Enhanced D1 Affinity in a Series of Piperazine Ring Substituted 1-Piperazino-3-Arylindans with Potential Atypical Antipsychotic Activity
| Autor: | Hans Otto Hansen, Klaus Peter Bogeso, Henrik Pedersen, Kristen Frederiksen, John Hyttel, Jørn Arnt |
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| Rok vydání: | 1995 |
| Předmět: |
Stereochemistry
Chemical synthesis Piperazines Mice Structure-Activity Relationship chemistry.chemical_compound Adrenergic Agents Receptors Adrenergic alpha-1 Drug Discovery Animals Structure–activity relationship Oxidopamine Receptor Bicyclic molecule Receptors Dopamine D2 Chemistry Receptors Dopamine D1 3T3 Cells Rats Dopamine D2 Receptor Antagonists Piperazine Dopamine receptor Indans Adrenergic alpha-1 Receptor Antagonists Dopamine Antagonists Molecular Medicine 2 3 4 5-Tetrahydro-7 8-dihydroxy-1-phenyl-1H-3-benzazepine Serotonin Antagonists Enantiomer Pharmacophore Antipsychotic Agents |
| Zdroj: | Journal of Medicinal Chemistry. 38:4380-4392 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00022a004 |
| Popis: | A study of the effect of aromatic substitution on D1 and D2 affinity in a series of previously reported trans-1-piperazino-3-phenylindans shows similar structure-activity relationships for the two receptor sites. 6-Substituted derivatives have affinity for both receptors, and 6-chloro-or 6-fluoro-substituted derivatives show preference for D1 receptors. D1 affinity and selectivity are significantly increased in a series of new piperazine ring substituted derivatives. Potent D1 and D2 antagonism in vivo are confined to derivatives with relatively small substituents in the 2-position of the piperazine ring (e.g. 2-methyl,2,2-dimethyl, 2-spirocyclobutyl or 2-spirocyclopentyl). Consequently, the effect of aromatic substitution is examined in a series of 1-(2,2-dimethylpiperazino)-3-arylindans. All these compounds except the 4-, 5-, 7- and 4'-chloro-substituted derivatives have potent D1 affinity (IC50's below 10 nM) and the majority of the compounds antagonize SK&F 38393-induced circling in 6-OHDA-lesioned rats with ED50 values about 1 mumol/kg. In vitro all compounds show preference for D1 receptors, but in vivo they are equally effective as D1 and D2 antagonists. The compounds have high affinity for 5-HT2 receptors and selected compounds show high affinity for alpha 1 adrenoceptors. Furthermore, a subgroup consisting of (-)-38, (-)-39, (-)-41, and (-)-54 does not induce catalepsy in rats. These compounds have the potential of being "atypical" antipsychotics and have consequently been selected for further studies. The non-receptor-blocking enantiomers are shown to be inhibitors of DA and NE uptake in accordance with previous observations in compounds unsubstituted in the piperazine ring. Two compounds, (+)-38 and (+)-40, block DA uptake with IC50 values below 10 nM. Finally, the observed structure-activity relationships are discussed in relation to previously published pharmacophore models for D2 and 5-HT2 receptors. It is concluded that the piperazine substituents might induce a different binding mode at the dopamine receptor sites, perhaps only at the D1 receptor site. |
| Databáze: | OpenAIRE |
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