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50 nM). Behavioral testing of the novel agents in rat indicated moderate locomotor arousal after systemic injection, and none after intragastric administration, indicating poor oral bioavailability.
doi:10.1016/j.bmc.2007.07.018 
Copyright © 2007 Elsevier Ltd All rights reserved.
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
Ruchika Chakrabartya, Jyoti Raoa, Aparna Anandb, Abhijeet Deb Royb, Raja Royb, G. Shankarc, P.R. Duac and Anil K. Saxenaa, 
, 
Received 6 May 2007;
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Abstract
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 D1, D2 and 5-HT2A receptor blocking activity where the ratio pKi (5-HT2A) to pKi (D2) 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).
Graphical abstract
Synthesis and potent neuroleptic activity of a novel 1,2,3,4,6,6a,7,11b,12,12a-decahydropyrazino[2′,1′:6,1]pyrido[3,4-b]indole derivative having D1, D2, and 5-HT2A receptor blocking activity (pKi (5-HT2A)/pKi (D2) = 1.42) is reported.
Keywords: Antipsychotic; D1 receptor; D2 receptor; 5-HT2A receptor; Decahydropyrazino[2′,1′:6,1]pyrido[3,4-b]indole; Neuroleptic; NMR; COSY; HMBC
Article Outline
- 1. Introduction
- 2. Chemistry
- 3. Results and discussion
- 4. Experimental
- 4.1. Chemistry
- 4.2. 1,2,3,4,6,7,12,12a(RS)-Octahydropyrazino[2′,1′:6,1]pyrido[3,4-b]indole (3)
- 4.3. (6aR*,11bS*)-1,2,3,4,6,6a,7,11b,12,12a(RS)-Decahydropyrazino[2′,1′:6,1]pyrido[3,4-b]indole (4)
- 4.4. (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 (5) and 1-(4-fluorophenyl)-4-{2,3,4,6,6a,7,11b,12,12a(RS)-octahydropyrazino[2′,1′:6,1]pyrido[3,4-b]indol-2yl}-butan-1-one (6)
- 4.5. 2-[(4-Methylphenyl)sulfonyl]-1,2,3,4,6,7,12,12a(RS)-octahydropyrazino[2′,1′:6,1]pyrido[3,4-b]indole (7)
- 4.6. (6aR*,11bS*)-2-[(4-Methylphenyl)sulfonyl]-1,2,3,4,6,6a,7,11b,12,12a(RS)-decahydropyrazino-[2′,1′:6,1]pyrido[3,4-b]indole (8)
- 4.7. (6aR*,11bS*)-1-(4-Fluorophenyl)-4-{2-[(4-methyl-phenyl)sulfonyl]}-1,2,3,4,6,6a,7,11b,12,12a(RS)-decahydropyrazino[2′,1′:6,1]pyrido[3,4-b]indol-7-yl}-butan-1-one (9)
- 4.8. (6aR*,11bS*)-1-(4-Fluorophenyl)-1,2,3,4,6,6a,7,11b,12,12a(RS)-decahydropyrazino[2′,1′:6,1]pyrido[3,4-b]indol-7-yl}-butan-1-one (10)
- Acknowledgements
- Supplementary data
- References
