trans-1-[(2-Phenylcyclopropyl)methyl]-4-arylpiperazines: mixed dopamine D(2)/D(4) receptor antagonists as potential antipsychotic agents.
The dopaminergic receptor profile of a series of trans-1-[(2-phenylcyclopropyl)methyl]-4-arylpiperazines was examined. Aromatic substitution patterns were varied with the goal of identifying a compound having affinities for the D(2) and D(4) receptors in a ratio similar to that observed for the atypical neuroleptic clozapine. The compounds (1S, 2S)-trans-1-[(2-phenylcyclopropyl)methyl]-4-(2, 4-dichlorophenyl)piperazine (5m) and (1S, 2S)-trans-1-[(2-phenylcyclopropyl)methyl]-4-(2, 4-dimethylphenyl)piperazine (5t) were selected for functional antagonists at D(2) and D(4) receptors and had a D(2)/D(4) ratio approximating that of clozapine; they proved inactive in behavioral tests of antipsychotic activity.
Zhang
X
X
Neurogen Corporation, 35 Northeast Industrial Road, Branford, Connecticut 06405, USA.
Hodgetts
K
K
Rachwal
S
S
Zhao
H
H
Wasley
J W
JW
Craven
K
K
Brodbeck
R
R
Kieltyka
A
A
Hoffman
D
D
Bacolod
M D
MD
Girard
B
B
Tran
J
J
Thurkauf
A
A
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D018492:Dopamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism; D050638:Receptors, Dopamine D4; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C415570:1-((2-phenylcyclopropyl)-methyl)-4-(2,4-dimethylphenyl)piperazine; C415569:1-((2-phenylcyclopropyl)methyl)-4-(2,4-dichlorophenyl)piperazine; D014150:Antipsychotic Agents; C493599:DRD4 protein, human; D018492:Dopamine Antagonists; C493601:Drd4 protein, rat; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4; D003577:Cytochrome P-450 Enzyme System