No abstract

311C90 (zolmitriptan zomig: (S)-4[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone)is a novel 5-HT 1B/1D receptor agonist with proven e cacy in the acute treatment of migraine. Here, we describe the receptor speci®city of the drug and its actions on trigeminal-evoked plasma protein extravasation into the dura mater of the anaesthetized guinea-pig. 2 At the`5-HT 1B -like' receptor mediating vascular contraction (rabbit saphenous vein), the compound was a potent (p[A 50 ]=6.79+0.06) partial agonist achieving 77+4% of the maximum e ect to 5-hydroxytryptamine (5-HT). In the same experiments, sumatriptan (p[A 50 ]=6.48+0.04) was half as potent as 311C90 and produced 97+2% of the 5-HT maximum e ect. Studies in which receptor inactivation methods were used to estimate the a nity (pK A ) and e cacy relative to 5-HT (t rel. ) for each agonist con®rmed that 311C90 exhibits higher a nity than sumatriptan (pK A =6.63+0.04 and 6.16+0.03, respectively) and that both drugs are partial agonists relative to 5-HT (t rel =0.61+0.03 and 0.63+0.10, respectively, compared to 5-HT=1.0). 3 Consistent with its e ects in rabbit saphenous vein, 311C90 also produced concentration-dependent contractions of primate basilar artery and human epicardial coronary artery rings. In basilar artery, agonist potency (p[A 50 ]=6.92+0.07) was similar to that demonstrated in rabbit saphenous vein, again being 2 ± 3 fold higher than for sumatriptan (p[A 50 ]=6.46+0.03). Both agonists produced about 50% of the maximum response obtained with 5-HT in the same preparations. In rings of human coronary artery, the absolute potency of 311C90 and sumatriptan was higher than in primate basilar artery (p[A 50 ]=7.3+0.1 and 6.7+0.1, respectively), but maximum e ects relative to 5-HT were lower (37+8% and 35+7%, respectively). In both types of vessel, the inability of 5-HT 1B/1D agonists to achieve the same maximum as the endogenous agonist 5-HT is explained by the additional presence of 5-HT 2A receptors. 4 311C90 displayed high a nity at human recombinant 5-HT 1D (formerly 5-HT 1Da ) and 5-HT 1B (formerly 5-HT 1Db ) receptors in transfected CHO-K1 cell membranes (pIC 50 values=9.16+0.12 and 8.32+0.09, respectively). In intact cells, the drug produced concentration-dependent inhibition of forskolin-stimulated adenylyl cyclase (p[A 50 ]=9.9 and 9.5, respectively) achieving the same maximum e ect as 5-HT. Excepting human recombinant 5-HT 1A and 5-ht 1F receptors at which the drug behaved as an agonist with modest a nity (pIC 50 =6.45+0.11 and 7.22+0.12, respectively), 311C90 exhibited low, or no detectable a nity (pK i or pK B 4 5.5) at numerous other monoamine receptors, including other 5-HT receptor subtypes. 5 When administered to anaesthetized guinea-pigs ten minutes before unilateral electrical stimulation of the trigeminal ganglion (1.2 mA, 5 Hz, 5 ms, 5 min), 311C90 (3 ± 30 mg kg 71 , i.v.) caused a dosedependent inhibition of [ 125 I]-albumin extravasation within the ipsilateral dura mater. At the same doses, the drug also produced dose-depen...

The purpose of this study was to use intravital microscopy to determine the effect of a selective adenosine A1 receptor agonist, GR79236 (1, 3 and 10 microg/kg i.v.), on neurogenic dural blood vessel dilation in anaesthetized rats. Vasodilation was evoked either by electrical stimulation of perivascular trigeminal nerves or by intravenous CGRP. GR79236 (1-10 microg/kg i.v.) caused a dose-dependent inhibition of neurogenic vasodilation, but had no significant effect on dural vasodilation caused by CGRP. GR79236 (1-3 microg/kg i.v.) had no effect on basal dural vessel diameter, but caused transient dose-dependant bradycardia and hypotension. Bradycardia was more prolonged following 10 microg/kg i.v. GR79236. Pre-treatment with the adenosine A1 receptor antagonist DPCPX (1 mg/kg i.v.) prevented the inhibitory effect of GR79236 (10 microg/kg i.v.) on neurogenic vasodilation as well as GR79236-induced bradycardia and hypotension. These data suggest that the inhibition of neurogenic vasodilation by GR79236 is mediated via the activation of prejunctional adenosine A1 receptors. Provided the systemic cardiovascular effects could be limited, such a mechanism may offer a novel approach to migraine therapy.

No abstract

Summary Collagen (10-40 μg kg−1), thrombin (1-10 units kg−1), adenosine diphosphate (ADP; 3-300 pμ kg−1), 1-0-hexadecyl Paf-acether and 1-0-octadecyl Paf-acether (1-300 ng kg−1) administered by bolus intravenous injection each caused dose-dependent thrombocytopoenia accompanied by marked hypotension in anaesthetized rabbits. Responses to ADP and the Paf-acether derivatives were transient in nature (3-8 min) whereas those induced by collagen and thrombin were always of longer duration (5-20 min) and frequently fatal at high doses. Responses to collagen, thrombin, and the Paf-acether derivatives were invariably accompanied by substantial, dose-related increases in plasma levels of thromboxane B2 in samples obtained 30 s after agonist administration, whereas following ADP, no change in plasma thromboxane B2 was detected at any dose level. Indomethacin (3.0 mg kg−1 by infusion) had no effect on responses to thrombin or Paf-acether, partially inhibited collagen-induced thrombocytopenia, and potentiated responses to ADP. In contrast, dazoxiben (10 mg kg−1 by infusion) partially but significantly inhibited responses to thrombin, whereas those induced by collagen, Paf-acether or ADP were unchanged. These results indicate that in this model of intravascular aggregation, whilst platelet responses to collagen and thrombin appear partially dependent on intact cyclic endoperoxide and thromboxane A2 synthetic capacity respectively, responses to ADP and Paf-acether are independent of arachidonate metabolism via cyclo-oxygenase despite measurably increased TXB2 formation in the latter case.