The effects of the enantiomers of a number of flexible and cis-constrained GABA analogues were tested on GABA C receptors expressed in Xenopus laevis oocytes using two-electrode voltage-clamp electrophysiology. (1S,2R)-cis-2-Aminomethylcyclopropane-1-carboxylic acid ((+)-CAMP), a potent and full agonist at the ρ1 (EC 50 ≈40μM, I max ≈100%) and ρ 2 (EC 50 ≈17μM, I max ≈100%) receptor subtypes, was found to be a potent partial agonist at ρ3 (EC 50 ≈28μM, I max ≈70%). (1R,2S)-cis-2-Aminomethylcyclopropane-1-carboxylic acid ((−)-CAMP), a weak antagonist at human ρ1 (IC 50 ≈890μM) and ρ2 (IC 50 ≈400μM) receptor subtypes, was also found to be a moderately potent antagonist at rat ρ3 (IC 50 ≈180μM). Similarly, (1R,4S)-4-aminocyclopent-2-ene-1-carboxylic acid ((+)-ACPECA) was a full agonist at ρ1 (EC 50 ≈135μM, I max ≈100%) and ρ2 (EC 50 ≈60μM, I max ≈100%), but only a partial agonist at ρ3 (EC 50 ≈112μM, I max ≈37%), while (1S,4R)-4-aminocyclopent-2-ene-1-carboxylic acid ((−)-ACPECA) was a weak antagonist at all three receptor subtypes (IC 50 >>300μM). 4-Amino-(S)-2-methylbutanoic acid ((S)-2MeGABA) and 4-amino-(R)-2-methylbutanoic acid ((R)-2MeGABA) followed the same trend, with (S)-2MeGABA acting as a full agonist at the ρ1 (EC 50 ≈65μM, I max ≈100%), and ρ2 (EC 50 ≈20μM, I max ≈100%) receptor subtypes, and a partial agonist at ρ3 (EC 50 ≈25μM, I max ≈90%). (R)-2MeGABA, however, was a moderately potent antagonist at all three receptor subtypes (IC 50 ≈16μM at ρ1, 125μM at ρ2 and 35μM at ρ3). On the basis of these expanded biological activity data and the solution-phase molecular structures obtained at the MP2/6-31+G* level of ab initio theory, a rationale is proposed for the genesis of this stereoselectivity effect.