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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

Supelco

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

Sigma-Aldrich

Aniline, ReagentPlus^®, 99%

Sigma-Aldrich

Naphthalene, 99%

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Aniline, ACS reagent, ≥99.5%

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Bromobenzene, ≥99.5% (GC)

Supelco

Naphthalene, analytical standard

Sigma-Aldrich

Naphthalene, suitable for scintillation, ≥99%

Supelco

Aniline, analytical standard

Sigma-Aldrich

Bromobenzene, ReagentPlus^®, 99%

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Naphthalene, certified reference material, TraceCERT^®, Manufactured by: Sigma-Aldrich Production GmbH, Switzerland

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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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Liquified Phenol, ≥89.0%

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Biphenyl, PESTANAL^®, analytical standard

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

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Phenol, BioXtra, ≥99.5% (GC)

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Thymol, ≥98.5%

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Phenol solution, BioReagent, Equilibrated with 10 mM Tris HCl, pH 8.0, 1 mM EDTA, for molecular biology

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Biphenyl, ReagentPlus^®, 99.5%

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

Supelco

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

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Biphenyl, ≥99%

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Phenol, unstabilized, purified by redistillation, ≥99%

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Thymol, FCC, FG

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2-Naphthol, BioXtra, ≥99.0% (GC)

Supelco

Pyridine, analytical standard

Supelco

Toluene, analytical standard

Sigma-Aldrich

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

Supelco

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

Sigma-Aldrich

Phenol, ≥99%

Sigma-Aldrich

2-Naphthol, 98%