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

Synthesis and Biological Evaluation of Nipecotic Acid and Guvacine Derived 1,3-Disubstituted Allenes as Inhibitors of Murine GABA Transporter mGAT1.
ChemMedChem. 2019 Apr 08;:
Authors: Schaarschmidt M, Höfner G, Wanner KT
Abstract
A new class of nipecotic acid and guvacine derivatives has been synthesized and characterized regarding 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 of the nipecotic acid or guvacine head with an aromatic residue. Among the compounds investigated, the nipecotic acid derivative 21p, possessing an o-terphenyl residue, was identified as highly selective and most potent mGAT1 inhibitor in this study. For the (R)-nipecotic acid derived form of 21p, the inhibitory potency in [3H]GABA-Uptake-Assays has been 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 that allows a broad variation of the terminal phenyl and biphenyl subunit.
PMID: 30957949 [PubMed - as supplied by publisher]

Source: ChemMedChem - April 7, 2019 Category: Chemistry Authors: Schaarschmidt M, Höfner G, Wanner KT Tags: ChemMedChem Source Type: research