Sites of Action of Noncompetitive GABA Antagonists in Houseflies and Rats: Three-Dimensional QSAR Analysis
✍ Scribed by Akamatsu, Miki; Ozoe, Yoshihisa; Ueno, Tamio; Fujita, Toshio; Mochida, Kazuo; Nakamura, Toshiie; Matsumura, Fumio
- Publisher
- John Wiley and Sons
- Year
- 1997
- Tongue
- English
- Weight
- 505 KB
- Volume
- 49
- Category
- Article
- ISSN
- 1526-498X
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✦ Synopsis
Quantitative structureÈactivity relationships for insecticidal activity (against houseÑies) and competitive activity against a speciÐc [35S]tert-butylbicyclophosphorothionate binding (to rat brain membranes) of some picrotoxinin-type 4-aminobutyric acid antagonists, including c-BHC, endosulfan, bicyclophosphates, dioxatricyclododecenes and related compounds, were examined three-dimensionally using comparative molecular Ðeld analysis (CoMFA). The antagonists were classiÐed into two series according to their molecular shapes : i.e. whether their structure was "linearlyÏ extended beyond the "mast-headÏ position of the "boat-likeÏ skeletons (series 1) or not (series 2). The CoMFA showed that the slopes in steric and electrostatic Ðelds around the molecule were signiÐcant for both series in governing the potency variations in insecticidal and binding activities. Hydrophobicity, a possible factor controlling transport behaviour of compounds, was signiÐcant in governing variations in insecticidal activity, but not for the case of the rat membrane binding. Assuming that there is a slight topological di †erence between series 1 and 2 compounds in terms of the mode of binding with the houseÑy receptor site, the insecticidal activity was analysable with a single equation for the combined set of compounds, but the rat membrane binding was not. The sterically and electrostatically favourable regions surrounding the molecular series indicated by CoMFA were roughly located at positions so as to interact with the binding subsites on the receptors proposed previously.