title: Preclinical studies characterizing the anti-migraine and cardiovascular effects of the selective 5-HT1D receptor agonist PNU-142633.
abstract: The present study describes the preclinical pharmacology of a highly selective 5-HT1D receptor agonist PNU-142633. PNU-142633 binds with a Ki of 6 nm at the human 5-HT1D receptor and a Ki of> 18 000 nm at the human 5-HT1B receptor. The intrinsic activity of PNU-142633 at the human 5-HT1D 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.
authors.affiliation: Department of Neurobiology and Structural, Analytical and Medicinal Chemistry, Pharmacia Corporation, Kalamazoo, MI 49001, USA. robert.b.mcall@pharmacia.com
authors.forename: R B
authors.initials: RB
authors.lastname: McCall
authors.forename: R
authors.initials: R
authors.lastname: Huff
authors.forename: C L
authors.initials: CL
authors.lastname: Chio
authors.forename: R
authors.initials: R
authors.lastname: TenBrink
authors.forename: C L
authors.initials: CL
authors.lastname: Bergh
authors.forename: M D
authors.initials: MD
authors.lastname: Ennis
authors.forename: N B
authors.initials: NB
authors.lastname: Ghazal
authors.forename: R L
authors.initials: RL
authors.lastname: Hoffman
authors.forename: K
authors.initials: K
authors.lastname: Meisheri
authors.forename: N R
authors.initials: NR
authors.lastname: Higdon
authors.forename: E
authors.initials: E
authors.lastname: Hall
mesh_terms: D000700:Analgesics / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002319:Cardiovascular System / Q000187:drug effects* / Q000378:metabolism; D002415:Cats; D002839:Chromans / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006224:Cricetinae; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D008881:Migraine Disorders / Q000188:drug therapy* / Q000378:metabolism; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000378:metabolism / Q000502:physiology*; D017366:Serotonin Receptor Agonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018170:Sumatriptan / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000700:Analgesics; D002839:Chromans; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D018170:Sumatriptan; C401885:PNU 142633F