High Affinity Hydroxypiperidine Analogues of 4-(2-Benzhydryloxyethyl)-1-(4-fluorobenzyl)piperidine for the Dopamine Transporter: Stereospecific Interactions in Vitro and in Vivo
| Autor: | Patrick M. Beardsley, Charles Cook, Sylesh K. Venkataraman, Clifford George, Matthew Davis, Sujit K. Ghorai, Aloke K. Dutta, Maarten E.A. Reith |
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| Rok vydání: | 2003 |
| Předmět: |
Male
Stereochemistry Dopamine Nerve Tissue Proteins In Vitro Techniques Motor Activity Crystallography X-Ray Ligands Discrimination Learning Mice Radioligand Assay Structure-Activity Relationship chemistry.chemical_compound Cocaine Dopamine Uptake Inhibitors Piperidines Drug Discovery medicine Animals Benzhydryl Compounds Dopamine transporter Cerebral Cortex Serotonin Plasma Membrane Transport Proteins Dopamine Plasma Membrane Transport Proteins Membrane Glycoproteins Norepinephrine Plasma Membrane Transport Proteins Molecular Structure Symporters biology Chemistry Membrane Transport Proteins Stereoisomerism GBR-12935 Corpus Striatum Rats Piperazine Norepinephrine transporter biology.protein Molecular Medicine Piperidine Enantiomer Carrier Proteins Reuptake inhibitor medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 46:1220-1228 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm020275k |
| Popis: | In our effort to develop high-affinity ligands for the dopamine transporter which might find potential use as cocaine medication, a polar hydroxy substituent was introduced into the piperidine ring of one of our disubstituted lead analogues derived from 1-[2-(diphenylmethoxy)-ethyl]-4-(3-phenylpropyl)piperazine (GBR 12935). Both cis- and trans-3-hydroxy derivatives were synthesized and the racemic trans isomer, (+/-)-5, was further resolved into two enantiomers. Newly synthesized compounds were characterized for their binding affinity at the dopamine, serotonin, and norepinephrine transporter systems in rat brain. The two enantiomers (+)-5 and (-)-5 exhibited marked differential affinities at the dopamine transporter with (+)-5 being 122-fold more potent than (-)-5 in inhibiting radiolabeled cocaine analogue binding (IC(50); 0.46 vs 56.7 nM) and 9-fold more active for inhibiting dopamine uptake (IC(50); 4.05 vs 38.0 nM). Furthermore, the most active (+)-5 was 22-fold more potent at the dopamine transporter compared to the standard GBR 12909. Absolute configuration of one of the enantiomers was determined unambiguously by X-ray structural analysis. In in vivo locomotor activity studies, the enantiomer (+)-5 and the racemic (+/-)-5, but not (-)-5, exhibited stimulant activity with a long duration of effect. All three compounds, (+)-5, (-)-5, and (+/-)-5, within the dose range tested, partially (50%) but incompletely (80%) produced cocaine-like responses in mice trained to discriminate 10 mg/kg ip cocaine from vehicle. Compound (-)-5 was distinctive in this regard in that, unlike (+)-5 and (+/-)-5, it did not affect locomotor activity yet, but similar to them, was able to engender (albeit incompletely) cocaine-like responses. |
| Databáze: | OpenAIRE |
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