Synthesis and receptor binding properties of 2β-alkynyl and 2β-(1,2,3-triazol)substituted 3β-(substituted phenyl)tropane derivatives

Jin, Chunyang; Navarro, Hernán A.; Carroll, F. Ivy

doi:10.1016/j.bmc.2008.04.008

Cited by 6 publications

(1 citation statement)

References 29 publications

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“…A variety of functional groups and substituents are well tolerated at 2-position of 3β-phenyltropanes without loss of high affinity for the DAT, yet the nature of the substituents at 2-position has a profound effect on the monoamine transporter selectivity. ,− We previously reported that the methyl group of the 2β- carbomethoxy substituent of cocaine can be replaced with large groups (e.g., isopropyl, cyclopropyl, phenyl, phenylethyl, etc.) without significant loss in binding affinity at the DAT .…”

Section: Resultsmentioning

confidence: 99%

Development of 3-Phenyltropane Analogues with High Affinity for the Dopamine and Serotonin Transporters and Low Affinity for the Norepinephrine Transporter

2008

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Previous studies showed that the mixed monoamine transporter inhibitor (6, RTI-112) reduced cocaine self-administration at a high level of serotonin transporter (5-HTT) occupancy with no detectable dopamine transporter (DAT) occupancy. In this study, a series of 3β-(substituted phenyl) tropane-2β-carboxylic acid methyl esters 7a-g, 3β-(4-methoxyphenyl)tropane-2β-carboxylic acid esters 8a-j, and 3β-(4-methoxyphenyl)-2β-[3-(4′-methylphenyl)isoxazol-5-yl]tropane (9) were synthesized and evaluated for their monoamine transporter binding affinities to identify potent and selective compounds for both the DAT and 5-HTT relative to the norepinephrine transporter (NET). A number of compounds showed high binding affinities for both the DAT and 5-HTT and low affinity for the NET. 3β-(4-Methoxyphenyl)tropane-2β-carboxylic acid 2-(3-iodo-4-aminophenyl)ethyl ester (8i) with an IC 50 value of 2.5 nM for the DAT and K i values of 3.5 nM and 2040 nM for the 5-HTT and NET, respectively, is the most potent and selective compound for the DAT and 5-HTT relative to the NET in this study.

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Section: Resultsmentioning

confidence: 99%

Development of 3-Phenyltropane Analogues with High Affinity for the Dopamine and Serotonin Transporters and Low Affinity for the Norepinephrine Transporter

2008

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Singular value decomposition analysis of the torsional angles of dopamine reuptake inhibitor GBR 12909 analogs: effect of force field and charges

et al. 2010

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Three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis of large, flexible molecules, such as the dopamine reuptake inhibitor GBR 12909 (1), is complicated by the fact that they can take on a wide range of closely-related conformations. The first step in the analysis is to classify the conformers into groups. Over 600 conformers each of a piperazine (2) and piperidine (3) analog of 1 were generated by random search conformational analysis using the Merck Molecular Force Field (MMFF94). Singular value decomposition (SVD) was used to group the conformers of 2 and 3 by the similarity of their non-ring torsional angles. SVD uncovered subtle differences in their conformer populations due to that fact that the conformers separate along different principal components, and ultimately to the fact that different torsional angles are the chief contributors to these components. The results were compared to our previous SVD analysis (Fiorentino, et al., Journal of Computational Chemistry, 2006, 27, 609-620) of conformer populations of 2 and 3 generated by the Tripos force field and Gasteiger-Hückel charges. Except for the dominant contribution of angle B3 to principal component 8 seen with both force fields, the angles which are chiefly responsible for the grouping of the conformers of 2 and 3 are different with both force fields. This illustrates that SVD is useful in identifying unique groupings of conformers in large data sets of flexible molecules-a first step in selecting representative conformers for 3D-QSAR modeling studies.

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Synthesis and structure–activity relationship of 3β-(4-alkylthio, -methylsulfinyl, and -methylsulfonylphenyl)tropane and 3β-(4-alkylthiophenyl)nortropane derivatives for monoamine transporters

Jin

Navarro

Carroll

2009

Bioorganic & Medicinal Chemistry

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Early studies led to the identification of 3β-(4-methoxyphenyl)tropane-2β-carboxylic acid methyl ester (5) with high affinity at the DAT (IC50 = 6.5 nM) and 5-HTT (Ki = 4.3 nM), while having much less affinity at the NET (Ki = 1110 nM). In the present study, we replaced the 4′-methoxy group of the 3β-phenyl ring with a bioisosteric 4′-methylthio group to give 7a. We also synthesized a number of 3β-(4-alkylthiophenyl)tropanes 7b-e, 3β-(4-methylsulfinylphenyl) and 3β-(4-methylsulfonylphenyl)tropane analogues 7f-h as well as the 3β-(4-alkylthiophenyl)nortropane derivatives 8-11 to further characterize the structure-activity relationship of this type of compound for binding at monoamine transporters. With exception of the 4′-methylsulfonyl analogue 7h, all the tested compounds possessed high binding affinities at the 5-HTT. The Ki values ranged from 0.19 nM to 49 nM. The 3β-(4-methylthiophenyl)tropane 7a and its N-(3-fluoropropyl) analogue 9a and N-allyl analogue 10a are the most selective compounds for the 5-HTT over the NET (NET/5-HTT = 314-364) in the series. However, none of the compounds showed selectivity similar to 5 for both the DAT and 5-HTT relative to the NET. This study provided useful SAR information for rational design of potent and selective monoamine transporter inhibitors.

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Synthesis and receptor binding properties of 2β-alkynyl and 2β-(1,2,3-triazol)substituted 3β-(substituted phenyl)tropane derivatives

Cited by 6 publications

References 29 publications

Development of 3-Phenyltropane Analogues with High Affinity for the Dopamine and Serotonin Transporters and Low Affinity for the Norepinephrine Transporter

Development of 3-Phenyltropane Analogues with High Affinity for the Dopamine and Serotonin Transporters and Low Affinity for the Norepinephrine Transporter

Singular value decomposition analysis of the torsional angles of dopamine reuptake inhibitor GBR 12909 analogs: effect of force field and charges

Synthesis and structure–activity relationship of 3β-(4-alkylthio, -methylsulfinyl, and -methylsulfonylphenyl)tropane and 3β-(4-alkylthiophenyl)nortropane derivatives for monoamine transporters

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