title: Isothiouronium compounds as gamma-aminobutyric acid agonists.
abstract: Analogues of gamma-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 omega-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.
mesh_terms: D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D003975:Diazepam / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007536:Isomerism; D007550:Isothiuronium / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives*; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D011963:Receptors, GABA-A; D007550:Isothiuronium; D005680:gamma-Aminobutyric Acid; D000612:4-Aminobutyrate Transaminase; D013890:Thiourea; D003975:Diazepam