Guanidino acids act as rho1 GABA(C) receptor antagonists.
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.
Chebib
Mary
M
Faculty of Pharmacy A15, The University of Sydney, Sydney, NSW 2006, Australia. maryc@pharm.usyd.edu.au
Gavande
Navnath
N
Wong
Kit Yee
KY
Park
Anna
A
Premoli
Isabella
I
Mewett
Kenneth N
KN
Allan
Robin D
RD
Duke
Rujee K
RK
Johnston
Graham A R
GA
Hanrahan
Jane R
JR
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D018756:GABA Antagonists / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000502:physiology; D006146:Guanidines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D009865:Oocytes / Q000737:chemistry / Q000378:metabolism; D011422:Propionates / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D018079:Receptors, GABA / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D013654:Taurine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism; D014982:Xenopus laevis; D015091:beta-Alanine / Q000378:metabolism
D018756:GABA Antagonists; D006146:Guanidines; D011422:Propionates; D018079:Receptors, GABA; D011994:Recombinant Proteins; C523978:rho1 GABA(C) receptor, human; D015091:beta-Alanine; D013654:Taurine; C009558:taurocyamine; C004946:glycocyamine; D005998:Glycine; C005775:guanidinopropionic acid