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Schaarschmidt, Maren; Hoefner, Georg; Wanner, Klaus T. (2019): Synthesis and Biological Evaluation of Nipecotic Acid and Guvacine Derived 1,3-Disubstituted Allenes as Inhibitors of Murine GABA Transporter mGAT1. In: Chemmedchem, Vol. 14, No. 12: pp. 1135-1151
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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-{(R-a)-1-[4-([1,1 ':2 ',1 ''-terphenyl]-2-yl)buta-2,3-dien-1-yl](3R)-piperidine-3-carboxylic acid} and rac-{(S-a)-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 [H-3]GABA uptake assays was determined as pIC(50)=6.78 +/- 0.08, and the binding affinity in MS Binding Assays as pK(i)=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.