted the 5-HT1D receptor, in all seven species.

Animals↗

PubMed1992

Cloning and pharmacological characterization of a novel human 5-hydroxytryptamine1D receptor subtype.

The canine RDC4 gene was used to isolate two distinct human serotonin receptor genes. The receptor encoded by clone RH-6 was the species homolog of RDC4 and was identical to a human serotonin 5-hydroxytryptamine1D (5-HT1D) receptor that was recently reported [Mol. Pharmacol. 40:143-148 (1991)]. The receptor encoded by RH-2 was a novel 5-HT receptor that was 61% identical to RH-6 and showed the greatest homology with the rat 5-HT1B receptor sequence (94%). The RH-2 gene contained an intronless, 1170-base pair, open reading frame that encoded a 390-amino acid protein that contained all of the hallmarks of a guanine nucleotide-binding protein-linked receptor. Heterologous expression of the RH-2 gene in Chinese hamster ovary cells led to the appearance of high affinity binding sites for 5-HT (Kd = 2.6 nM, Bmax = 2.9 pmol/mg of membrane protein), and the receptor expressed in Chinese hamster ovary cells was coupled to inhibition of adenylyl cyclase. Competition binding experiments using compounds that are selective for various 5-HT receptor subtypes showed the highest correlation with a 5-HT1D-like receptor (r = 0.89) and a low correlation with 5-HT1B-like receptors. Examples of the 5-HT1D-like pharmacology displayed by RH-2 include high affinity for the 5-HT1D-selective compound sumatriptan (Ki = 9.4 nM) and for the alpha 2-adrenergic receptor antagonist rauwolscine (Ki = 47 nM). Therefore, despite the close genetic relationship between RH-2 and the rat 5-HT1B receptor, our results indicate that the receptor encoded by RH-2 2 is best classified as a human 5-HT1D receptor subtype and defines a second member of the human 5-HT1D receptor family.

Amino Acid Sequence↗

PubMed1992

Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine.

Sumatriptan and the ergot alkaloids are useful tools for deciphering drug mechanisms in migraine and related headaches. Both neuronal and vascular mechanisms have been proposed on the basis of actions of 5-HT at receptors resembling the 5-HT1D subtype. In this Viewpoint article, Michael A. Moskowitz argues that blockade of neural transmission and the neurogenic inflammatory response provides a mechanism by which sumatriptan and ergot alkaloids alleviate vascular headaches. He postulates, with similar arguments, that sumatriptan and ergot alkaloids may block headaches that develop from meningovascular inflammatory disorders such as from viral and bacterial meningitis and from the sequelae of head injury.

Ergot Alkaloids↗

PubMed1992

Clinical effects and mechanism of action of sumatriptan in migraine.

Sumatriptan is a novel, highly effective drug against migraine and cluster headache attacks. It shows a remarkably selective pharmacological profile in animals. Determination of its mechanism of action in human should further the understanding of the pathophysiology of migraine and cluster headache. We, therefore, review current knowledge on the clinical and pharmacological effects of sumatriptan. Important pharmacological actions of sumatriptan are (i) poor penetration of the blood-brain barrier suggesting a peripheral point of action; (ii) 5-HT1-like/5-HT1d receptor-mediated vasoconstriction of large cerebral arteries and dural vessels; and (iii) blockade of neurogenic dural inflammation via 5-HT1d autoreceptor-mediated inhibition of vasoactive neuropeptides within the trigeminovascular system. Future research will tell which mechanism is involved in the pathophysiology of migraine and cluster headache.

Animals↗

PubMed1992

Psychoactivity and abuse potential of sumatriptan.

Sumatriptan is a 5-HT1D agonist of therapeutic use in migraine and cluster headaches. To determine the profile of psychoactivity and abuse potential, a double-blind Latin-square crossover study was conducted in 12 male subjects with histories of substance abuse. The effects of subcutaneous placebo, sumatriptan (8 and 16 mg), and morphine (10 and 20 mg) were assessed on measures of subjective, behavioral, and physiologic responses including signs, symptoms, Addiction Research Center Inventory scales, onset of drug effects and miosis. Sumatriptan was psychoactive, was discriminated from placebo, produced a dose-related decrease on euphoria scores, elevated scores on measures of apathetic sedation and disliking, and lacked identification as a prototypic drug of abuse. There were no clinically significant effects on heart rate, pupil size, or blood pressure. In contrast, morphine (the positive control) produced expected dose-response relationships on measures of reinforcing and physiologic effects. The study suggests that sumatriptan has a low abuse potential.

Adult↗

PubMed1992

Non 5-HT1A/5-HT1C [3H]5-HT binding sites in the hamster, opossum, and rabbit brain show similar regional distribution but different sensitivity to beta-adrenoceptor antagonists.

We have used receptor autoradiography to investigate the distribution and pharmacological profile of non 5-HT1A/5-HT1C[3H]5-hydroxytryptamine binding sites in the brain of rabbits, hamsters and opossums. These data were compared to those found under similar conditions in the brain of rats and guinea pigs, species which are known to possess 5-HT1B and 5-HT1D receptors, respectively. In the presence of 100 nM 8-OH-DPAT and mesulergine, the regional distribution of [3H]5-hydroxytryptamine binding sites was very similar in the brain of all species investigated; densest labelling was observed in the globus pallidus, substantia nigra and superior colliculus. In all species, 5-carboxamidotryptamine competed for the labelled sites in a biphasic manner and metergoline displayed a subnanomolar affinity. In contrast, the beta-adrenoceptor blocking agents (-)propranolol, (-)pindolol, and (+/-)SDZ 21009 were potent displacers only in the rat, hamster and opossum brains. These data indicate that non 5-HT1A/5-HT1C[3H]5-HT binding sites display a high affinity for these agents in a particular rodent suborder as well as in opossum, a phylogenetically unrelated species.

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

PubMed1992

Metitepine distinguishes two receptors mediating inhibition of [3H]-5-hydroxytryptamine release in guinea pig hippocampus.

Inhibition of [3H]-5-hydroxytryptamine ([3H]-5-HT) release from guinea pig brain slices via activation of the terminal 5-HT autoreceptor has previously been characterised as a model of 5-HT1D receptor activation, based on the rank potencies of a range of agonists, and the potent antagonism of the inhibitory effects of 5-HT by metitepine. The present study uses this model, in slices of the guinea pig hippocampus, to examine the antagonist potency of metitepine against the 5-HT receptor agonists sumatriptan, 5-carboxamidotryptamine (5-CT) and 5-HT. Addition of metitepine to the perfusion buffer (30, 300 and 1000 nmol/l) significantly shifted the concentration-response curve to 5-HT, producing a Schild slope of 1.1, and a pA2 value of 7.6. However, the ability of metitepine to antagonise the effects of sumatriptan or 5-CT in this model was less marked. A clear-cut shift in the concentration-response curve to sumatriptan was only achieved at 1000 nmol/l metitepine (apparent pA2 = 6.7), and this was similar to the ability of metitepine to attenuate the effects of 5-CT (apparent pA2 7.0 at 300 nmol/l and 6.7 at 1000 nmol/l). These findings suggest heterogeneity in the receptor mediating inhibition of [3H]-5-HT release in guinea pig hippocampus.

Animals↗

PubMed1992

Characterization of a novel 5-HT4 receptor antagonist of the azabicycloalkyl benzimidazolone class: DAU 6285.

Three chemical classes of serotonin 5-HT4 receptor agonists have been identified so far: 5-substituted indoles (e.g. 5-HT), benzamides (e.g. renzapride) and benzimidazolones (e.g. BIMU 8). In a search for 5-HT4 receptor antagonists, we have discovered that the benzimidazolone derivative DAU 6285 (for structure see text), is 3-5 times more potent than tropisetron in blocking 5-HT, renzapride and BIMU 8 induced stimulation of adenylate cyclase activity in mouse embryo colliculi neurons. Schild plot analysis yielded Ki values of 220, 181 and 255 nmol/l, respectively. In addition, DAU 6285 showed poor activity as a 5-HT3 receptor ligand with respect to tropisetron, as demonstrated by in vitro binding studies (Ki, 322 vs 2.8 nmol/l) and by its antagonistic activity in the Bezold-Jarisch reflex test (ID50, 231 vs 0.5 micrograms/kg, i.v.). No significant binding (Ki greater than 10 mumol/l) of DAU 6285 to serotonergic 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, and 5-HT2 receptors as well as to adrenergic alpha 1, alpha 2, dopaminergic D1, D2 or muscarinic M1-M3 receptor subtypes was found. The data indicate that DAU 6285 has a somewhat higher affinity than tropisetron for 5-HT4 receptors, a property confirmed in functional tests, and much lower affinity than tropisetron for 5-HT3 receptors. The compound represents a new interesting tool for investigating the pharmacological and physiological properties of 5-HT4 receptors.

Animals↗

PubMed1992

5-HT1-like receptor mediated changes in porcine carotid haemodynamics: are 5-HT1D receptors involved?

5-Hydroxytryptamine (5-HT) reduces porcine arteriovenous shunting in the carotid vascular bed by stimulation of both 5-HT1-like and 5-HT2 receptors and increases capillary flow to some tissues, like the skin and ears, by different 5-HT1-like receptors. In view of the heterogeneous nature of the 5-HT1-like receptors and the relative selectivity for the 5-HT1D binding sites of sumatriptan, which also reduces porcine arteriovenous shunting and slightly increases capillary blood flow towards skin and ears by 5-HT1-like receptors, we have attempted to determine whether one or both of these carotid 5-HT1-like receptors belong to the 5-HT1D subtype. Pentobarbitone anaesthetized pigs, subjected to bilateral cervical vagosympathectomy, received either 5-HT (2 micrograms.kg-1.min-1) in the carotid artery or cumulative i.v. doses of sumatriptan (10, 30, 100 and 300 micrograms.kg-1). Their effect on the total carotid blood flow and its distribution into capillary and arteriovenous anastomotic parts was determined with radioactive microspheres. The effect of metergoline (1 mg.kg-1), a substance with a very high affinity for the 5-HT1D receptor as well as for the 5-HT1A, 5-HT1B, 5-HT1C and 5-HT2 receptors, was studied on the responses to 5-HT and sumatriptan. Both 5-HT and sumatriptan reduced carotid arteriovenous anastomotic blood flow. 5-HT and, to a lesser extent, sumatriptan also increased capillary blood flow towards some tissues. Metergoline by itself did not affect the distribution of porcine carotid blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

5-HT1D binding sites in various species: similar pharmacological profile in dog, monkey, calf, guinea-pig and human brain membranes.

Radioligand binding studies were performed in membranes of calf caudate, guinea-pig cortex, dog caudate and whole brain, monkey caudate and whole brain, and human caudate using the novel iodinated radioligand, Serotonin-5-O-Carboxymethyl-Glycyl[125I] Tyrosinamide (abbreviated [125I]GTI for the sake of simplicity), a ligand known to label 5-HT1B and 5-HT1D sites. In all membrane preparations tested, [125I]GTI labelled high affinity sites with the following rank order of affinity: 5-carboxamidotryptamine greater than 5-HT = DHE = ergotamine greater than or equal to sumatriptan greater than or equal to metergoline = CGS 12066 greater than or equal to yohimbine = methysergide greater than or equal to methiothepin greater than 8-OH-DPAT greater than or equal to mianserin greater than or equal to CP 93129 greater than or equal to (-)pindolol = ketanserin greater than or equal to isamoltane = mesulergine greater than or equal to corynanthine = spiperone greater than MDL 72222. The affinity profiles were very similar in the membranes of the different species, especially in dog, monkey and human brain. The pharmacological profile of [125I]GTI binding (determined with up to 25 different drugs) was fully comparable to the binding profile reported previously in human substantia nigra (using [125I]GTI) or in a variety of brain preparations known to contain 5-HT1D sites using [3H]5-HT as a radioligand.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

"5-HT1R" or 5-HT1D sites? Evidence for 5-HT1D binding sites in rabbit brain.

Radioligand binding studies were performed in membranes of rabbit whole brain and striatum using the novel iodinated radioligand for 5-hydroxytryptamine 5-HT1B and 5-HT1D sites, Serotonin-5-O-Carboxymethyl-Glycyl[125I]Tyrosinamide ([125I]GTI). [125I]GTI labelled a finite number of high affinity sites in rabbit brain membranes, Bmax = 191 +/- 47 fmol/mg protein, pKD (-log mol/l) = 8.50 +/- 0.13, n = 5. The pharmacological profile of [125I]GTI binding was fully comparable to that reported previously in human and other brain preparations known to possess 5-HT1D sites (using either [3H]5-HT or [125I]GTI) and displayed a characteristic rank order of affinity: 5-carboxamido-tryptamine greater than 5-HT = dihydroergotamine greater than or equal to ergotamine greater than or equal to sumatriptan greater than or equal to CGS 12066 greater than or equal to metergoline greater than yohimbine greater than or equal to methysergide greater than ICYP greater than 8-OH-DPAT greater than or equal to CP 93129 greater than (-)pindolol greater than ketanserin greater than isamoltane greater than mesulergine greater than corynanthine greater than buspirone greater than MDL 72222. Autoradiographic studies were performed on rabbit brain slices using [3H]5-HT in the presence of 100 nmol/l 8-OH-DPAT and mesulergine (in order to mask 5-HT1A and 5-HT1C binding sites) and [125I]CYP (iodocyanopindolol) in the presence of 3 mumol/l isoprenaline and 100 nmol/l 8-OH-DPAT (in order to mask beta adrenoceptor and 5-HT1A binding sites). There was no detectable specific binding of [125I]CYP through the brain, thus excluding the presence of 5-HT1B sites in rabbit brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

5-HT1C receptor antagonists have anxiolytic-like actions in the rat social interaction model.

The effects of a range of 5-HT receptor antagonists were examined in an animal model of anxiety--the social interaction test. Six antagonists with high affinity for 5-HT1C receptors; mianserin, (+) mianserin, 1-naphthyl piperazine, ICI 169 369, pizotifen and LY 53857 all increased the time spent in active social interaction by pairs of weight-matched rats under high light unfamiliar conditions. As locomotion was only increased by 1-NP and then only at high doses, the effect of the drugs is consistent with anxiolysis. These properties were shared by the benzodiazepine anxiolytic chlordiazepoxide but not by the specific 5-HT2 antagonists ketanserin and altanserin, nor by the 5-HT1A and 5-HT1B antagonists cyanopindolol and pindolol. Similarly, neither the adrenergic alpha 2 antagonist idazoxan, the alpha 2 antagonist and putative 5-HT1D partial agonist yohimbine nor the H1 antagonist mepyramine had any significant effect. Since (+)mianserin, LY 53857 and ICI 169 369 at least have low affinity for 5-HT3 receptors these receptors are also unlikely to be involved. The results therefore imply that the observed anxiolytic effects of the drugs are likely to be mediated by 5-HT1C receptor blockade.

Animals↗

PubMed1992

Molecular cloning and functional characterization of a human 5-HT1B serotonin receptor: a homologue of the rat 5-HT1B receptor with 5-HT1D-like pharmacological specificity.

We describe a genomic clone encoding the human 5-HT1B receptor. This apparently intronless gene encodes a 390 amino acid polypeptide homologous to the rat 5-HT1B serotonin receptor, with which it shares 93% amino acid sequence identity. Remarkably, [3H]5-hydroxytryptamine binding studies with transfected HeLa cells show that the human 5-HT1B receptor has a pharmacological profile that is markedly different from that of the corresponding rat receptor. Instead, human 5-HT1B drug specificity is highly similar to that of the human 5-HT1D receptor, with which it shares 59% amino acid sequence identity. The human 5-HT1B receptor, like the 5-HT1D receptor, can couple to Gi proteins. The presence of the threonine355 in the human receptor rather than an asparagine, as found in the corresponding rat gene product, may explain much of the marked pharmacological difference between the human and rat 5-HT1B receptors.

Amino Acid Sequence↗

PubMed1992

Further characterization of the 5-hydroxytryptamine 5-HT1-like receptor mediating contraction of guinea-pig iliac artery.

We recently described a 5-hydroxytryptamine 5-HT1-like receptor mediating contraction in guinea-pig isolated iliac artery. The present study was aimed at characterizing this receptor with respect to the currently recognized 5-HT1 receptor subtypes (5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D). The potencies of 13 drugs tested as agonists correlated with their affinities for 5-HT1D binding sites only. The concentration-response curve for 5-carboxamidotryptamine (5-CT, a 5-HT1-like receptor agonist) was unaffected by propranolol (10 microM), which is reported to have affinity for 5-HT1A, 5-HT1B and 5-HT1C recognition sites. Yohimbine (3 microM) and metergoline (1 microM) antagonized 5-CT with pKB values of 6.15 and 6.96, respectively. These values are close to those found in a functional correlate of 5-HT1D sites in the same species, namely the presynaptic 5-HT autoreceptor in guinea-pig brain cortex. The overall results support the view that the receptor studied is of the 5-HT1D subtype. The receptor shares close similarities with other vascular 5-HT1-like receptors mediating contraction, for example the receptor present in dog saphenous vein.

Animals↗

PubMed1992

Peripheral 5-carboxamidotryptamine induces hindlimb scratching by stimulating 5-HT1A receptors in rats.

Treatment of rats with 5-carboxamidotryptamine (5-CT) or 5-methoxy-tryptamine (5-MeOT) induces a hindlimb scratch response. These compounds have high affinity for 5-HT1A and 5-HT1D receptors. The selective 5-HT1A receptor agonist N,N-dipropyl-5-CT (DP-5-CT) also induced hindlimb scratching while the selective 5-HT1D receptor agonist, sumatriptan, did not. 5-CT-induced hindlimb scratching was inhibited dose-dependently by several 5-HT1A antagonists (BMY 7378, NAN-190, MDL 73005EF and pindobind-5-HT1A) as well as the non-selective 5-HT antagonist, methiothepin. Pretreatment of rats with the serotonin (5-HT) synthesis inhibitor, p-chlorophenylalanine (PCPA) or the 5-HT depleting agent, reserpine, markedly attenuated 5-CT-induced hindlimb scratching. These data suggest that hindlimb scratching induced by 5-HT agonists may not be centrally mediated but rather may be mediated by a neuronal 5-HT1A receptor localized outside the blood-brain barrier.

5-Methoxytryptamine↗