2014
DOI: 10.1007/s11064-014-1264-8
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Abstract: Uptake of the major excitatory neurotransmitter in the CNS, (S)-glutamate, is mediated by a family of excitatory amino acid transporters (EAAT). Previously we have explored the structure-activity relationship (SAR) of a series of EAAT1 selective inhibitors, leading to the development of the potent inhibitors UCPH-101 and UCPH-102. In the present study, we set out to improve the solubility properties of these EAAT1 inhibitors with the objective to develop analogs more suited as pharmacological tools for in vivo… Show more

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Cited by 5 publications
(10 citation statements)
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“…We previously published data on the oral bioavailability and BBB penetration for the two analogues UCPH-101 [6] and UCPH-103 [8] in rats (Figure 1, Ta ble 1). No BBB penetration couldb e detected for UCPH-101 (2 h, 10 mg kg À1 ), and the brain concentration of UCPH-103a fter 2h (10 mg kg À1 )w as determined to be only 0.75 mm.W es peculated that the different abilities to penetrate the BBB could be due to the size of the R 2 substituent( 4-methoxyphenyl versus methyl).…”
Section: Resultsmentioning
confidence: 99%
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“…We previously published data on the oral bioavailability and BBB penetration for the two analogues UCPH-101 [6] and UCPH-103 [8] in rats (Figure 1, Ta ble 1). No BBB penetration couldb e detected for UCPH-101 (2 h, 10 mg kg À1 ), and the brain concentration of UCPH-103a fter 2h (10 mg kg À1 )w as determined to be only 0.75 mm.W es peculated that the different abilities to penetrate the BBB could be due to the size of the R 2 substituent( 4-methoxyphenyl versus methyl).…”
Section: Resultsmentioning
confidence: 99%
“…In the course of our previous work on the EAATs we discovered the first class of selectiveE AAT1 inhibitors [5,6] and subsequently conducted elaborate structure-activity relationship (SAR) studies to optimize the inhibitory potencies as well as the pharmacokinetic properties of this inhibitor class. [7][8][9][10] The analogue UCPH-101h as become as tandard tool compound in the EAATf ield ( Figure 1);h owever,a si td oes not penetrate the blood-brain barrier( BBB), it is not suitable for in vivo studies. [11][12][13][14] Herein we report that the close analogue UCPH-102, in contrastt oU CPH-101, is able to cross the BBB, and we present Although the selectivee xcitatory amino acid transporter subtype 1( EAAT1) inhibitor UCPH-101h as become as tandard pharmacological toolc ompound for in vitro and ex vivo studies in the EAATr esearch field, its inability to penetrate the blood-brain barrierm akes it unsuitable for in vivo studies.…”
Section: Introductionmentioning
confidence: 99%
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“…Structure-activity-relationship analyses led to the synthesis of two potent inhibitors, UCPH-101 and UCPH-102 [ 152 ]. Animal experiments have to gain information on their activity on the excitatory amino acid transporter (EAAT).…”
Section: Studies On Genetic Polymorphisms Among Military Personnelmentioning
confidence: 99%
“…[1][2][3][4] In the course of our search for subtype-selective inhibitors, as eries of highly selectiveE AAT1 inhibitors with the general formula I ( Figure 1) was discovered,w itht he most potent analogues being UCPH-101a nd UCPH-102. [5][6][7][8][9] UCPH-101 has subsequently been applieda sapharmacological tool in several studies exploring the physiological functions and therapeutic potentialinEAAT1 and other EAATs . [10][11][12][13] Six key conclusions from our previously published structureactivity relationship (SAR) studies on this class of inhibitors are: 1) An aryl or heteroaryl group is required as the R 1 substituent.…”
Section: Introductionmentioning
confidence: 99%