Structural analogues of ZAPA as GABAA agonists

Structural analogues of ZAPA, Z-3-(aminoiminomethyl)thio]prop-2-enoic acid, an isothiouronium analogue of GABA, are potent GABA_A agonists as seen in the isolated guinea-pig ileum and in the facilitation of ³H]diazepam binding to rat brain membranes. Compounds with guanidino or amidine groups replacing the amino functionality of GABA were also found to be active. The highest activity was displayed by the isothiouronium salts in which the conformational flexibility of the molecule is restricted by a Z-substituted carbon–carbon double bond. A series of bis-isothiouronium compounds was prepared from aliphatic ,ω-bis-thioureas as mixtures of E and Z adducts. Maximum GABA_A agonist activity for this series was found with a C₆–C₈ carbon chain, and the results were consistent with an interaction at the GABA_A receptor with only one end of the molecule, rather than the more potent effect expected of a molecule bridging two active sites. GABA_A antagonist/partial agonist activity was observed on the guinea-pig isolated ileum for a number of different analogue types, with the most potent being bis-isothiouronium derivatives. None of the substituted derivatives of ZAPA was as active as ZAPA itself, and maximum GABA_A activity was found in the n-pentyl and n-hexyl analogues.