Substituted 4-aminopiperidines having high in vitro affinity and selectivity for the cloned human dopamine D₄ receptor

We have discovered two substituted 4-aminopiperidine compounds having high in vitro affinity and selectivity for the human dopamine D₄ 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 (K(i)) 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.