Antagonist properties of arylaminopyridazine GABA derivatives at the Ascaris muscle GABA receptor.
1. In a previous study, it was shown that the potency order for two arylamino-pyridazine derivatives, SR95531 and SR95103, was different in Ascaris suum when compared to vertebrate preparations. SR95531, the most potent analogue at the vertebrate GABAA receptor, was found to be very weak at antagonizing GABA responses in Ascaris, but SR95103, approximately 20 times less potent than SR95531 in vertebrate preparations, was more potent than SR95531 in Ascaris. These results suggested the existence of different accessory binding sites at the Ascaris GABA receptor. 2. To test this hypothesis, the effects of a series of arylaminopyridazine derivatives of GABA on the GABA response in Ascaris suum muscle were investigated using a two-microelectrode current-clamp technique. 3. The results showed that SR42627, a potent antagonist at the GABAA receptor, was one of the weakest analogues in Ascaris muscle. In contrast, SR95132, virtually inactive in vertebrate preparations, was equipotent to SR95103, the most potent analogue of the series in Ascaris muscle. 4. The three most potent analogues in Ascaris, SR95103, SR95132 and SR42666, displace GABA dose-response curves to the right without decreasing the maximal response. The modified Schild plots for these compounds are consistent with a competitive mechanism involving two molecules of GABA and only one molecule of antagonist interacting with the receptor. The estimated dissociation constants for SR95103, SR95132 and SR42666 are, respectively, 64, 65 and 105 mumol l-1. 5. Structure-activity relationships for this series of compounds were examined in Ascaris and compared to those in vertebrates. Substitution on the pyridazine ring in the 4-position, while detrimental for the antagonist potency at the vertebrate GABAA receptor, appears to be a prerequisite for antagonistic activity on the Ascaris muscle GABA receptor. These results are interpreted in terms of the accessory binding site theory of Ariëns, and suggest the existence of different accessory binding sites on the Ascaris GABA receptor.
Duittoz
A H
AH
Department of Preclinical Veterinary Sciences, University of Edinburgh, Summerhall.
Martin
R J
RJ
D000818:Animals; D001200:Ascaris / Q000502:physiology*; D004553:Electric Conductivity / Q000187:drug effects; D018756:GABA Antagonists; D009132:Muscles / Q000187:drug effects* / Q000502:physiology; D011724:Pyridazines / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000502:physiology*; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D018756:GABA Antagonists; D011724:Pyridazines; D011963:Receptors, GABA-A; C044796:2-(carboxy-3'-propyl)-3-amino-4-methyl-6-phenylpyridazinium chloride