cis-1,3,4,6,7,11b-Hexahydro-2-methyl-7-phenyl-2H-pyrazino[2,1-a]isoquinoline: a new atypical antidepressant
| Autor: | Jerry M. Frankenheim, Ronald C. Griffith, Robert J. Gentile, Roger C. Robichaud |
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| Rok vydání: | 1984 |
| Předmět: |
Models
Molecular Imipramine Stereochemistry Mianserin Chloroacetyl chloride Acylation chemistry.chemical_compound Dogs Drug Discovery medicine Animals Receptors Cholinergic Chloroacetamide Isoquinoline Amination Pyrilamine Absolute configuration Brain Isoquinolines Antidepressive Agents Rats Quinuclidinyl Benzilate chemistry Receptors Histamine Molecular Medicine Enantiomer medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 27:995-1003 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Molecular modelling studies suggested the synthesis of cis-1,3,4,6,7, 11b-hexahydro-2-methyl-7-phenyl-2H-pyrazino[2,1-a]isoquinoline (7a) as a rigid analogue of the atypical antidepressant mianserin. Acylation of 2,2-diphenylethylamine with chloroacetyl chloride gives the chloroacetamide (2). Cyclization of 2 with P2O5 in xylene provides 1-(chloromethyl)-3,4-dihydro-4-phenylisoquinoline (3). Amination of 3, followed by reduction, gives the isomeric (aminomethyl)tetrahydroisoquinolines (4a and 5). Treatment of 4a with diethyl oxalate, followed by reduction of the diamide with borane, provides 7a. A variety of N-substituted, aromatic substituted, and optically resolved derivatives were prepared and evaluated for anticholinergic, antihistaminic, and antidepressant activity. In particular, the target cis isomer 7a as predicted from the modelling studies appears to possess excellent atypical antidepressant activity. This activity resides in the (+)-S,S optical isomer 10, which has the same absolute configuration as (+)-mianserin. |
| Databáze: | OpenAIRE |
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