GABA(B)-agonistic activity of certain baclofen homologues

Abstract

Baclofen (1) is a potent and selective agonist for bicuculline-insensitive GABA(B) receptors and is used clinically as an antispastic and muscle relaxant agent. In the search for new bioactive chemical entities that bind specifically to GABA(B) receptors, we report here the synthesis of certain baclofen homologues, namely (R,S)-5-amino-3-arylpentanoic acid hydrochlorides (R,S)-1a-h as well as (R,S)-5-amino-3-methylpentanoic acid [(RS)-1i] to be evaluated as GABA(B)R agonists. Compound 1a is an agonist to GABA(B) receptors with an EC₅₀ value of 46 μM on tsA201 cells transfected with GABA(B1b)/GABA(B2)/Gqz5, being the most active congener among all the synthesized compounds.

Figure 1

Chemical structures of baclofen (1), (R)-homobaclofen (2), (RS)-5-amino-2-(4-chloro- phenyl)pentanoic acid (3), 5-aminopentanoic acid (DAVA, 4) and the target compounds (RS)-1a–i.

Scheme 1

Synthesis of the target compounds 1a–d.

Scheme 2

Synthesis of the target compounds 1e–h.

Scheme 3

Synthesis of the target compound 1i.

Figure 2

Concentration-response curves of compounds 1a, 1e, 1f and (RS)-baclofen on wild type GABA_BR1b co-expressed with GABA_BR2 and the chimeric G protein Gαq-z5. The curves are representative for the average pharmacological profile of the agonists. The Ca²⁺ measurement assays were performed as described in the materials and methods section.