Synthesis and Biological Evaluation of Nipecotic Acid and Guvacine Derived 1,3‐Disubstituted Allenes as Inhibitors of Murine GABA Transporter mGAT1

Abstract

A new class of nipecotic acid and guvacine derivatives has been synthesized and characterized for their inhibitory potency at mGAT1–4 and binding affinity for mGAT1. Compounds of the described class are defined by a four‐carbon‐atom allenyl spacer connecting the nitrogen atom of the nipecotic acid or guvacine head with an aromatic residue. Among the compounds investigated, the mixture of nipecotic acid derivatives rac‐{(Ra)‐1‐[4‐([1,1′:2′,1′′‐terphenyl]‐2‐yl)buta‐2,3‐dien‐1‐yl](3R)‐piperidine‐3‐carboxylic acid} and rac‐{(Sa)‐1‐[4‐([1,1′:2′,1′′‐terphenyl]‐2‐yl)buta‐2,3‐dien‐1‐yl](3R)‐piperidine‐3‐carboxylic acid} (21 p), possessing an o‐terphenyl residue, was identified as highly selective and the most potent mGAT1 inhibitor in this study. For the (R)‐nipecotic acid derived form of 21 p, the inhibitory potency in [3H]GABA uptake assays was determined as pIC50=6.78±0.08, and the binding affinity in MS Binding Assays as pKi=7.10±0.12. The synthesis of the designed compounds was carried out by a two‐step procedure, generating the allene moiety via allenylation of terminal alkynes which allows broad variation of the terminal phenyl and biphenyl subunit.

Synthesis of Functionalized Tetrasubstituted Allenes by the Addition of Bis(trimethylsilyl)ketene Acetals to Ynones Catalyzed by Gold(I)

“…Over the years, research on allene chemistry has continuously grown and evolved, as these compounds are highly versatile and present in various natural products, bioactive compounds, and drugs . Allenes are recognized as crucial precursors to more complex organic compounds .…”

Synthesis and biological evaluation of novel N-substituted nipecotic acid derivatives with tricyclic cage structures in the lipophilic domain as GABA uptake inhibitors

“…In order to increase lipophilicity and BBB permeation di-and triaryl residues were added via a linker to the amino nitrogen of the parent compounds. GAT inhibitors of this general structure have been synthesized in large numbers and broad structural diversity [27][28][29][30][31][32][33]. This includes the most prominent GAT inhibitor Tiagabine 6, a mGAT1 selective inhibitor, which is used in the treatment of epileptic seizures [34,35].…”