| Autor: |
Emond, P., Garreau, L., Chalon, S., Boazi, M., Caillet, M., Bricard, J., Frangin, Y., Mauclaire, L., Besnard, J.-C., Guilloteau, D. |
| Zdroj: |
Journal of Medicinal Chemistry; April 25, 1997, Vol. 40 Issue: 9 p1366-1372, 7p |
| Abstrakt: |
Two novel series of iodinated N-substituted analogs of 2β-carbomethoxy-3β-(4-iodophenyl)tropane (β-CIT) and N-(3-iodoprop-(2E)-enyl)-2β-carbomethoxy-3β-(3,4-disubstituted phenyl)nortropane were synthesized. They were evaluated for their inhibitory properties on dopamine (DAT), serotonin (5-HTT), and norepinephrine (NET) transporters in rat brain homogenates using [3H]GBR-12935, [3H]paroxetine, and [3H]nisoxetine as specific ligands. All new N-substituted analogs of β-CIT exhibited higher DAT selectivity over both 5-HTT and NET than β-CIT. Moreover compounds with the N-substituents propynyl (6), crotyl (4), 2-bromoprop-(2E)-enyl (5), and 3-iodoprop-(2E)-enyl (3d) showed similar to higher DAT affinities than β-CIT (respectively 14, 15, 30, and 30 nM vs 27 nM). Compound 3d was found to be the most selective DAT agent of this series (5-HTT/DAT = 32.0 vs 0.1 for β-CIT). The N-(3-iodoprop-(2E)-enyl) chain linked to the tropane nitrogen was therefore maintained on the tropane structure, and phenyl substitution was carried out in order to improve DAT affinity. Ki values of N-(3-iodoprop-(2E)-enyl)-2β-carbomethoxy-3β-(3,4-disubstituted phenyl)nortropanes revealed that phenyl, 4-isopropyl, and 4-n-propyl derivatives weakly inhibited specific binding to DAT, whereas phenyl substitution with 4-methyl (3c), 3,4-dichloro (3b), and 4-iodo (3d) yielded high-DAT reuptake agents with increased DAT selectivity compared to β-CIT. These results demonstrate that the combination of a nitrogen and a phenyl substitution yields compounds with high affinity and selectivity for the dopamine transporter which are usable as SPECT markers for DA neurons. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
|
