Identification of a second glycine‐like fragment on the strychnine molecule

Abstract

Strychnine is a complex molecule that inhibits the physiological actions of glycine, an important inhibitory neurotransmitter in the spinal cord, brain stem, and other areas of many vertebrates. Since 1987, we have employed atomistic molecular modeling tools to find an explanation at the molecular level for how this antagonism works. We have located a second glycine-like fragment in the strychnine molecule that, when compared to glycine in a three pair atom analysis, provides an excellent topological and electronic charge congruence. The topological congruence in the second glycine-like fragment is much better than with the first fragment reported in 1987 when using a truncated strychnine molecule in the quantum mechanical analysis. A fourth negative atom, a characteristic of antagonists which we reported earlier (Aprison and Lipkowitz: J Neurosci Res 30:442-446, 1991; Aprison and Lipkowitz: J Neurosci Res 31:166-174, 1992) was found in strychnine. This result follows the pattern reported recently for the three weak glycine antagonists N,N-dimethylmuscimol, N-methyl-THIP, and iso-THAO, a bicyclic 5-isoxazolol zwitterion.

Agonist pharmacology of two Drosophila GABA receptor splice variants

“…Similarly, glycine-like motifs have been identified in strychnine, the competitive antagonist of inhibitory glycine receptors (Aprison et al, 1995). That mutations of GABAA receptor subunits which reduce the potency of these antagonists also reduce the potency of GABA (Sigel et al, 1992;Amin & Weiss, 1993) suggests that agonists and antagonists do indeed share a common binding site.…”

On a molecular comparison of strong and weak antagonists at the glycinergic receptor

“…In addition, in the upper left corner of Figure 1, we show the least squares fit of glycine with strychnine recently reported from our group (Aprison et al, 1995). The comparisons are based on fits of three atoms on one molecule with the corresponding three atoms on the other as depicted in the figure (the atom numbers of strychnine precede those corresponding atoms of glycine in Fig.…”

“…In the receptor we find one pendant group being negatively charged and the other being positively charged. Moreover, the positive guanidinium group in arginine (AA2 18) has two positively charged terminal nitrogens (with their attached hydrogens) that fit well with the two complementary negatively charged atoms in strychnine (N7 and C,) that we have previously proposed as two of the three binding sites (Aprison et al, 1995). Similarly charged atoms have been identified in each antagonist.…”

“…In this period we also had studied three weak glycine antagonists that were discovered by Brehm et al (1986) and Krogsgaard-Larsen et al (1982, 1983, namely Iso-THAO, N,N-dimethyl-muscimol and Nmethyl-THIP Lipkowitz, 1991, 1992). Recently we reported the location of a second glycine-like fragment on the strychnine molecule (Aprison et al, 1995). These aforementioned characteristics were found in each of the four compounds.…”

“…The left side of R-5135 contains two nitrogen atoms (N, and N,) with their associated hydrogens that are positively charged. The carbony1 oxygen (0,) corresponds to the fourth attachment site in our current theory of drug antagonism at the glycinergic receptor Lipkowitz, 1991, 1993;Aprison et al, 1995). When this molecule was superimposed on strychnine (lower portion of Fig.…”