title: On a molecular comparison of strong and weak antagonists at the glycinergic receptor.
abstract: Using molecular modeling techniques, we studied nine glycine antagonists in order to try to identify the molecular descriptors that characterize 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 confirm 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 synapse. Furthermore, in the case of antagonists we have postulated the presence of a fourth atom that can attach to the top of the chloride ion channel. Each of the nine antagonists has such a fourth negative atom and the latter property gives each of these compounds their antagonistic characteristic. Further, only in the case of strychnine is there evidence that at its positively charged end does the positive charge extend to cover a region that could bind through electrostatic domains to a tertiary carboxyl group in an amino acid like aspartate. Published molecular biological data show that such an amino acid is present in the portion of the polypeptides identified in the glycine receptor. The bidentate binding is superior to the single site attachment that is present in the other eight weak glycine antagonists. In addition, the two negative atom sites in each antagonist are also in a position to participate in electrostatic binding through bidentate involvement with the 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 after strychnine, the eight weak glycine antagonists listed above are in order of decreasing potency, i.e., N,N-dimethyl-muscimol is the best of the weak antagonists and iso-THAO should be the weakest.
authors.affiliation: Section of Applied and Theoretical Neurobiology, Indiana University Medical Center, Indianapolis 46202, USA.
authors.forename: M H
authors.initials: MH
authors.lastname: Aprison
authors.forename: E
authors.initials: E
authors.lastname: Galvez-Ruano
authors.forename: K B
authors.initials: KB
authors.lastname: Lipkowitz
mesh_terms: D001381:Azepines / Q000737:chemistry; D001665:Binding Sites; D005998:Glycine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000737:chemistry*; D007555:Isoxazoles / Q000737:chemistry; D008956:Models, Chemical; D008958:Models, Molecular; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D013331:Strychnine / Q000737:chemistry*
chemical_list: D001381:Azepines; D007555:Isoxazoles; D018009:Receptors, Glycine; C038164:5,6,7,8-tetrahydro-4H-isoxazolo(4,5-d)azepin-3-ol; C073462:5,6,7,8-tetrahydro-4H-isoxazolo(4,3-c)azepin-3-ol; D013331:Strychnine; D005998:Glycine