3-Thienyl- and 3-furylaminobutyric acids. Synthesis and binding GABAB receptor studies

Abstract

Baclofen (beta-(p-chlorophenyl)-GABA) is a selective agonist for the bicuculline-insensitive GABAB receptor. The search for new compounds that bind to the GABAB receptor is very important to clarify structural requirements. We report herein the synthesis and the binding studies of variously substituted 3-thienyl- and 3-furylaminobutyric acids. 4-Amino-3-(5-methyl-2-thienyl)butyric acid (5d) and 4-amino-3-(5-chloro-2-thienyl)butyric acid (5h) are potent and specific ligands for GABAB receptor. The IC50 values for the displacement of (R)-(-)-[3H]baclofen are 1.34 and 0.61 microM for 5d and 5h, respectively, as compared to 0.33 microM for baclofen.

Development of Bifunctional Thiourea Organocatalysts Derived from a Chloramphenicol Base Scaffold and their Use in the Enantioselective Alcoholysis of meso Cyclic Anhydrides

“…The synthetic utility of this method was investigated in the enantioselective synthesis of ( R )‐(−)‐baclofen, which is used widely as an antispastic agent (Scheme ) . The meso ‐anhydride 16 i was prepared, using the reported procedure, from 4‐chlorobenzaldehyde 18 in 54 % yield over three steps .…”

Molecular modelling and conformational analysis of a GABAB antagonist

“…The p-chlorophenyl moiety has been replaced by a furan, thiophen, benzo[b]furan, benzo[b]thiophen or quinoline ring [5,6]. These variations led to the discovery of specific GABAB agonists and antagonists, 3-heteroaromatic baclofen analogues [7 9].…”

“…These variations led to the discovery of specific GABAB agonists and antagonists, 3-heteroaromatic baclofen analogues [7 9]. The most potent among these exhibit ICs0 values in the micromolar range [5,6]. Previously, conformational analysis has enabled us to identify six features that are necessary for GABAB affinity of 3-heteroaromatic baclofen analogues: (i) a carboxylate group; (ii) a primary ammonium group; (iii) a mean distance between ionized moieties of about 4.6 A; (iv) an aromatic ring (phenyl, thienyl, benzo[b]furan) bound to C~; (v) a lipophilic substituent in the para position (phenyl) or in position 5 (thienyl and benzo[b]furan), a position sensitive to steric bulk; and (vi) another lipophilic substituent in position 7 (benzo[b]furan) [10].…”

The anti-spasticity drug baclofen alleviates collagen-induced arthritis and regulates dendritic cells

“…Baclofen, which is a structural analog of GABA, is a selective agonist for GABA B Rs (Fig. S1A) (Hill and Bowery, 1981;Berthelot et al, 1991;Bowery, 1993). This analog is used clinically as a muscle relaxant in patients with spasticity (Bowery, 2006).…”