title: 3-[3-(Piperidin-1-yl)propyl]indoles as highly selective h5-HT(1D) receptor agonists.
abstract: Several 5-HT(1D/1B) receptor agonists are now entering the marketplace as treatments for migraine. This paper describes the development of selective h5-HT(1D) receptor agonists as potential antimigraine agents which may produce fewer side effects. A series of 3-[3-(piperidin-1-yl)propyl]indoles has been synthesized which has led to the identification of 80 (L-772,405), a high-affinity h5-HT(1D) receptor full agonist having 170-fold selectivity for h5-HT(1D) receptors over h5-HT(1B) receptors. L-772,405 also shows very good selectivity over a range of other serotonin and nonserotonin receptors and has excellent bioavailability following subcutaneous administration in rats. It therefore constitutes a valuable tool to delineate the role of h5-HT(1D) receptors in migraine. Molecular modeling and physical properties have been utilized to postulate the binding conformation of these compounds in the receptor cavity.
authors.affiliation: Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U.K.
authors.forename: M G
authors.initials: MG
authors.lastname: Russell
authors.forename: V G
authors.initials: VG
authors.lastname: Matassa
authors.forename: R R
authors.initials: RR
authors.lastname: Pengilley
authors.forename: M B
authors.initials: MB
authors.lastname: van Niel
authors.forename: B
authors.initials: B
authors.lastname: Sohal
authors.forename: A P
authors.initials: AP
authors.lastname: Watt
authors.forename: L
authors.initials: L
authors.lastname: Hitzel
authors.forename: M S
authors.initials: MS
authors.lastname: Beer
authors.forename: J A
authors.initials: JA
authors.lastname: Stanton
authors.forename: H B
authors.initials: HB
authors.lastname: Broughton
authors.forename: J L
authors.initials: JL
authors.lastname: Castro
mesh_terms: D000818:Animals; D001682:Biological Availability; D016466:CHO Cells; D003198:Computer Simulation; D006224:Cricetinae; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D014162:Transfection; D014230:Triazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D007211:Indoles; C402271:L 772405; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D011994:Recombinant Proteins; D017366:Serotonin Receptor Agonists; D014230:Triazoles; D016244:Guanosine 5'-O-(3-Thiotriphosphate)