Isothiouronium compounds as γ‐aminobutyric acid agonists

Abstract

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; [3H]‐GABA and [3H]‐diazepam binding to rat brain membranes; and GABA uptake and transamination. For the homologous series of α‐isothiouronium alkanoic acids, maximum GABA‐mimetic activity was found at 3‐[(aminoiminomethyl)thio]propanoic acid. 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. Both isomers were moderately potent at inhibiting the uptake of [3H]‐GABA into rat brain slices. 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. 1986 British Pharmacological Society