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 GABAC receptors

Abstract

1. This study investigated the effects of a number of GABA analogues on rat ρ3 GABAC receptors expressed in Xenopus oocytes using 2-electrode voltage clamp methods. 2. The potency order of agonists was muscimol (EC50 = 1.9±0.1 μM) (+)-trans-3-aminocyclopentanecarboxylic acids ((+)-TACP; EC50=2.7±0.9 μM) trans-4-aminocrotonic acid (TACA; EC50=3.8±0.3 μM) GABA (EC50=4.0±0.3 μM) > thiomuscimol (EC50=24.8±2.6 μM) > (±)-cis-2-aminomethylcyclopropane-carboxylic acid ((±)-CAMP; EC50 = 52.6±8.7μM) > cis-4-aminocrotonic acid (CACA; EC50=139.4±5.2 μM). 3. The potency order of antagonists was (±)-trans-2-aminomethylcyclopropanecarboxylic acid ((±)-TAMP; KB=4.8±1.8 μM) (1, 2, 5, 6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA; KB=4.8±0.8 μM) > (piperidin-4-yl)methylphosphinic acid (P4MPA; KB=10.2±2.3 μm) 4, 5, 6, 7-tetrahydroisoxazolo[5, 4-c]pyridin-3-ol (THIP; KB=10.2±0.3 μM) imidazole-4-acetic acid (I4AA; KB=12.6±2.7 μM) > 3-aminopropylphosphonic acid (3-APA; KB=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 GABAC receptors. 5. 2-MeTACA affects ρ1 and ρ2 but not ρ3 GABAC receptors. In contrast, (±)-TAMP is a partial agonist at ρ1 and ρ2 GABAC receptors, while at rat ρ3 GABAC 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 GABAC receptors in vitro.