SUBSTITUTED 4-AMINOPIPERIDINES HAVING HIGH IN-VITRO AFFINITY AND SELECTIVITY FOR THE CLONED HUMAN DOPAMINE D-4 RECEPTOR

We have discovered two substituted 4-aminopiperidine compounds having high in vitro affinity and selectivity for the human dopamine D-4 rece ptor. Both compounds, -[1-(phenylmethyl)-4-piperidinyl]-2-pyridinylami ne (U-99363E), and its 3-isopropoxy analog (U-101958), were found thro ugh a routine receptor binding screen. The determined affinities (K-i) of these compounds for the cloned human dopamine D-4 receptor were 2. 2 and 1.4 nM, respectively. They exhibited at least 100-fold lower aff inities for dopamine D-2 and for other dopaminergic, serotonergic and adrenergic receptors. Both compounds were found to antagonize quinpiro le-induced mitogenesis in Chinese hamster ovary cells expressing the h uman dopamine D-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-4 receptor antagonis ts reported, and may have utility in in vitro investigations requiring selective tagging or blockade of dopamine D-4 sites. (C) 1997 Elsevie r Science B.V.