ON A MOLECULAR COMPARISON OF STRONG AND WEAK ANTAGONISTS AT THE GLYCINERGIC RECEPTOR

Using molecular modeling techniques, we studied nine glycine antagonis ts in order to try to identify the molecular descriptors that characte rize strychnine as a strong antagonist and N,N-dimethyl-muscimol, iso- THIA, THIA, N-methyl-THIP, iso-THAZ, THAZ, iso-THPO, and iso-THAO (see Experimental for chemical names) as weak glycine antagonists, We conf irm that all nine compounds have the three-atom regions (two negative and one positive) that we have postulated are necessary to permit such compounds to attach to the recognition site in the glycinergic synaps e, Furthermore, in the case of antagonists we have postulated the pres ence of a fourth atom that can attach to the top of the chloride ion c hannel, Each of the nine antagonists has such a fourth negative atom a nd the latter property gives each of these compounds their antagonisti c characteristic, Further, only in the case of strychnine is there evi dence that at its positively charged end does the positive charge exte nd to cover a region that could bind through electrostatic domains to a tertiary carboxyl group in an amino acid like aspartate, Published m olecular biological data show that such an amino acid is present in th e portion of the polypeptides identified in the glycine receptor, The bidentate binding is superior to the single site attachment that is pr esent in the other eight weak glycine antagonists, In addition, the tw o negative atom sites in each antagonist are also in a position to par ticipate in electrostatic binding through bidentate involvement with t he positively charged guanidinium group of arginine, The latter amino acid also has been identified in the portion of the polypeptide chain at the glycine receptor, Finally, our molecular data predict that afte r strychnine, the eight weak glycine antagonists listed above are in o rder of decreasing potency, i.e., N,N-dimethyl-muscimol is the best of the weak antagonists and iso-THAO should be the weakest. (C) 1995 Wil ey Liss, Inc.