ON IDENTIFYING A 2ND MOLECULAR ANTAGONISTIC MECHANISM OPERATIVE AT THE GLYCINE RECEPTOR

We used molecular modeling techniques to examine six reported antagoni sts of glycine with varying K-i values against strychnine. We found th e data suggest two groups operating with different mechanisms. In grou p 1 (strychnine, brucine, Pitrazepin, and bicuculline methobromide) th e antagonist contains two or three sites that can electrostatically bi nd to the three comparable groups of opposite charge in the recognitio n site where the natural neurotransmitter binds, thus opening the chlo ride channel. In addition, when in this position, the antagonist is ab le to also block the now opened chloride channel with a different port ion of its structure. In many cases, this involves an interaction betw een a carbonyl group on the antagonist and the guanidinium group of ar ginine which is part of the polypeptide segment of the outer mouth of the chloride channel (Grenningloh et al., Nature 330:25-26, 1987). In group 2 (R5135 and 1,5-diphenyl-3,7-diazaadamantan-9-ol) the antagonis t contains charged sites but when one of these molecules attaches to t he recognition site, the chloride channel is not opened. In addition, R5135 contains a carbonyl group which attaches to arginine as pointed out in the text, whereas 1,5-diphenyl-3,7-diazaadamantan-9-ol contains a phenyl group that can block the channel. (C) 1995 Wiley-Liss, Inc.