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Preclinical Studies Characterizing the Anti-Migraine and Cardiovascular Effects of the Selective 5-HT 1D Receptor Agonist PNU-142633

2002; SAGE Publishing; Volume: 22; Issue: 10 Linguagem: Inglês

10.1046/j.1468-2982.2002.00459.x

1468-2982

RB McCall, Rita M. Huff, CL Chio, Ruth E. TenBrink, CL Bergh, MD Ennis, NB Ghazal, RL Hoffman, Kaushik D. Meisheri, NR Higdon, Edward D. Hall,

Nicotinic Acetylcholine Receptors Study

The present study describes the preclinical pharmacology of a highly selective 5-HT 1D receptor agonist PNU-142633. PNU-142633 binds with a Ki of 6 nM at the human 5-HT 1D receptor and a Ki of > 18 000 nM at the human 5-HT 1B receptor. The intrinsic activity of PNU-142633 at the human 5-HT 1D receptor was determined to be 70% that of 5-HT in a cytosensor cell-based assay compared with 84% for that of sumatriptan. PNU-142633 was equally effective as sumatriptan and a half-log more potent than sumatriptan in preventing plasma protein extravasation induced by electrical stimulation of the trigeminal ganglion. Like sumatriptan, PNU-142633 reduced the increase in cat nucleus trigeminal caudalis blood flow elicited by electrical stimulation of the trigeminal ganglion compared with the vehicle control. The direct vasoconstrictor potential of PNU-142633 was evaluated in vascular beds. Sumatriptan increased vascular resistance in carotid, meningeal and coronary arteries while PNU-142633 failed to alter resistance in these vascular beds. These data are discussed in relation to the clinical findings of PNU-142633 in a phase II acute migraine study.