Chromeno[3,4-c]pyridin-5-ones: selective human dopamine D4 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 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.
Unangst
P C
PC
Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
Capiris
T
T
Connor
D T
DT
Heffner
T G
TG
MacKenzie
R G
RG
Miller
S R
SR
Pugsley
T A
TA
Wise
L D
LD
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000378:metabolism; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D065127:Dopamine D2 Receptor Antagonists; D006801:Humans; D007700:Kinetics; D007980:Levodopa / Q000378:metabolism; D008956:Models, Chemical; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis* / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000235:genetics; D050638:Receptors, Dopamine D4; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D007980:Levodopa; D010879:Piperazines; D011725:Pyridines; D011728:Pyridones; D011758:Pyrroles; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4; D013449:Sulfonamides; C099630:3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine; C493599:DRD4 protein, human; C493601:Drd4 protein, rat; C100448:sonepiprazole; D000096926:Benzenesulfonamides