trans-4-Amino-2-methylbut-2-enoic acid (2-MeTACA) and (+/-)-trans-2-aminomethylcyclopropanecarboxylic acid ((+/-)-TAMP) can differentiate rat rho3 from human rho1 and rho2 recombinant GABA(C) receptors.
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.
Vien
Jimmy
J
Department of Pharmacology, University of Sydney, NSW 2006, Australia.
Duke
Rujee K
RK
Mewett
Kenneth N
KN
Johnston
Graham A R
GA
Shingai
Ryuzo
R
Chebib
Mary
M
D000613:Aminobutyrates; D000818:Animals; D002087:Butyrates; D020148:Butyric Acid / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000494:pharmacology*; D003521:Cyclopropanes / Q000494:pharmacology*; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D021122:Protein Subunits; D051381:Rats; D018079:Receptors, GABA / Q000187:drug effects* / Q000502:physiology; D011994:Recombinant Proteins; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
C469433:2-aminomethylcyclopropanecarboxylic acid; C469431:4-Amino-2-methylbut-2-enoic acid; D000613:Aminobutyrates; D002087:Butyrates; D002264:Carboxylic Acids; D003521:Cyclopropanes; D018755:GABA Agonists; D018756:GABA Antagonists; C087200:GABA-C receptor; D007473:Ion Channels; D021122:Protein Subunits; D018079:Receptors, GABA; D011994:Recombinant Proteins; D020148:Butyric Acid