Identifying agonistic and antagonistic mechanisms operative at the GABA receptor

Journal of Neuroscience Research
E Galvez-RuanoK B Lipkowitz

Abstract

Based on our molecular modeling investigations of the glycinergic receptor, we expanded our studies to similarly investigate the GABAergic receptor. New data suggest there may exist a slightly different agonistic mechanism for the molecules described herein as compared to glycine. The origin of this is undoubtedly the fact that, while glycine has a positive and two negative binding sites, it is significantly shorter than GABA and the other GABA agonists. Clearly, discovery of more glycine agonists is needed to further clarify this point. Moreover, we find a remarkedly different antagonistic mechanism exists for this phylogenetically newer inhibitory system in the central nervous system (CNS) than recently reported for strychnine and eight weaker glycine antagonists. We used GABA and six agonists (muscimol, dihydromuscimol, THIP, isoguvacine, trans-3-aminocyclopentane-1-carboxylic acid, piperidine-4-sulfonic acid) and five antagonists (bicuculline-N15-methobromide, R5135, pitrazepin, iso-THAZ and securinine) to derive our conclusions. We found that each of the agonists have three clearly defined atoms that can serve as attachment points at the GABAA receptor site. One of the three attachment atoms includes a carbonyl or carboxyl...Continue Reading

References

Jan 1, 1992·Journal of Neuroscience Research·M H Aprison, K B Lipkowitz
Jun 1, 1989·Journal of Neuroscience Research·M H Aprison, K B Lipkowitz
Mar 18, 1985·Brain Research·J A BeutlerS J Enna
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Aug 11, 1981·Molecular and Cellular Biochemistry·P Krogsgaard-Larsen, E Falch
Apr 6, 1984·Neuroscience Letters·B H GähwilerH J Wüthrich
Aug 15, 1995·Journal of Neuroscience Research·E Galvez-RuanoM H Aprison
Jun 1, 1995·Journal of Neuroscience Research·M H AprisonK B Lipkowitz
Feb 15, 1995·Journal of Neuroscience Research·M H AprisonK B Lipkowitz

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Citations

Feb 1, 1996·Journal of Neuroscience Research·M H AprisonK B Lipkowitz
Jul 27, 1999·Pharmacology, Biochemistry, and Behavior·A C FerrazC Da Cunha
Mar 2, 2010·Chemical & Pharmaceutical Bulletin·Guo-cai WangWen-cai Ye
Aug 21, 2015·Organic Letters·Heeoon Han, Amos B Smith
Dec 7, 2007·Journal of Natural Products·Ayumi OhsakiHaruaki Ishiyama
May 28, 2009·Natural Product Reports·Steven M Weinreb
Jul 9, 2014·Chemical Communications : Chem Comm·Nan MaSheng Jiang
Feb 1, 2013·Chemical Communications : Chem Comm·Hideki Miyatake-OndozabalKarl Gademann

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