Studies on the neuropharmacological activity of bicuculline and related compounds.

Bicuculline and 3 chemical derivatives were assayed on a variety of biological systems. Consistent with reports of studies on other animals, some of these compounds caused convulsions in insects and blocked inhibitory postsynaptic potentials in insect muscle. They all potently inhibited mouse brain acetylcholinesterase. Bicuculline and its analogs inhibited the binding of GABA in vitro to sites in crayfish muscle membranes which have properties of receptor sites; this site of action could explain the activity of bicuculline at arthropod neuromuscular junctions. These compounds, at high concentrations (over 100 muM), also inhibited GABA uptake by mouse brain homogenates at 0 degrees C apparently non-competitively. Bicucine methyl ester inhibited GABA transport by brain at 37 degrees C, consistent with non-specific membrane effects at high concentrations of drug. These and other observations cast doubt upon the specificity of bicuculline-like compounds for action on GABA synapses, especially for in vitro studies at high drug concentrations (over 10 muM). The neuroactivity of low doses of bicuculline is apparently not explained by these in vitro effects, and could very well be due to inhibition of GABA synapses at either receptor or ionophore sites. At physiological conditions of pH and temperature, bicuculline is hydrolyzed at its lactone moiety to the less active compound bicucine; this could lead to underestimates of the biological activity of bicuculline. More stable analogs studied so far are not more potent, however.