Synthesis and In Silico Evaluation of GABA, Pregabalin and Baclofen N-Heterocyclic Analogues as GABAB Receptor Agonists

γ-amino butyric acid (GABA) is an inhibitory neurotransmitter whose deficiency has been associated with various neurological disorders. However, its low liposolubility limits its use as a supplement. Thus, multiple investigations have focused on searching for lipophilic GABA analogs that can modulate the activity of the GABAB receptor, which could be associated with the etiology of some central nervous system disorders. The GABA analogs available on the market are Vigabatrin, Gabapentin as well as Pregabalin and Baclofen. In this work, we report on the synthesis of GABA analogs, taking the scaffold of GABA, Pregabalin, and Baclofen as a starting point. The analogs include structural features that could favor the affinity of the molecules for the GABAB receptor, such as heterocyclic rings in the γ-position and alkyl or p-Cl-phenyl substituents (in analogy to Pregabalin and Baclofen, respectively). These analogs were synthesized by a sequence of reactions involving an N-alkylation, a 1,4-conjugated addition of dialkyl and diarylcuprates and a basic hydrolysis. Furthermore, a computational molecular docking over the GABAB receptor was performed to evaluate the interaction of each compound in the Baclofen binding site. With this information, we evaluated our compounds as GABAB agonists through a QSAR analysis. Finally, by means of molecular similarity analysis, and in silico ADME prediction, we support our three best compounds (8a–b, 8d) as potential GABAB receptor agonists.