Design, synthesis, and evaluation of chromen-2-ones as potent and selective human dopamine D4 antagonists.
The discovery of a series of chromen-2-ones with selective affinity for the dopamine (DA) D4 receptor is described. Target compounds were tested for binding to cloned human DA D2L, D3, and D4.2 receptor subtypes expressed in Chinese hamster ovary K1 cells. Several compounds demonstrated high affinity (<20 nM, K(i)) and greater than 100-fold selectivity for DA D4.2 versus DA D2L receptors. The results of a SAR study are discussed within. In a DA D4 functional assay measuring [(3)H]thymidine uptake, target compounds showed antagonist activity at the D4.2 receptor. Compound 22, 7-[(2-phenylaminoethylamino)methyl]chromen-2-one, increased DOPA (L-3,4-dihydroxyphenylalanine) accumulation 51% in the hippocampus and 23% in the striatum of rat brains when dosed orally at 20 mg/kg.
Kesten
S R
SR
Departments of Chemistry and Therapeutics, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA.
Heffner
T G
TG
Johnson
S J
SJ
Pugsley
T A
TA
Wright
J L
JL
Wise
L D
LD
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D004298:Dopamine / Q000096:biosynthesis; D018492:Dopamine Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D015195:Drug Design; D006801:Humans; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D050638:Receptors, Dopamine D4; D013216:Reflex, Startle / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy; D013329:Structure-Activity Relationship
D014150:Antipsychotic Agents; D001578:Benzopyrans; C493599:DRD4 protein, human; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; C493600:Drd4 protein, mouse; C493601:Drd4 protein, rat; D010879:Piperazines; D050638:Receptors, Dopamine D4; D004298:Dopamine