RECEPTOR SPECIFICITY AND TRIGEMINO-VASCULAR INHIBITORY ACTIONS OF A NOVEL 5-HT1B 1D RECEPTOR PARTIAL AGONIST, 311C90 (ZOLMITRIPTAN)/

1 311C90 (zolmitriptan zomig: ino)ethyl]-1H-indole-5-yl]methyl]-2-oxaz olidinone) is a novel 5-HT1B/1D receptor agonist with proven efficacy in the acute treatment of migraine. Here, we describe the receptor spe cificity of the drug and its actions on trigeminal-evoked plasma prote in extravasation into the dura mater of the anaesthetized guinea-pig. 2 At the '5-HT1B-like' receptor mediating vascular contraction (rabbit saphenous vein), the compound a potent (p[A(50)]=6.79+/-0.06) partial agonist achieving 77+/-4% of the maximum effect to 5-hydroxytryptamin e (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 es timate the affinity (pK(A)) and efficacy relative to 5-HT (tau(red)) f or each agonist confirmed that 311C90 exhibits higher affinity than su matriptan (pK(A)=6.63+/-0.04 and 6.16+/-0.03, respectively) and that b oth drugs are partial agonists relative to 5-HT (tau(red)=0.61+/-0.03 and 0.63+/-0.10, respectively, compared to 5-HT=10). 3 Consistent with its effects in rabbit saphenous vein, 311C90 also produced concentrat ion-dependent contractions of primate basilar artery and human epicard ial coronary artery rings. In basilar artery, agonist potency (p[A(50) ]=6.92+/-0.07) was Similar to that demonstrated in rabbit saphenous ve in, 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 obtain ed with 5-HT in the same preparations. In rings of human coronary arte ry, 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-HT1B/1D agonists to achieve the same maximum as the endogenous agonist 5-HT is explained by the additional presence of 5-HT2A receptors. 4 311C90 di splayed high affinity at human recombinant 5-HT1D (formerly 5-HT1D alp ha) and 5-HT1B (formerly 5-HT1D beta) receptors in transfected CHO-K1 cell membranes (pIC(50) values=9.16+/-0.12 and 8.32+/-0.09, respective ly). In intact cells, the drug produced concentration-dependent inhibi tion of forskolin-stimulated adenylyl cyclase (p[A(50)]=9.9 and 9.5, r espectively) achieving the same maximum effect as 5-HT. Excepting huma n recombinant 5-HT1A 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+/-0.1 2, respectively), 311C90 exhibited low, or no detectable affinity (pK( i) or pK(B) less than or equal to 5.5) at numerous other monoamine rec eptors, including other 5-HT receptor subtypes. 5 When administered to anaesthetized guinea-pigs ten minutes before unilateral electrical st imulation of the trigeminal ganglion (1.2 mA, 5 Hz, 5 ms, 5 min), 311C 90 (3-30 mu g kg(-1), i.v.) caused a dose-dependent inhibition of [I-1 25]-albumin extravasation within the ipsilateral dura mater. At the sa me doses, the drug also produced dose-dependent falls in cranial vascu lar conductance (32.3+/-7.5% at 30 mu g kg(-1)), as measured in the ea r by laser doppler flowmetry. 6 These results show that 311C90, a nove l member of the 5-HT1B/1D agonist drug class, exhibits a high degree o f pharmacological specificity. Its potent partial agonist action at '5 -HT1B-like' receptors in intracranial arteries, coupled with potent ag onism at 5-HT1D and 5-HT1B receptors and an ability to inhibit neuroge nic plasma protein extravasation in the dura, are consistent with its utility as an effective acute treatment for migraine.