Synthesis and biological evaluation of novel N -substituted nipecotic acid derivatives with tricyclic cage structures in
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Medicinal Chemistry Research https://doi.org/10.1007/s00044-020-02647-9
ORIGINAL RESEARCH
Synthesis and biological evaluation of novel N-substituted nipecotic acid derivatives with tricyclic cage structures in the lipophilic domain as GABA uptake inhibitors Heinrich-Karl A. Rudy1 Georg Höfner1 Klaus T. Wanner ●
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Received: 27 July 2020 / Accepted: 6 October 2020 © The Author(s) 2020
Abstract A new class of GABA reuptake inhibitors with sterically demanding, highly rigid tricyclic cage structures as the lipophilic domain was synthesized and investigated in regard to their biological activity at the murine GABA transporters (mGAT1–mGAT4). The construction of these compounds, consisting of nipecotic acid, a symmetric tricyclic amine, and a plain hydrocarbon linker connecting the two subunits via their amino nitrogens, was accomplished via reductive amination of a nipecotic acid derivative with an N-alkyl substituent displaying a terminal aldehyde function with tricyclic secondary amines. The target compounds varied with regard to spacer length, the bridge size of one of the bridges, and the substituents of the tricyclic skeleton to study the impact of these changes on their potency. Among the tested compounds nipecotic acid ethyl ester derivates with phenyl residues attached to the cage subunit showed reasonable inhibitory potency and subtype selectivity in favor of mGAT3 and mGAT4, respectively. Keywords GABA transporters GABA uptake inhibitor Nipecotic acid Polycycles Cage structures ●
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Introduction A balanced interplay between excitatory and inhibitory neurotransmission represents the fundamental basis for proper functioning of the central nervous system (CNS) in mammals. A disruption of this interplay due to, for example, an insufficient signaling of GABAergic neurons can lead to or intensify neurological disorders like Alzheimer’s disease (AD) [1, 2], depression [3], epilepsy [4, 5], or Parkinson’s disease (PD) [6–8]. One approach to influence the GABAergic neurotransmission and thus to treat the aforementioned diseases is to increase the release and the concentration of γ-aminobutyric acid 1 (GABA),
Supplementary information The online version of this article (https:// doi.org/10.1007/s00044-020-02647-9) contains supplementary material, which is available to authorized users. * Klaus T. Wanner [email protected] 1
Department of Pharmacy – Center for Drug Research, LudwigMaximilians-Universität München, Butenandtstraße 5-13, Haus C, D-81377 Munich, Germany
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representing the predominant inhibitory neurotransmitter in the CNS [9–11], in the synaptic cleft. As GABA is quickly removed from the synaptic cleft by reuptake into the presynaptic neurons and surrounding glia cells this may be achieved by inhibition of the GABA transporters (GATs) in charge of this process [12–14]. GATs are membrane-bound transport proteins of the solute carrier family 6. They consist of 12 transmembrane helices and translocate their substrate GABA through the cell membrane by
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