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Isothiouronium compounds as γ‐aminobutyric acid agonists
Author(s) -
Allan Robin D.,
Dickenson Helena W.,
Hiern Barry P.,
Johnston Graham A.R.,
Kazlauskas Rymantas
Publication year - 1986
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1986.tb10214.x
Subject(s) - muscimol , agonist , chemistry , gabaa receptor , stereochemistry , thio , receptor , propanoic acid , nipecotic acid , biochemistry , neurotransmitter
1 Analogues of γ‐aminobutyric acid (GABA) incorporating an isothiouronium salt as a replacement for a protonated amino functional group have been investigated for activity on: GABA receptors in the guinea‐pig ileum; [ 3 H]‐GABA and [ 3 H]‐diazepam binding to rat brain membranes; and GABA uptake and transamination. 2 For the homologous series of α‐isothiouronium alkanoic acids, maximum GABA‐mimetic activity was found at 3‐[(aminoiminomethyl)thio]propanoic acid. 3 Introduction of unsaturation into this compound gave two isomeric conformationally restricted analogues. The trans isomer was inactive at GABA receptors while the cis compound ((Z)‐3‐[(aminoiminomethyl)thio]prop‐2‐enoic acid (ZAPA)) was more potent than muscimol and GABA as a GABA agonist with respect to low affinity GABA receptor sites. 4 Both isomers were moderately potent at inhibiting the uptake of [ 3 H]‐GABA into rat brain slices. 5 Comparison of possible conformations of the two unsaturated isomers by interactive computer graphics modelling and comparison with muscimol has led to a plausible active conformation of ZAPA, which may be a selective and potent agonist for low affinity GABA binding sites.