title: Substituted 4-aminopiperidines having high in vitro affinity and selectivity for the cloned human dopamine D4 receptor.
abstract: We have discovered two substituted 4-aminopiperidine compounds having high in vitro affinity and selectivity for the human dopamine D1 receptor. Both compounds, 3-ethoxy-N-methyl-N-[1-(phenylmethyl)-4-piperidinyl]-2-pyridinylamine (U-99363E), and its 3-isopropoxy analog (U-101958), were found through a routine receptor binding screen. The determined affinities (Ki) of these compounds for the cloned human dopamine D4 receptor were 2.2 and 1.4 nM, respectively. They exhibited at least 100-fold lower affinities for dopamine D2 and for other dopaminergic, serotonergic and adrenergic receptors. Both compounds were found to antagonize quinpirole-induced mitogenesis in Chinese hamster ovary cells expressing the human dopamine D4 receptor. In spite of their poor metabolic stability and low bioavailability. U-99363E and U-101958 appear to be among the first high-affinity, highly selective dopamine D4 receptor antagonists reported, and may have utility in in vitro investigations requiring selective tagging or blockade of dopamine D4 sites.
authors.affiliation: Pharmacia & Upjohn, Inc., Kalamazoo, MI 49001, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Schlachter
authors.forename: T J
authors.initials: TJ
authors.lastname: Poel
authors.forename: C F
authors.initials: CF
authors.lastname: Lawson
authors.forename: D M
authors.initials: DM
authors.lastname: Dinh
authors.forename: M E
authors.initials: ME
authors.lastname: Lajiness
authors.forename: A G
authors.initials: AG
authors.lastname: Romero
authors.forename: S A
authors.initials: SA
authors.lastname: Rees
authors.forename: J N
authors.initials: JN
authors.lastname: Duncan
authors.forename: M W
authors.initials: MW
authors.lastname: Smith
mesh_terms: D000631:Aminopyridines / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism; D050638:Receptors, Dopamine D4; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000631:Aminopyridines; C493599:DRD4 protein, human; D010880:Piperidines; D017448:Receptors, Dopamine D2; D011994:Recombinant Proteins; D050638:Receptors, Dopamine D4; C106117:U 101958; C106116:U 99363