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.
Highlights
A balanced interplay between excitatory and inhibitory neurotransmission represents the fundamental basis for proper functioning of the central nervous system (CNS) in mammals
For all other species including human, dog, or rat they are denominated as GABA transporters (GATs)-1 (≡ mGAT1), BGT-1 (≡ mGAT2), GAT-2 (≡ mGAT3), and GAT-3 (≡ mGAT4) whereby the individual transporter name is provided with a prefix such as h for human to indicate the individual species
As direct precursors for the preparation of the target compounds rac-11 their carboxylic acid esters rac-19 should be employed. Their synthesis should be accomplished by linking of the tricyclic amines 14 with suitable N-substituted nipecotic acid derivatives via reductive amination (Fig. 4)
Summary
A balanced interplay between excitatory and inhibitory neurotransmission represents the fundamental basis for proper functioning of the central nervous system (CNS) in mammals. 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 cotransport of sodium and chloride ions [15, 16]. For all other species including human, dog, or rat they are denominated as GAT-1 (≡ mGAT1), BGT-1 (≡ mGAT2), GAT-2 (≡ mGAT3), and GAT-3 (≡ mGAT4) whereby the individual transporter name is provided with a prefix such as h for human to indicate the individual species This nomenclature has been adopted by the Gene Nomenclature Committee of the Human Genome Organization (HUGO) but without any Medicinal Chemistry Research (2021) 30:586–609 γ-aminobutyric acid (GABA)
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