Diastereoselective synthesis of ()-(3 aminocyclopentanyl)alkylphosphinic acids, conformationally restricted analogues of GABA. Organic and Biomolecular Chemistry 4

A divergent synthesis of both diastereoisomers of (±)-(3-aminocyclopentane)alkylphosphinic acid is described. Both diastereoisomers are obtained in 5 steps from the key (±)-(3-hydroxycyclopent-1-ene)alkylphosphinate esters which are prepared via a palladium catalysed C-P bond forming reaction

Guanidino Acids Act as q1 GABA C Receptor Antagonists

Abstract GABA C receptors play a role in myopia, memory-related disorders and circadian rhythms signifying a need to develop potent and selective agents for this class of receptors. Guanidino analogs related to glycine, b-alanine and taurine were evaluated at human q 1 GABA C receptors expressed in Xenopus oocytes using 2-electrode voltage clamp methods. Of the 12 analogs tested, 8 analogs were active as antagonists and the remaining were inactive. (S)-2-Guanidinopropionic acid (IC 50 = 2.2 lM) and guanidinoacetic acid (IC 50 = 5.4 lM; K B = 7.75 lM [pK B = 5.11 ± 0.06]) were the most potent being competitive antagonists at this receptor. In contrast, the b-alanine and GABA guanidino analogs showed reduced activity, indicating the distance between the carboxyl carbon and terminal nitrogen of the guanidino group is critical for activity. Substituting the C2-position of guanidinoacetic acid with various alkyl groups reduced activity indicating that steric effects may impact on activity. The results of this study contribute to the structure-activity-relationship profile required in developing novel therapeutic agents

trans-4-Amino-2-methylbut-2-enoic acid (2-MeTACA) and (±)-trans-2-aminomethylcyclopropanecarboxylic acid ((±)-TAMP) can differentiate rat ρ3 from human ρ1 and ρ2 recombinant GABA(C) receptors

1. This study investigated the effects of a number of GABA analogues on rat ρ3 GABA(C) receptors expressed in Xenopus oocytes using 2-electrode voltage clamp methods. 2. The potency order of agonists was muscimol (EC(50)=1.9±0.1 μM) (+)-trans-3-aminocyclopentanecarboxylic acids ((+)-TACP; EC(50)=2.7±0.9 μM) trans-4-aminocrotonic acid (TACA; EC(50)=3.8±0.3 μM) GABA (EC(50)=4.0±0.3 μM) > thiomuscimol (EC(50)=24.8±2.6 μM) > (±)-cis-2-aminomethylcyclopropane-carboxylic acid ((±)-CAMP; EC(50)=52.6±8.7 μM) > cis-4-aminocrotonic acid (CACA; EC(50)=139.4±5.2 μM). 3. The potency order of antagonists was (±)-trans-2-aminomethylcyclopropanecarboxylic acid ((±)-TAMP; K(B)=4.8±1.8 μM) (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA; K(B)=4.8±0.8 μM) > (piperidin-4-yl)methylphosphinic acid (P4MPA; K(B)=10.2±2.3 μM) 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP; K(B)=10.2±0.3  μM) imidazole-4-acetic acid (I4AA; K(B)=12.6±2.7 μM) > 3-aminopropylphosphonic acid (3-APA; K(B)=35.8±13.5 μM). 4. trans-4-Amino-2-methylbut-2-enoic acid (2-MeTACA; 300 μM) had no effect as an agonist or an antagonist indicating that the C2 methyl substituent is sterically interacting with the ligand-binding site of rat ρ3 GABA(C) receptors. 5. 2-MeTACA affects ρ1 and ρ2 but not ρ3 GABA(C) receptors. In contrast, (±)-TAMP is a partial agonist at ρ1 and ρ2 GABA(C) receptors, while at rat ρ3 GABA(C) receptors it is an antagonist. Thus, 2-MeTACA and (±)-TAMP could be important pharmacological tools because they may functionally differentiate between ρ1, ρ2 and ρ3 GABA(C) receptors in vitro