Chromeno[3,4-c]pyridin-5-ones: selective human dopamine D4 receptor antagonists as potential antipsychotic agents.
Article Details
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Unangst PC, Capiris T, Connor DT, Heffner TG, MacKenzie RG, Miller SR, Pugsley TA, Wise LD
Chromeno[3,4-c]pyridin-5-ones: selective human dopamine D4 receptor antagonists as potential antipsychotic agents.
J Med Chem. 1997 Aug 15;40(17):2688-93.
- PubMed ID
- 9276014 [ View in PubMed]
- Abstract
The discovery of a series of chromeno[3,4-c]pyridin-5-ones with selective affinity for the dopamine D4 receptor is described. Target compounds were tested for binding to cloned human dopamine D2, D3, and D4 receptor subtypes expressed in Chinese hamster ovary (CHO) K-1 cells. Several compounds demonstrated single digit nanomolar Ki values for binding to the D4 receptor with several hundred-fold selectivities toward the D2 and D3 receptors. A limited SAR study of this series is discussed. In a mitogenesis assay measuring [3H]thymidine uptake, the target compounds showed antagonist to weak partial agonist activity at the D4 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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Clozapine Dopamine D2 receptor Ki (nM) 91 N/A N/A Details Clozapine Dopamine D3 receptor Ki (nM) 222 N/A N/A Details Clozapine Dopamine D4 receptor Ki (nM) 16 N/A N/A Details Haloperidol Dopamine D2 receptor Ki (nM) 1.6 N/A N/A Details Haloperidol Dopamine D3 receptor Ki (nM) 2.2 N/A N/A Details