Abstract
A new scaffold of highly potent and mGAT1-selective inhibitors has been developed. Compounds in this class are characterized by an alkyne-type spacer connecting nipecotic acid with an aromatic moiety. Preliminary evaluations made it apparent that a nipecotic acid derivative with an N-butynyl linker and a terminal 2-biphenyl residue exhibiting a binding affinity (pK(i)) of 7.61 +/- 0.03 to mGAT1 and uptake inhibition (pIC(50)) of 7.00 +/- 0.06 selective for mGAT1 could serve as a hit compound. Docking calculations for compounds based on this structure in an hGAT1 homology modeling study indicated binding affinities similar to or even higher than that of the well-known mGAT1 inhibitor tiagabine. Synthesis of the designed compounds was readily carried out by two consecutive cross-coupling reactions, giving flexible access to variously substituted biphenyl subunits. With an appropriate substitution pattern of the biphenyl moiety, the binding affinity of enantiopure (R)-nipecotic acid derivatives to mGAT1 increased to pK(i)=8.33 +/- 0.01, and the uptake inhibitory potency up to pIC(50)=7.72 +/- 0.02.
Item Type: | Journal article |
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Faculties: | Chemistry and Pharmacy > Department of Pharmacy |
Subjects: | 500 Science > 540 Chemistry |
ISSN: | 1860-7179 |
Language: | English |
Item ID: | 54487 |
Date Deposited: | 14. Jun 2018, 09:56 |
Last Modified: | 04. Nov 2020, 13:34 |