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

311C90 (zolmitriptan zomig: ( S )‐4[[3‐[2‐(dimethylamino)ethyl]‐1 H ‐indol‐5‐yl]methyl]‐2‐oxazolidinone) is a novel 5‐HT 1B/1D receptor agonist with proven efficacy in the acute treatment of migraine. Here, we describe the receptor specificity of the drug and its actions on trigeminal‐evoked plasma protein extravasation into the dura mater of the anaesthetized guinea‐pig. 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 effect 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 effect. Studies in which receptor inactivation methods were used to estimate the affinity (p K A ) and efficacy relative to 5‐HT (τ rel. ) for each agonist confirmed that 311C90 exhibits higher affinity than sumatriptan (p K A =6.63±0.04 and 6.16±0.03, respectively) and that both drugs are partial agonists relative to 5‐HT (τ rel =0.61±0.03 and 0.63±0.10, respectively, compared to 5‐HT=1.0). Consistent with its effects 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 effects 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. 311C90 displayed high affinity at human recombinant 5‐HT 1D (formerly 5‐HT 1Dα ) and 5‐HT 1B (formerly 5‐HT 1Dβ ) 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 effect as 5‐HT. Excepting human recombinant 5‐HT 1A and 5‐ht 1F receptors at which the drug behaved as an agonist with modest affinity (pIC 50 =6.45±0.11 and 7.22±0.12, respectively), 311C90 exhibited low, or no detectable affinity (p K i or p K B 5.5) at numerous other monoamine receptors, including other 5‐HT receptor subtypes. 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 μg kg −1 , i.v.) caused a dose‐dependent inhibition of [ 125 I]‐albumin extravasation within the ipsilateral dura mater. At the same doses, the drug also produced dose‐dependent falls in cranial vascular conductance (32.3±7.5% at 30 μg kg −1 ), as measured in the ear by laser doppler flowmetry. These results show that 311C90, a novel member of the 5‐HT 1B/1D agonist drug class, exhibits a high degree of pharmacological specificity. Its potent partial agonist action at ‘5‐HT 1B ‐like’ receptors in intracranial arteries, coupled with potent agonism at 5‐HT 1D and 5‐HT 1B receptors and an ability to inhibit neurogenic plasma protein extravasation in the dura, are consistent with its utility as an effective acute treatment for migraine.British Journal of Pharmacology (1997) 121 , 157–164; doi: 10.1038/sj.bjp.0701041