Novel γ-Aminobutyric Acid ρ₁Receptor Antagonists; Synthesis, Pharmacological Activity and Structure−Activity Relationships

Abstract

Gamma-aminobutyric acid (GABA) analogues based on 4-amino-cyclopent-1-enyl phosphinic acid ( 34- 42) and 3-aminocyclobutane phosphinic acids ( 51, 52, 56, 57) were investigated in order to obtain selective homomeric rho 1 GABA C receptor antagonists. The effect of the stereochemistry and phosphinic acid substituent of these compounds on potency and selectivity within the GABA receptor subtypes was investigated. Compounds of high potency at GABA C rho 1 receptors ( 36, K B = 0.78 microM) and selectivity greater than 100 times ( 41, K B = 4.97 microM) were obtained. The data obtained was analyzed along with the known set of GABA C rho 1 receptor-ligands, leading to the development of a pharmacophore model for this receptor, which can be used for in silico screening.

Synthesis and Biological Applications of Phosphinates and Derivatives

“…This characteristic of GABA can be utilized to provide selective ligands through the generation of conformationally restricted analogues [69]. In 2008, Hanrahan described the synthesis, the pharmacological activity and structure-activity relationships of restricted phosphinic acid analogues of γ-aminobutyric acid and investigated the three major GABA receptor subtypes [70]. The approach was to replace the carboxylic acid by a bioisostere, the phosphinic acid, known to reduce activity at GABA A receptors (Fig.…”

“…After protection of 4-hydroxycyclopentenone with TBDMSCl and subsequent reduction and trapping of the enolate intermediate as the triflate, Kumar et al formed the P-C bond using a pallado-catalyzed coupling reaction for a variety of alkyl-H-phosphinates with 2.5 mol% of Pd(PPh 3 ) 4 [70]. The alkylphosphinate esters were isolated in 76-99% yields using mild conditions.…”

Novel Cyclic Phosphinic Acids as GABAC ρ Receptor Antagonists: Design, Synthesis, and Pharmacology

“…17 (S)-4-ACPBPA 6 is the most potent and selective GABA C receptor antagonist of this series. Interestingly, (S)-4-ACPBPA 6 is a conformationally restricted analogue of the orally active GABA B/C receptor antagonist 3-aminopropyl-n-butylphosphinic acid 7 (CGP36742 or SGS742) (GABA B , GABA C , and GABA A : IC 50 = 38, 62, and 508 μM, respectively).…”

Synthesis of γ‐Aminobutyric Acid Analogs

“…Both reaction pathways proceed in moderate to good overall yield and high diastereomeric excess [389]. Similar methodology has been used for the enantioselective synthesis of the 4-amino-cyclopent-1-enyl phosphinic acid analogs from (R)-and (S)-4-(tert-butyldimethylsilyloxy)cyclopent-1-enyl trifluoromethanesulfonate [390]. Allylic bromination of ethyl cyclohex-3-ene-1-carboxylate (578) gave the unsaturated bromo ester (579) (Scheme 14.157).…”