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.

journal_name

J Neurochem

authors

Krogsgaard-Larsen P,Hjeds H,Curtis DR,Leah JD,Peet MJ

doi

10.1111/j.1471-4159.1982.tb12573.x

subject

Has Abstract

pub_date

1982-11-01 00:00:00

pages

1319-24

issue

5

eissn

0022-3042

issn

1471-4159

journal_volume

39

pub_type

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