Synthesis, Pharmacology and X‐Ray Studies of Baclofen Analogues.

Baclofen (β-p-chlorophenyl-GABA) is the reference selective agonist for the bicuculline-insensitive GABAB receptor. The search for new compounds having a high affinity for the GABAB receptor is very important to clarify structural requirements. In that sense, we report the synthesis, binding studies and X-ray determinations of various 3-heteroaromatic γ-aminobutyric acids. Biochemical investigations concerning their abilities to displace [3H] muscimol (GABAA) and [3H] baclofen (GABAB) in binding studies showed that the 4-amino-3-(5-methoxybenzo[b]furan-2-yl)butanoic acid 6a (IC50 = 22.16 μM/R (−) [3H] baclofen; IC50 = 5.6 μM/RS [3H] baclofen) has a specific affinity for the GABAB receptor. The crystal structure of compounds 6a and 6b associated with computer graphics molecular superimpositions allows some structural requirements for GABAB receptor ligands to be proposed.