Synthesis and Pharmacological Evaluation of 3-(3,4-Dichlorophenyl)-1-indanamine Derivatives as Nonselective Ligands for Biogenic Amine Transporters

Han, Yu; Kim, In Jong; Folk, J.E.; Tian, Xinrong; Rothman, Richard B.; Baumann, Michael H.; Dersch, Christina M.; Flippen‐Anderson, Judith L.; Parrish, Damon A.; Jacobson, and Arthur E.; Rice, Kenner C.

doi:10.1021/jm0305873

Cited by 59 publications

(40 citation statements)

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“…We decided to increase the steric effect by reducing the flexibility of the side chain through an additional ring. [21][22][23] The introduction of an unsaturated six-membered ring with a double bond between C2 and C3 resulted in compound 21 with a high affinity for the DAT (Ki ) 1 nM) and moderate affinity for the SERT (Ki ) 127 nM). Because 21 displayed the highest affinity for the NET (Ki ) 43 nM) in this series, it might prove useful as a prototype for compounds able to simultaneously block the DAT and the NET.…”

Section: Resultsmentioning

confidence: 99%

“…However, functional data from uptake-inhibition studies clearly suggest that 9 would be more efficacious than 11 for that purpose. The highest binding affinity for the NET was observed with a compound where the movement of the sidechain was restrained by an additional ring system (22). Although progress was made toward finding ligands able to interact with both DATs and SERTs or DATs and NETs, their affinities for the SERTs and NETs need to be increased.…”

Section: Discussionmentioning

confidence: 99%

“…4 Recently, we reported on a series of ligands that completely lacked selectivity, thus blocking all three transporter types simultaneously. 22 Compounds that vary in their transporter affinity and selectivity may help unravel the pharmacological mechanisms relevant to stimulant abuse. To further elucidate the role of the different transporter systems in cocaine reward and craving, novel ligands with different selectivities for each of the three transporter sites must be obtained.…”

Section: Introductionmentioning

confidence: 99%

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Design and Synthesis of Promiscuous High-Affinity Monoamine Transporter Ligands: Unraveling Transporter Selectivity

et al. 2006

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A series of 4-[2-[bis(4-fluorophenyl)methoxy]ethyl]-piperidines and 4-[2-[(bisphenyl)methoxy]ethyl]-piperidines with different types of substituents in the phenylpropyl side-chain were synthesized and examined for their ability to bind to the dopamine transporter (DAT), the serotonin transporter (SERT), and the norepinephrine transporter (NET). All of the compounds showed high binding affinities for the DAT in the low to subnanomolar range. Their ability to bind to the SERT and the NET, while maintaining their high affinity for the DAT, could be altered by substitution in positions C2 and C3 of the phenylpropyl side-chain. This approach gave rise to a new set of compounds with selectivity for the DAT, the DAT and the SERT, or the DAT and the NET. Six compounds (7, 9, 11, 12, 14, and 20) with relatively low SERT/DAT ratios were selected for additional study in biogenic amine uptake inhibition assays based on the biogenic amine transporter binding results. Some of the new ligands can serve as pharmacological tools to block DAT or DAT and another transporter simultaneously.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Design and Synthesis of Promiscuous High-Affinity Monoamine Transporter Ligands: Unraveling Transporter Selectivity

et al. 2006

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“…ted metabolite, N-ethylaminopropiophenone, appears to be the bioactive metabolite since this compound potently releases NE (EC 50 = 99.3 nM) with less potent effects on 5-HT release (EC 50 = 2118 nM). Interestingly, N-ethylaminopropiophenone is not a DAT substrate, but instead blocks DA reuptake (EC 50 = 1014 nM) [63]. In the case of phendimetrazine, the N-demethylated metabolite phenmetrazine potently releases NE and DA ( Table 2).…”

Section: Appetite Suppressantsmentioning

confidence: 99%

Therapeutic Potential of Monoamine Transporter Substrates

Rothman¹,

Baumann²

2006

CTMC

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Monoamine transporter proteins are targets for many psychoactive compounds, including therapeutic and abused stimulant drugs. This paper reviews recent work from our laboratory investigating the interaction of stimulants with transporters in brain tissue. We illustrate how determining the precise mechanism of stimulant drug action (uptake inhibitor vs. substrate) can provide unique opportunities for medication discovery. An important lesson learned from this work is that drugs which display equipotent substrate activity at dopamine (DA) and serotonin (5-HT) transporters have minimal abuse liability and few stimulant side-effects, yet are able to suppress ongoing drug-seeking behavior. As a specific example, we describe the development of PAL-287 (α-methylnapthylethylamine), a dual DA/5-HT releasing agent that suppresses cocaine self-administration in rhesus monkeys, without the adverse effects associated with older phenylethylamine 5-HT releasers (e.g., fenfluramine) and DA releasers (e.g., amphetamine). Our findings demonstrate the feasibility of developing non-amphetamine releasing agents as potential treatments for substance abuse disorders and other psychiatric conditions.

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“…14,[25][26][27] In contrast to the extensive structure-activity relationship (SAR) studies for DAT-selective ligands, fewer SAR studies have been focused on the discovery and development of ligands with a variety of transporter selectivity for both DAT and SERT. 14,[28][29][30][31] Novel ligands that differ in their transporter affinity and SERT:DAT ratio may help reveal the pharmacological mechanisms relevant to stimulant abuse, and also lead to an high efficacy medication for cocaine abuse, with few adverse reactions. Such a medication may also reduce the incidence of HIV infection.…”

Section: Graphical Abstract Introductionmentioning

confidence: 99%

Design and Synthesis of 2- and 3-Substituted-3-phenylpropyl Analogs of 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and 1-[2-(Diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine: Role of Amino, Fluoro, Hydroxyl, Methoxyl, Methyl, Methylene, and Oxo Substituents on Affinity for the Dopamine and Serotonin Transporters

et al. 2008

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In our search for potential cocaine-abuse therapeutic agents, novel derivatives of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909, 1) and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (GBR 12935, 2) with various substituents in positions C2 and C3 of the phenylpropyl side chain were designed, synthesized and evaluated for their ability to bind to the dopamine transporter (DAT) and the serotonin transporter (SERT). The affinities of these ligands for DAT and SERT were controlled by the position of the substituents and their electronic and steric effects. This information could help us better understand and predict the influence of structural modification, and to discover new high-affinity DAT ligands possessing a range of affinities for SERT. The C2 series showed a quite different structure-activity relationship from the C3 series. In the C2 series, the substituent in the S configuration with a lone-pair of electrons significantly enhanced the affinity for DAT, whereas the steric effect of the substituent was detrimental to DAT binding affinity. In the C3 series, neither the lone electron pair nor the steric effect of the substituent seemed to affect DAT binding affinity, while sp 2 hybridized substituents had a detrimental effect on affinity for DAT. 2-Fluoro-substituted analogs (S)-10 and (R)-10 displayed substantial enantioselectivity in transporter affinity. In the Author Manuscript series, (S)-10 had the highest DAT binding affinity and good DAT selectivity. The 2-aminosubstituted (R)-8 showed the highest SERT binding affinity in this series and essentially the same affinity for DAT (K i = 22 and 20 nM, respectively). Thus, (R)-8 might be a lead for the discovery of a dual-action transporter ligand able to simultaneously block DAT and SERT. Compounds 16 and 18, the oxygenated derivatives of 2, possessed the best selectivity for DAT (SERT/DAT ratio = 254 and 250, respectively). HHS Public Access Graphical Abstract Introduction

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Synthesis and Pharmacological Evaluation of 3-(3,4-Dichlorophenyl)-1-indanamine Derivatives as Nonselective Ligands for Biogenic Amine Transporters

Cited by 59 publications

References 21 publications

Design and Synthesis of Promiscuous High-Affinity Monoamine Transporter Ligands: Unraveling Transporter Selectivity

Design and Synthesis of Promiscuous High-Affinity Monoamine Transporter Ligands: Unraveling Transporter Selectivity

Therapeutic Potential of Monoamine Transporter Substrates

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