Theories regarding the pathophysiology of migraine have been dominated since 1938 by the work of Graham and Wolff. Arch. Neurol. Psychiatry, 39:737-63, 1938. They proposed that the cause of migraine headache was vasodilatation of extracranial vessels. This view was supported by knowledge that ergot alkaloids and sumatriptan, a hydrophilic 5-HT.sub.1 agonist which does not cross the blood-brain barrier, contract cephalic vascular smooth muscle and are effective in the treatment of migraine. Humphrey, et al., Ann. NY Acad. Sci., 600:587-600, 1990. Recent work by Moskowitz has shown, however, that the occurrence of migraine headaches is independent of changes in vessel diameter. Cephalalgia, 12:5-7, 1992.
Moskowitz has proposed that currently unknown triggers for pain stimulate trigeminal ganglia which innervate vasculature within the cephalic tissue, giving rise to release of vasoactive neuropeptides from axons on the vasculature. These released neuropeptides then activate a series of events, a consequence of which is pain. This neurogenic inflammation is blocked by sumatriptan and ergot alkaloids by mechanisms involving 5-HT receptors, believed to be closely related to the 5-HT.sub.1D subtype, located on the trigeminovascular fibers. Neurology, 43(suppl. 3):S16-S20 1993.
Serotonin (5-HT) exhibits diverse physiological activity mediated by at least seven receptor classes, the most heterogeneous of which appears to be 5-HT.sub.1. A human gene which expresses one of these 5-HT.sub.1 receptor subtypes, named 5-HT.sub.1F, was isolated by Kao and coworkers. Proc. Natl. Acad. Sci. USA, 90:408-412, 1993. This 5-HT.sub.1F receptor exhibits a pharmacological profile distinct from any serotonergic receptor yet described. The high affinity of sumatriptan at this subtype, K.sub.i =23 nM, suggests a role of the 5-HT.sub.1F receptor in migraine.
This invention relates to novel 5-HT.sub.1F agonists which inhibit peptide extravasation due to stimulation of the trigeminal ganglia, and are therefore useful for the treatment of migraine and associated disorders.
USPTO Backgrounds
USPTO Backgrounds