Substituted 4-aminopiperidines having high in vitro affinity and selectivity for the cloned human dopamine D sub(4) receptor

• Published in: European journal of pharmacology Vol. 322; no. 2-3; pp. 283 - 286
• Main Authors: Schlachter, S K, Poel, T J, Lawson, C F, Dinh, D M, Lajiness, ME, Romero, A G, Rees, SA, Duncan, J N, Smith, M W
• Format: Journal Article
• Language: English
• Published: 01-03-1997
• ISSN: 0014-2999

We have discovered two substituted 4-aminopiperidine compounds having high in vitro affinity and selectivity for the human dopamine D sub(4) receptor. Both compounds, 3-ethoxy-N-methyl-N-[1-(phenylmethyl)-4-piperidinyl]-2-pyridinylam i ne (U-99363E), and its 3-isopropoxy analog (U-101958), were found through a routine receptor binding screen. The determined affinities (K sub(i)) of these compounds for the cloned human dopamine D sub(4) receptor were 2.2 and 1.4 nM, respectively. They exhibited at least 100-fold lower affinities for dopamine D sub(2) and for other dopaminergic, serotonergic and adrenergic receptors. Both compounds were found to antagonize quinpirole-induced mitogenesis in Chinese hamster ovary cell expressing the human dopamine D sub(4) 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 D sub(4) receptor antagonists reported, and may have utility in in vitro investigations requiring selective tagging or blockade of dopamine D sub(4) sites.