Isoindol-1-one analogues of 4-(2'-methoxyphenyl)-1-[2'-[N-(2'-pyridyl)-p-iodobenzamido]ethyl]pipera zine (p-MPPI) as 5-HT1A receptor ligands
| Autor: | Z-P. Zhuang, Mu Mu, Hank F. Kung, M.-P. Kung |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
Male
Biodistribution Indoles Stereochemistry Aminopyridines Isoindoles Ligands Chemical synthesis Hippocampus Piperazines Iodine Radioisotopes Rats Sprague-Dawley chemistry.chemical_compound In vivo Heterocyclic Compounds Amide Drug Discovery Animals Humans Chromatography High Pressure Liquid Tomography Emission-Computed Single-Photon Bicyclic molecule Ligand Rats Piperazine Kinetics chemistry Models Chemical Receptors Serotonin Lactam Microsomes Liver Molecular Medicine Serotonin Antagonists Receptors Serotonin 5-HT1 |
| Zdroj: | Journal of medicinal chemistry. 41(2) |
| ISSN: | 0022-2623 |
| Popis: | In developing radioiodinated antagonists for in vivo imaging of 5-HT1A receptors with SPECT, a series of new arylpiperazine benzamido derivatives, including 4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridyl)-p-iodobenzamido]ethyl]p iperazine (p-MPPI, 31) (Kd = 0.36 nM), as potential ligands for 5-HT1A receptors were reported previously. However, rapid in vivo metabolism may have caused the breakdown of the amide bond of [123I]-31 and rendered this agent obsolete as an in vivo imaging agent in humans. To improve the in vivo stability of 31, a series of cyclized amide analogues were designed and synthesized. In vitro binding, metabolic stability, and in vivo biodistribution of these new derivatives were investigated. Several five-membered-ring isoindol-1-ones displayed very high in vitro binding affinity, especially 2-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-6-nitro-3-phenyl-2, 3-dihydroisoindol-1-one, 15, 3-hydroxy-6-iodo-2-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}- 3- phenyl-2,3-dihydroisoindol-1-one, 18, and 6-iodo-2-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-3-phenyl-2, 3-dihydroisoindol-1-one, 21, which showed Ki values of 0.05, 0.65, and 0.07 nM, respectively. The affinities for 5-HT1A receptors of other cyclized amide derivatives, 5-(4-bromophenyl)-1-{2-[4-(2-methoxyphenyl)- piperazin-1-yl]ethyl}pyrrolidin-2-one, 25, 5-(4-iodophenyl)-1-{2-[4-(2-methoxyphenyl)piperazin- 1-yl]ethyl}pyrrolidin-2-one, 27, and 2-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-2,3-dihydro- isoindol-1-one, 29, were 1.09, 2.54, and 14.9 nM, respectively. Compared to [125I]-31, iodinated cyclized amide derivatives [125I]-21 and [125I]-27 displayed a slower metabolism in human liver microsomal and cytosolic preparations. Biodistribution of [125I]-21 and [125I]-27 in rats (after an i.v. injection) displayed moderate to low brain uptakes with little or no specific localization in hippocampal region, where 5-HT1A receptors are concentrated. These data indicate that the new iodinated ligands showed high binding affinities and better metabolic stability but displayed unexpectedly low selective binding to 5-HT1A receptors in vivo. Additional structural modifications may be needed to correct the unfavorable properties displayed for these iodinated cyclized amide derivatives for in vivo biodistribution in rats. |
| Databáze: | OpenAIRE |
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