Rational design, synthesis and evaluation of (6aR( *),11bS( *))-1-(4-fluorophenyl)-4-{7-[4-(4-fluorophenyl)-4-oxobutyl]1,2,3,4,6,6a,7,11b,12,12a(RS)-decahydropyrazino[2',1':6,1]pyrido[3,4-b]indol-2-yl}-butan-1-one as a potential neuroleptic agent.
In our pursuit to prepare a potent antipsychotic compound, a novel 1,2,3,4,6,6a,7,11b,12,12a-decahydropyrazino[2',1':6,1]pyrido[3,4-b]indole derivative was synthesized which incorporates the butyrophenone substructure twice. This molecule has shown D(1), D(2) and 5-HT(2A) receptor blocking activity where the ratio pK(i) (5-HT(2A)) to pK(i) (D(2)) is 1.42 better than risperidone (1.15). It blocks amphetamine induced hyperactivity/stereotypy and secondary conditioned avoidance responses in rodents at lower doses than those required for the neuroleptic drugs haloperidol and centbutindole (biriperone).
Chakrabarty
Ruchika
R
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow-226001, India.
Rao
Jyoti
J
Anand
Aparna
A
Roy
Abhijeet Deb
AD
Roy
Raja
R
Shankar
G
G
Dua
P R
PR
Saxena
Anil K
AK
D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D002074:Butanones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D015195:Drug Design; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors*; D058830:Serotonin 5-HT2 Receptor Antagonists; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C525626:6aR,11bS -1-(4-fluorophenyl)-4-(7-(4-(4-fluorophenyl)-4-oxobutyl)1,2,3,4,6,6a,7,11b,12,12a(RS)-decahydropyrazino(2',1':6,1)pyrido(3,4-b)indol-2-yl)-butan-1-one; D014150:Antipsychotic Agents; D002074:Butanones; D065127:Dopamine D2 Receptor Antagonists; D007211:Indoles; D017447:Receptors, Dopamine D1; D058830:Serotonin 5-HT2 Receptor Antagonists