Chromeno[3,4-c]pyridin-5-ones: Selective human dopamine D-4 receptor antagonists as potential antipsychotic agents

The discovery of a series of chromeno[3,4-c]pyridin-5-ones with selective: affinity for the dopamine D-4 receptor is described. Target compounds were tested for binding to cloned human dopamine D-2, D-3, and D-4 receptor subtypes expressed in Chinese hamster ovary (CHO) K-l cells. Several compounds demonstrated single digit nanomolar K-i values for binding to the D-4 receptor with several hundred-fold selectivities toward the D-2 and D-3 receptors. A,limited SAR study of this series is discussed. In a mitogenesis assay measuring [H-3]thymidine uptake, the target compounds showed antagonist to weak partial agonist activity at the D-4 receptor, with intrinsic activities ranging from 0 to 35%. Compound 6, 3-benzyl-8-methyl-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one, increased DOPA. (L-3,4-dihydroxyphenylalanine) synthesis 84% in the hippocampus and 10% in the striatum of rat brain when dosed orally at. 10 mg/kg.