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QSAR study and synthesis of new phenyltropanes as ligands of the dopamine transporter (DAT).

QSAR study and synthesis of new phenyltropanes as ligands of the dopamine transporter (DAT).

Bioorganic & medicinal chemistry (2012-02-04)

Sylvie Mavel, Zoya Mincheva, Nathalie Méheux, Yvan Carcenac, Denis Guilloteau, Mohamed Abarbri, Patrick Emond

ABSTRACT

The dopamine transporter (DAT) plays a pivotal role in the regulation of dopamine neurotransmission, and is involved in a number of physiological functions and brain disorders. Furthermore the DAT analysis by molecular imaging techniques is a useful tool for the diagnosis and follow up treatment of diseases involving the DAT. In order to predict the affinity of new derivatives for the DAT, different QSAR molecular modeling models based on cocaine were compared. We have evaluated in these models tropane derivatives synthesized with original synthons which coupled properties of both fluorine and iodine atoms. One compound showed a high in vitro affinity and selectivity for the DAT (K(i)=0.87±0.04 nM). This compound should be radiolabeled with radioiodine for further investigations by SPECT.

MATERIALS

Product Number

Brand

Product Description

Sigma-Aldrich

Toluene, ACS reagent, ≥99.5%

Sigma-Aldrich

Toluene, ACS reagent, ≥99.5%

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Toluene, ACS reagent, ≥99.5%

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Pyridine, biotech. grade, ≥99.9%

Supelco

Biphenyl, PESTANAL^®, analytical standard

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Thymol, meets analytical specification of Ph. Eur., BP, NF, 99-101%

Supelco

Melting point standard 79-81°C, analytical standard

Sigma-Aldrich

Phenol, BioUltra, for molecular biology, TE-saturated, ~73% (T)

Sigma-Aldrich

Phenol, BioUltra, for molecular biology, ≥99.5% (GC)

Supelco

Phenol solution, 100 μg/mL in acetonitrile, PESTANAL^®, analytical standard

Sigma-Aldrich

Thymol, FCC, FG

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Phenol solution, 5000 μg/mL in methanol, certified reference material

Supelco

Phenol, PESTANAL^®, analytical standard

Supelco

Toluene, analytical standard

Sigma-Aldrich

Phenol, puriss. p.a., ACS reagent, reag. Ph. Eur., 99.0-100.5%

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2-Naphthol, BioXtra, ≥99.0% (GC)

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Phenol, unstabilized, purified by redistillation, ≥99%

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Biphenyl, ≥99%

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Phenol, ≥99%

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Biphenyl, ReagentPlus^®, 99.5%

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2-Naphthol, 98%

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Thymol, ≥98.5%

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Phenol solution, BioReagent, Saturated with 0.01 M citrate buffer, pH 4.3 ± 0.2, for molecular biology

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Phenol, for molecular biology

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Liquified Phenol, ≥89.0%

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Phenol, BioXtra, ≥99.5% (GC)

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Toluene, HPLC Plus, for HPLC, GC, and residue analysis, ≥99.9%

Sigma-Aldrich

2-Naphthol, 99%

Sigma-Aldrich

Pyridine, ≥99%

Supelco

Phenol solution, certified reference material, 500 μg/mL in methanol