Synthesis of γ-Aminobutyric Acid (GABA) Analogues Conformationally Restricted by Bicyclo[3.1.0]hexane/hexene or [4.1.0]Heptane/heptene Backbones as Potent Betaine/GABA Transporter Inhibitors

Abstract

Novel γ-aminobutyric acid (GABA) analogues 3–5, having a bicyclo[3.1.0]­hexene, [4.1.0]­heptane, or [4.1.0]­heptene backbone, respectively, were designed from the bioactive form analysis of the previous inhibitor 2 with a bicyclo[3.1.0]­hexane backbone. Compounds 3–5 and 2 were synthesized from a common 1,7-diene intermediate 6 using ring-closing metathesis (RCM) to construct the key bicyclo backbones. Compounds 3–5 strongly inhibit betaine/GABA transporter 1 (BGT1) uptake, but compound 4 stands out with its selective low micromolar potency.