sumatriptan, Imitrex
What intracranial tissues in humans contain sumatriptan-sensitive serotonin 5-HT1-type receptors?

De Keyser J, Vauquelin G, De Backer JP, De Vos H, Wilczak N.

Department of Neurology, Vrije Universiteit Brussel, Belgium.

We investigated the presence of sumatriptan-sensitive serotonin (5-HT)1 receptors in different human tissues by using a radioligand-binding technique with [3H]5-HT. Sumatriptan displaced [3H]5-HT from frontal cortical and striatal membranes in a biphasic manner, with a high-affinity site corresponding to binding to the 5-HT1D receptor. In blood platelet membranes, sumatriptan displaced [3H]5-HT with a 100-fold lower affinity. Sumatriptan failed to displace [3H]5-HT in membranes from large cerebral arteries, pial vessels, coronary arteries and dura mater. These findings suggest that either there are no sumatriptan-sensitive 5-HT1 receptors on intracranial blood vessels or they are so small in number that they cannot be detected by the radioligand-binding technique. Other mechanisms, possibly centrally mediated, may be responsible for the antimigraine action of sumatriptan.

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sumatriptan, Imitrex
Characterization of the enzyme responsible for the metabolism of sumatriptan in human liver.

Dixon CM, Park GR, Tarbit MH.

Department of Drug Metabolism III, Glaxo Group Research Ltd, Ware, Herts, U.K.

Studies have been undertaken to investigate the enzymes responsible for the metabolism of [14C]sumatriptan in man. Oxidative deamination of sumatriptan to form the indole acetic acid derivative is the only phase 1 pathway evident in man and both cytochrome P450 (P450) and monoamine oxidase (MAO) are capable of catalysing this type of reaction. The metabolism of [14C]sumatriptan was therefore investigated in vitro in a preparation derived from human liver, which was shown, by the use of the probe substrates [14C]testosterone (P450), [3H]5HT (MAO-A) and [14C]benzylamine (MAO-B) to be a rich source of both enzyme systems. Incubation with clorgyline and deprenyl, probe inhibitors of MAO-A and MAO-B, respectively, showed that [14C]sumatriptan was metabolized by MAO-A; there was no evidence of P450 involvement in its metabolism. The data in this study therefore indicate that the enzyme MAO-A is the major enzyme responsible for the metabolism of sumatriptan in human liver.

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sumatriptan, Imitrex
Characterization of 5-hydroxytryptamine receptors in rabbit isolated iliac artery.

Yildiz O, Tuncer M.

Department of Pharmacology, Faculty of Medicine, Gulhane Military Medical Academy, Ankara, Turkey.

To characterize the 5-hydroxytryptamine (5-HT) receptors, the contractile effects of both 5-HT and the 5-HT1-like receptor agonist sumatriptan were investigated in isolated open ring preparations of the rabbit common iliac artery. 5-HT induced concentration-dependent contractions. Sumatriptan did not induce any contraction of unstimulated preparations, whereas it elicited concentration-dependent contractions in preparations given a moderate tone with a threshold concentration of prostaglandin F2 alpha. In vessel segments precontracted with prostaglandin F2 alpha, Emax values for 5-HT and sumatriptan reached about 85% and 30% of the phenylephrine maximal effect, respectively. The mean EC50 values for sumatriptan and 5-HT were 3.34 microM and 1.5 microM, respectively. Pargyline, cocaine or normetanephrine were without significant effect on the contractions induced by 5-HT or sumatriptan. The 5-HT3 receptor antagonist tropisetron (1 microM) had no effect on 5-HT- and sumatriptan-induced contractions. The 5-HT2 receptor antagonist ketanserin (0.1-1 microM) produced parallel displacements to the right of the 5-HT and phenylephrine concentration-effect curves, without significant reduction in the maximum responses. The pA2 values were 7.85 +/- 0.19 and 7.9 +/- 0.16, respectively. Ketanserin had no effect on the sumatriptan concentration-effect curves. The nonselective 5-HT receptor antagonists methysergide (0.3 microM) and methiothepin (0.01 microM) shifted the concentration-response curve to sumatriptan to the right (mean pKB values of 6.91 and 8.68, respectively). The pA2 value for prazosin against 5-HT (9.98 +/- 0.43) was not significantly different from the value against phenylephrine (9.27 +/- 0.20). These results suggest that the sumatriptan-induced contraction is mediated by a 5-HT1-like receptor, whereas an additional mechanism, probably an alpha 1-adrenoceptor stimulation, plays a role in the contraction induced by 5-HT in the rabbit iliac artery.

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sumatriptan, Imitrex
Comparison of contractile responses to 5-hydroxytryptamine and sumatriptan in human isolated coronary artery: synergy with the thromboxane A2-receptor agonist, U46619.

Cocks TM, Kemp BK, Pruneau D, Angus JA.

Baker Medical Research Institute, Melbourne, Victoria, Australia.

1. The interaction between the thromboxane A2 receptor agonist, U46619 and two 5-hydroxytryptamine (5-HT) receptor agonists, the non-selective, naturally occurring agonist, 5-HT and the selective 5-HT1-like agonist, sumatriptan were studied in human epicardial coronary arteries in vitro. 2. Coronary artery rings (2-4 mm in diameter) were prepared from epicardial arteries from explant hearts of patients undergoing heart transplant (cardiomyopathy, n = 13; ischaemic heart disease, n = 10) and unused donor hearts (n = 5). Each ring of artery was set at optimal resting conditions to record changes in isometric force. 3. The majority of artery rings developed phasic, rhythmic contractions either spontaneously or in response to all vasoconstrictor agonists tested. Both the spontaneous and agonist-induced phasic contractions were abolished by nifedipine (0.1 microM). 4. Concentration-contraction curves to 5-HT-receptor agonists and noradrenaline (NA), were first constructed in artery rings that did not develop phasic activity. 5-HT and ergometrine were the most potent agonists with EC50 values of 6.8 +/- 0.2 and 7.7 +/- 0.2 (-log M) respectively. Potencies (EC50's) to sumatriptan, methysergide and noradrenaline could not be determined due to their poor ability to contract the coronary artery. Maximum contractions (Emax; normalized as a percentage of the contraction to a maximum-depolarizing concentration of K+ in physiological salt solution (KPSS)) for 5-HT, ergometrine, sumatriptan, methysergide and noradrenaline were 40 +/- 10, 9 +/- 3, < 5, < 5 and < 5% respectively. 5. In arteries without phasic activity, U46619 (1 nM) caused an increase in force of 3.8 +/- 1% KPSS.(ABSTRACT TRUNCATED AT 250 WORDS)

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sumatriptan, Imitrex
Role of threonine 342 in helix 7 of the 5-hydroxytryptamine type 1D receptor in ligand binding: an indirect mechanism for receptor selectivity.

Smolyar A, Osman R.

Department of Physiology and Biophysics, Mount Sinai School of Medicine, City University of New York, New York 10029-6574.

Recent mutations of the 5-hydroxytryptamine (5-HT)1B and 5-HT1D receptor subtypes suggest that a threonine in the seventh transmembrane helix may be responsible for the selectivity of these receptors. A molecular dynamics simulation of a three-dimensional model of the 5-HT1D receptor interacting with a selective agonist, sumatriptan, shows that, although Thr342 in helix 7 does not have a direct interaction with sumatriptan, it contributes to the selectivity of this receptor through an indirect mechanism. The hydrogen bond between O gamma-H of Thr342 and the backbone C = O of Phe338 stabilizes a bent conformation of the helix that is formed due to the interaction between sumatriptan and Asp339 at one end and Tyr346 at the other end. The indirect mechanism may explain the small change in the affinity for the selective agonist sumatriptan of the receptor in which Thr342 was mutated to asparagine.

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sumatriptan, Imitrex
Amplification of sumatriptan-induced contractions with phenylephrine, histamine and KCl in the isolated human mesenteric artery: in-vitro evidence for sumatriptan-induced mesenteric ischaemia.

Gul H, Yildiz O.

Gulhane Military Medical Academy, School of Medicine, Department of Pharmacology, 06018 Etlik, Ankara, Turkey.

Sumatriptan, a 5-HT(1B/1D/1F) receptor agonist, is used to relieve migraine headache. Sumatriptan contracts some arteries either directly or after modest precontraction with non-serotonergic agonists. Sumatriptan can cause myocardial ischaemia and myocardial infarction. While previous in-vitro studies have shown that sumatriptan has no or only weak contractile activity in human omental arteries, recent clinical studies suggest that sumatriptan may induce mesenteric ischaemia. The aim of this study was to investigate the presence of contractile 5-HT(1B) receptors in the human mesenteric artery and to establish whether the weak sumatriptan-induced contractions are amplified by precontraction with various contractile substances. The study was performed in organ baths using endothelium-denuded isolated human mesenteric arteries. Sumatriptan induced concentration-dependent contractions in some mesenteric arteries [ E(max) 61+/-10% of the maximum contraction induced by 80 mM KCl, pD(2) (-log(10)EC(50)) 6.56+/-0.20, n=9]. In the other mesenteric arteries, sumatriptan induced only very weak ( E(max) <5%) or no contraction ( n=13). GR127935 (3 nM), a selective 5-HT(1B) receptor antagonist, antagonized sumatriptan-induced contractions insurmountably in sumatriptan-sensitive arteries. When the resting tension of the arterial rings was increased moderately by threshold concentrations (EC(10)-EC(20) of maximum contraction induced by 80 mM KCl) with the non-5-HT receptor agonists phenylephrine (10-100 nM), histamine (100 nM-1 microM) or the depolarizing agent KCl (4-10 mM), 5-HT(1B) receptor-mediated responses were amplified in sumatriptan-insensitive arteries (with phenylephrine E(max) 82+/-17%, pD(2) 6.64+/-0.20, n=7; with histamine E(max) 107+/-26%, pD(2) 6.16+/-0.14, n=6; with KCl E(max) 78+/-16%, pD(2) 6.45+/-0.15, n=7). These results show that sumatriptan induced concentration-dependent contractions in sumatriptan-sensitive mesenteric arteries and that 5-HT(1B) receptors were present and active in these vessels. However, in sumatriptan-insensitive arteries, precontraction is required for sumatriptan to induce concentration-dependent contractions. These findings suggest that sumatriptan may induce ischaemia in human mesenteric vasculature directly or in the presence of precontractile risk factors.

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sumatriptan, Imitrex
Conformationally restricted sumatriptan analogues, CP-122,288 and CP-122,638 exhibit enhanced potency against neurogenic inflammation in dura mater.

Lee WS, Moskowitz MA.

Stroke Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston 02114.

CP-122,288 and CP-122,638 blocked plasma protein extravasation response within dura mater following trigeminal ganglion stimulation. The threshold (1 and 0.1 pmol/kg, respectively) was remarkably lower than for sumatriptan (7 nmol/kg), as was the dose at maximum response. As with sumatriptan, substance P-induced plasma leakage was unaffected by either compound, and metergoline only partially (27%) reversed the effects of CP-122,288. The data suggest the importance of modifications at the aminoethyl side chain to the actions of sumatriptan and possibly to the treatment of migraine headache.

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