Possible Antimigraine Mechanisms of Action of the 5HT1F Receptor Agonist LY334370
Shepheard S, Edvinsson L, Cumberbatch M, Williamson D, Mason G, Webb J, Boyce S, Hill R, Hargreaves R
This study investigated whether the selective 5HT1F receptor agonist LY334370 has other possible antimigraine mechanisms in addition to the proposed inhibition of dural plasma extravasation. LY334370 (up to 10(−5) M) had no vasoconstrictor effects on human cerebral arteries in vitro. It had no effect (up to 10 mg kg-1, i.v.) on neurogenic vasodilation of dural blood vessels produced by electrical stimulation of the dura mater in anesthetized rats. Nor had it any effect (at 3 mg kg-1, i.v.) on the hyperalgesia produced by injection of carrageenan into the paw of conscious rats or on nociceptive reflex responses in the spinalized, decerebrate rabbit (up to 3 mg per kg, i.v.), indicating that it has no general analgesic properties. However, it significantly inhibited activation of second-order neurons in the trigeminal nucleus caudalis produced by electrical stimulation of the dura mater in anesthetized rats at 3 mg per kg, i.v. These results provide evidence to suggest that LY334370 has a central mechanism of action in blocking the transmission of nociceptive impulses within the trigeminal nucleus caudalis and that this may represent a mechanism through which it has its antimigraine effect. Novel Potent 5-HT(1F) Receptor Agonists: Structure-Activity Studies of a Series of Substituted N-[3-(1-methyl-4-piperidinyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]amides
Filla SA, Mathes BM, Johnson KW, Phebus LA, Cohen ML, Nelson DL, Zgombick JM, Erickson JA, Schenck KW, Wainscott DB, Branchek TA, Schaus JM
J Med Chem 2003;46:3060–3071
Compound 1a (LY334370), a selective 5-HT(1F) receptor agonist (SSOFRA), inhibited dural inflammation in the neurogenic plasma protein extravasation model of migraine and demonstrated clinical efficacy for the acute treatment of migraine. Although 1a was greater than 100-fold selective over both the 5-HT(1B) and 5-HT(1D) receptors, it exhibited appreciable 5-HT(1A) receptor affinity. Described here is the synthesis and evaluation of a series of pyrrolo[2,3-c]pyridine and pyrrolo[3,2-b]pyridine (2a and 3a) as well as pyrrolo[3,2-d]pyrimidine (4a) analogues of 1a, compounds prepared in an effort to identify SSOFRAs with improved selectivity over other 5-HT(1) receptor subtypes. The pyrrolo[3,2-b]pyridine analogue 3a showed high 5-HT(1F) receptor affinity but offered no improvement in selectivity compared to 1a. However, the C-5 acetamide derivative, 3b, was greater than 100-fold selective over the 5-HT(1A), 5-HT(1B), and 5-HT(1D) receptors. SAR studies of this series determined that alkylamides in particular exhibited high selectivity for the 5-HT(1F) receptor. Replacement at C-5 with other substituents decreased affinity or selectivity. These SAR studies identified SSOFRAs that demonstrated oral activity in the neurogenic plasma protein extravasation model, a model indicative of antimigraine activity.