title: Synthesis and structure-affinity relationship investigations of 5-aminomethyl and 5-carbamoyl analogues of the antipsychotic sertindole. A new class of selective alpha1 adrenoceptor antagonists.
abstract: A new class of selective alpha(1) adrenoceptor antagonists derived from the antipsychotic drug sertindole is described. The most potent and selective compound 1-(2-(4-[5-aminomethyl-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl)ethyl)-2-imidazolidinone (11) binds with 0.50 nM affinity for alpha(1) adrenergic receptors and with more than 44 times lower affinity for dopamine D(2),D(3), D(4) and serotonin 5-HT(1A), 5-HT(1B), 5-HT(2A) and 5-HT(2C) receptors. The molecular features providing high affinity for adrenergic alpha(1) receptors and high selectivity towards dopamine D(2) and serotonin 5-HT(2A) and 5-HT(2C) receptors are discussed.
authors.affiliation: Medicinal Chemistry Research, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Valby, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Balle
authors.forename: Jens
authors.initials: J
authors.lastname: Perregaard
authors.forename: Anna K
authors.initials: AK
authors.lastname: Larsen
authors.forename: Martha Teresa
authors.initials: MT
authors.lastname: Ramirez
authors.forename: Karina
authors.initials: K
authors.lastname: Krøjer Søby
authors.forename: Tommy
authors.initials: T
authors.lastname: Liljefors
authors.forename: Kim
authors.initials: K
authors.lastname: Andersen
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D016466:CHO Cells; D002853:Chromatography, Liquid; D006224:Cricetinae; D018492:Dopamine Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008958:Models, Molecular; D008968:Molecular Conformation; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D007093:Imidazoles; D007202:Indicators and Reagents; D007211:Indoles; D018340:Receptors, Adrenergic, alpha-1; D011985:Receptors, Serotonin; C066304:sertindole