title: The sensitivity of gamma-aminobutyric acid antagonists to thiocyanate is related to the absence of a functional anionic group in their structure.
abstract: Pyridazinyl derivatives of gamma-aminobutyric acid (GABA) have recently been shown to be selective, reversible and competitive GABAA antagonists. Unlike what is observed with all other GABAA antagonists, the affinity of these compounds for the GABAA receptor is not modified by thiocyanate. The chemical structure of these pyridazinyl-GABA derivatives differs from that of other GABAA antagonists by the presence of a free carboxylic group in their structure. We speculated that this could explain their lack of sensitivity to thiocyanate. Consequently, we synthesized three structural analogues of these pyridazinyl-GABA derivatives in which we replaced the free carboxyl group by a cyano group. These compounds displaced [3H]GABA from rat brain membranes and reversed the GABA-induced enhancement of [3H]diazepam binding. However their affinity for the GABAA receptor increased 10- to 20-fold in the presence of thiocyanate. Thus, sensitivity to thiocyanate appears to be related more to the absence of an anionic functional group than to the agonist or antagonist nature of the GABAA ligand.
authors.affiliation: Department de Pharmacochimie Moléculaire, Centre de Neurochimie du CNRS, Université Louis Pasteur, Strasbourg, France.
authors.forename: C G
authors.initials: CG
authors.lastname: Wermuth
authors.forename: J P
authors.initials: JP
authors.lastname: Chambon
authors.forename: M
authors.initials: M
authors.lastname: Heaulme
authors.forename: A
authors.initials: A
authors.lastname: Melikian
authors.forename: G
authors.initials: G
authors.lastname: Schlewer
authors.forename: R
authors.initials: R
authors.lastname: Leyris
authors.forename: K
authors.initials: K
authors.lastname: Biziére
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D003975:Diazepam / Q000378:metabolism; D018756:GABA Antagonists; D066298:In Vitro Techniques; D011724:Pyridazines / Q000378:metabolism*; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism; D013329:Structure-Activity Relationship; D013861:Thiocyanates / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D018756:GABA Antagonists; D011724:Pyridazines; D011963:Receptors, GABA-A; D013861:Thiocyanates; D005680:gamma-Aminobutyric Acid; C031760:thiocyanate; D003975:Diazepam