Orally active benzamide antipsychotic agents with affinity for dopamine D2, serotonin 5-HT1A, and adrenergic alpha1 receptors.
New antipsychotic drugs are needed because current therapy is ineffective for many schizophrenics and because treatment is often accompanied by extrapyramidal symptoms and dyskinesias. This paper describes the design, synthesis, and evaluation of a series of related (aminomethyl)benzamides in assays predictive of antipsychotic activity in humans. These compounds had notable affinity for dopamine D2, serotonin 5-HT1A, and alpha1-adrenergic receptors. The arylpiperazine 1-[3-[[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]methyl]benzoyl]p ipe ridine (mazapertine, 6) was chosen because of its overall profile for evaluation in human clinical trials. The corresponding 4-arylpiperidine derivative 67 was also highly active indicating that the aniline nitrogen of 6 is not required for activity. Other particularly active structures include homopiperidine amide 14 and N-methylcyclohexylamide 31.
Reitz
A B
AB
Drug Discovery Division, R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania 19477, USA.
Baxter
E W
EW
Codd
E E
EE
Davis
C B
CB
Jordan
A D
AD
Maryanoff
B E
BE
Maryanoff
C A
CA
McDonnell
M E
ME
Powell
E T
ET
Renzi
M J
MJ
Schott
M R
MR
Scott
M K
MK
Shank
R P
RP
Vaught
J L
JL
D018663:Adrenergic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced; D002540:Cerebral Cortex / Q000378:metabolism; D003213:Conditioning, Psychological / Q000187:drug effects; D003342:Corpus Striatum / Q000378:metabolism; D015259:Dopamine Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008297:Male; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D018490:Serotonin Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
C112576:1-(3-((4-(2-isopropoxyphenyl)-1-piperidinyl)methyl)-benzoyl)piperidine hydrochloride; C112577:2-(isopropoxyphenyl)piperazine-N-homopiperidinyl-3-(piperazinylmethyl)benzamide; D018663:Adrenergic Agents; D014150:Antipsychotic Agents; D015259:Dopamine Agents; D010879:Piperazines; D010880:Piperidines; D018340:Receptors, Adrenergic, alpha-1; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D018490:Serotonin Agents; C086897:mazapertine succinate