title: 2-(1-Naphthyloxy)ethylamines with enhanced affinity for human 5-HT1D beta (h5-HT1B) serotonin receptors.
abstract: Although the beta-adrenergic antagonist propranolol (1) binds at rodent 5-HT1B serotonin receptors, it displays low affinity (Ki > 10,000 nM) for its species homologue 5-HT1D beta (i.e., h5-HT1B) receptors. The structure of propranolol was systematically modified in an attempt to enhance its affinity for the latter population of receptors. Removal of the alkyl hydroxyl group, shortening of the O-alkyl chain from three to two methylene groups, and variation of the terminal amine substituent resulted in compounds, such as N-monomethyl-2-(1-naphthyloxy)-ethylamine (11; Ki = 26 nM), that display significantly higher h5-HT1B affinity than propranolol. Compound 11 was shown to bind equally well at human 5-HT1D alpha (h5-HT1D) receptors (Ki = 34 nM) and was further demonstrated to possess h5-HT1B agonist character in an adenylate cyclase assay. It would appear that such (aryloxy)alkylamines may represent a novel class of 5-HT1D receptor agonists.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia/Virginia Commonwealth University, Richmond 23298, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Ismaiel
authors.forename: M
authors.initials: M
authors.lastname: Dukat
authors.forename: H
authors.initials: H
authors.lastname: Law
authors.forename: R
authors.initials: R
authors.lastname: Kamboj
authors.forename: E
authors.initials: E
authors.lastname: Fan
authors.forename: D K
authors.initials: DK
authors.lastname: Lee
authors.forename: L
authors.initials: L
authors.lastname: Mazzocco
authors.forename: D
authors.initials: D
authors.lastname: Buekschkens
authors.forename: M
authors.initials: M
authors.lastname: Teitler
authors.forename: M E
authors.initials: ME
authors.lastname: Pierson
authors.forename: R A
authors.initials: RA
authors.lastname: Glennon
mesh_terms: D000262:Adenylyl Cyclases / Q000032:analysis / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D011433:Propranolol / Q000031:analogs & derivatives* / Q000378:metabolism; D011485:Protein Binding; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis / Q000378:metabolism*
chemical_list: C110199:N-monomethyl-2-(1-naphthyloxy)ethylamine; D009281:Naphthalenes; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D012701:Serotonin; D011433:Propranolol; D000262:Adenylyl Cyclases