Receptor specificity and trigemino‐vascular inhibitory actions of a novel 5‐HT_1B/1D receptor partial agonist, 311C90 (zolmitriptan)

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...

A triptan too far?

“…Zolmitriptan was the second of the 5HT 1B/1D class to be marketed in the United Kingdom after sumatriptan and was designed to be more lipophilic35 and to be a potent partial agonist 36. Both aims were achieved and its activity in preclinical models is well established as it has been used as a laboratory tool for considering some issues surrounding the potential central sites of action of this class of compounds 37-39…”

Determination of zolmitriptan enantiomers in rat liver microsomes by chiral high performance liquid chromatography with ?uorescence detection

“…Zolmitriptan (311C90) is a new potent selective 5-HT 1B/1D receptor partial agonist (Martin, 1994;Martin et al, 1997) that has recently been approved for use in the acute treatment of migraine and related vascular headaches. The main metabolic pathway of zolmitriptan involves CYP1A2 with isolated human hepatocytes (Wild et al, 1999) and rat hepatic microsomes (Yu et al, 2003).…”

A Review of the Pharmacokinetics, Pharmacodynamics and Efficacy of Zolmitriptan in the Acute Abortive Treatment of Migraine

“…14,29 In addition zolmitriptan has a modest affi nity for 5-HT1A and 5-HT1F receptors. 29 The N-desmethyl zolmitriptan (183C91) metabolite of zolmitriptan has similar receptor binding profi le to that of the parent compound. However, it is approximately 2 to 8 fold more potent than zolmitriptan at the 5-HT1B/1D receptors.…”