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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. 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±8.7 μM) > cis‐4‐aminocrotonic acid (CACA; EC50=139.4±5.2 μM). 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). 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. 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. British Journal of Pharmacology (2002) 135, 883–890; doi:10.1038/sj.bjp.0704432

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, β-alanine and taurine were evaluated at human ρ 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 μM) and guanidinoacetic acid (IC 50  = 5.4 μM; K B  = 7.75 μM [p K B  = 5.11 ± 0.06]) were the most potent being competitive antagonists at this receptor. In contrast, the β-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.

Issue Title: Special Issue in Honor of Dr. Graham A. R. Johnston. Guest Editors: Philip M. Beart, Vladimir J. Balcar GABAC 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, β-alanine and taurine were evaluated at human ρ1GABAC 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 (IC50 = 2.2 μM) and guanidinoacetic acid (IC50 = 5.4 μM; K B = 7.75 μM [pK B = 5.11 ± 0.06]) were the most potent being competitive antagonists at this receptor. In contrast, the β-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.

GABA sub(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, beta -alanine and taurine were evaluated at human rho sub(1)GABA sub(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 sub(50)=2.2 mu M) and guanidinoacetic acid (IC sub(50)=5.4 mu M; K sub(B)=7.75 mu M [pK sub(B)=5.11 plus or minus 0; 0.06]) were the most potent being competitive antagonists at this receptor. In contrast, the beta -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.

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, beta-alanine and taurine were evaluated at human rho(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 microM) and guanidinoacetic acid (IC(50) = 5.4 microM; K (B) = 7.75 microM [pK (B) = 5.11 +/- 0.06]) were the most potent being competitive antagonists at this receptor. In contrast, the beta-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.

1. This study investigated the effects of a number of GABA analogues on rat rho3 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 microM) (+)-trans-3-aminocyclopentanecarboxylic acids ((+)-TACP; EC(50)=2.7 +/- 0.9 microM) trans-4-aminocrotonic acid (TACA; EC(50)=3.8 +/-0.3 microM) GABA (EC(50)=4.0 +/- 0.3 microM) > thiomuscimol (EC(50)=24.8 +/- 2.6 microM) > (+/-)-cis-2-aminomethylcyclopropane-carboxylic acid ((+/-)-CAMP; EC(50)=52.6 +/-8.7 microM) > cis-4-aminocrotonic acid (CACA; EC(50)=139.4 +/- 5.2 microM). 3. The potency order of antagonists was (+/-)-trans-2-aminomethylcyclopropanecarboxylic acid ((+/-)-TAMP; K(B)=4.8+/-1.8 microM) (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA; K(B)=4.8 +/-0.8 microM) > (piperidin-4-yl)methylphosphinic acid (P4MPA; K(B)=10.2+/-2.3 microM) 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP; K(B)=10.2+/-0.3 microM) imidazole-4-acetic acid (I4AA; K(B)=12.6+/-2.7 microM) > 3-aminopropylphosphonic acid (3-APA; K(B)=35.8+/-13.5 microM). 4. trans-4-Amino-2-methylbut-2-enoic acid (2-MeTACA; 300 microM) 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 rho3 GABA(C) receptors. 5. 2-MeTACA affects rho1 and rho2 but not rho3 GABA(C) receptors. In contrast, (plus minus)-TAMP is a partial agonist at rho1 and rho2 GABA(C) receptors, while at rat rho3 GABA(C) receptors it is an antagonist. Thus, 2-MeTACA and (+/-)-TAMP could be important pharmacological tools because they may functionally differentiate between rho1, rho2 and rho3 GABA(C) receptors in vitro.

1. This study investigated the effects of a number of GABA analogues on rat rho3 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 microM) (+)-trans-3-aminocyclopentanecarboxylic acids ((+)-TACP; EC(50)=2.7 +/- 0.9 microM) trans-4-aminocrotonic acid (TACA; EC(50)=3.8 +/-0.3 microM) GABA (EC(50)=4.0 +/- 0.3 microM) > thiomuscimol (EC(50)=24.8 +/- 2.6 microM) > (+/-)-cis-2-aminomethylcyclopropane-carboxylic acid ((+/-)-CAMP; EC(50)=52.6 +/-8.7 microM) > cis-4-aminocrotonic acid (CACA; EC(50)=139.4 +/- 5.2 microM). 3. The potency order of antagonists was (+/-)-trans-2-aminomethylcyclopropanecarboxylic acid ((+/-)-TAMP; K(B)=4.8+/-1.8 microM) (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA; K(B)=4.8 +/-0.8 microM) > (piperidin-4-yl)methylphosphinic acid (P4MPA; K(B)=10.2+/-2.3 microM) 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP; K(B)=10.2+/-0.3 microM) imidazole-4-acetic acid (I4AA; K(B)=12.6+/-2.7 microM) > 3-aminopropylphosphonic acid (3-APA; K(B)=35.8+/-13.5 microM). 4. trans-4-Amino-2-methylbut-2-enoic acid (2-MeTACA; 300 microM) 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 rho3 GABA(C) receptors. 5. 2-MeTACA affects rho1 and rho2 but not rho3 GABA(C) receptors. In contrast, (plus minus)-TAMP is a partial agonist at rho1 and rho2 GABA(C) receptors, while at rat rho3 GABA(C) receptors it is an antagonist. Thus, 2-MeTACA and (+/-)-TAMP could be important pharmacological tools because they may functionally differentiate between rho1, rho2 and rho3 GABA(C) receptors in vitro.