Glycine Antagonists Structurally Related to Muscimol, THIP, or Isoguvacine

Abstract

Microelectrophoretic methods were used to study the effects on cat spinal neurones of a number of compounds structurally related to the gamma-aminobutyric acid (GABA) agonists muscimol, THIP, and isoguvacine. While N-methylmuscimol was an agonist at bicuculline methochloride-sensitive GABA receptors, somewhat weaker than GABA and THIP, neither N,N-dimethylmuscimol nor N-methyl-THIP interfered significantly with GABA receptors in vivo or binding sites in vitro. Both N,N-dimethylmuscimol and N-methyl-THIP, however, reversibly antagonized the depressant action of glycine. The seven-membered ring analogues of THIP, namely THIA (5,6,7,8-tetrahydro-4H-isoxazolo[5,4-c]azepin-3-ol), THAZ (5,6,7,8-tetrahydro-4H-isoxazolo[4,5-d]azepin-3-ol) and iso-THAZ (5,6,7,8-tetrahydro-4H-isoxazolo[3,4-d]azepin-3-ol), also blocked neuronal inhibition by glycine, iso-THAZ being the most potent compound. The conformationally mobile isomer of THAZ and iso-THAZ, 3-PYOL (5-(3-pyrrolidinyl)-3-isoxazolol), was a much less selective glycine antagonist, being also an antagonist of GABA, 3,4-TAZA (2,5,6,7-tetrahydro-1H-azepine-4-carboxylic acid) and 4,5-TAZA (2,3,6,7-tetrahydro-1H-azepine-4-carboxylic acid), which are amino acid analogues of THIA and THAZ, respectively, and ring homologues of isoguvacine, were also shown to be glycine antagonists. The mechanism of action of the present class of zwitterionic glycine antagonists is unknown. The compounds are much less potent than strychnine.

A novel antagonist, phenylbenzene ω‐phosphono‐α‐amino acid, for strychnine‐sensitive glycine receptors in the rat spinal cord

“…Thus, glycine functions as an inhibitory transmitter and as a modulator of excitatory amino acid transmission mediated by NMDA receptors (Ottersen & Storm-Mathisen, 1990). In the case of strychnine-sensitive glycine receptors, a few antagonists including strychnine have been discovered which block selectively the actions of glycine on neurones of the mammalian CNS (Curtis et al, 1971;Krogsgaard-Larsen et al, 1982;Curtis & Malik, 1985;Simmonds & Turner, 1985;Brehm et al, 1986;Braestrup et al, 1986). …”

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

“…Hence there is now a self-consistency in the location of this fourth attachment site for all the glycine antagonists we have studied. With our present data it may now be possible to explain, using theoretical methods, why strychnine is a strong antagonist against glycine neurophysiologically, whereas the other three antagonists are much weaker, as reported by Brehm et al (1986) and Krogsgaard-Larsen et al (1982, 1983. That work is in progress and will be reported in the near future.…”

Convulsants Acting at the Inhibitory Glycine Receptor

“…A similar overlap in binding specificity exists for structural analogues of muscimol, a selective high-affinity (Ki = 5 nM; KROGSGAARD-LARSEN et al 1982) agonist at the GABAA receptor. In a series of structure-activity studies on heterocyclic muscimol derivatives, KROGSGAARD-LARSEN et al (1982) have identified structural determinants of ligand specificity for glycine and GABAA receptors. The amino group of muscimol correlates to the 4amino group of GABA; incorporation into a piperidine ring of this nitrogen generates the heterocyclic zwitterion, 4,5,6,7 -tetrahydroisoxazolo-[5 ,4-c] pyridin-3-ol (THIP) ( Fig.…”