GABAA Rα1 Inhibitors

Chemical inhibitors of GABAA Rα1 operate through various modes of action to impede the receptor's regular function, which is typically to mediate inhibitory neurotransmission by allowing chloride ions to flow into neurons upon activation by GABA. Bicuculline and picrotoxin are two such inhibitors. Bicuculline competes directly with GABA by binding to its site on the GABAA Rα1, effectively blocking GABA's ability to open the chloride channel. This results in a reduction of chloride ion influx, impeding the hyperpolarization of the neuron. Picrotoxin, on the other hand, acts by occluding the chloride channel associated with GABAA Rα1. It non-selectively binds within the channel pore, preventing the chloride ions from passing through and thereby inhibiting the receptor's ability to hyperpolarize the neuron.

Other inhibitors, such as strychnine, tetracaine, and penicillin G, disrupt GABAA Rα1 function by different mechanisms. Strychnine inhibits GABAA Rα1 by non-competitively binding to the chloride channel, thereby obstructing its ionotropic activity. Tetracaine reduces the probability of the chloride channel opening by binding to the membrane-spanning regions of the receptor, which leads to a decrease in the receptor's responsiveness. Penicillin G, while its primary action is not on GABAA Rα1, can nonspecifically bind to the receptor and favor a closed state of the chloride channel, reducing its activity. Agents like FG 7142 and methaqualone modulate the receptor allosterically. FG 7142 binds to a distinct site, causing a conformational change that diminishes the receptor's response to GABA. Methaqualone also targets an allosteric site, altering the receptor structure in a way that diminishes its sensitivity to GABA. Additional inhibitors, such as TBPS, thujone, pentylenetetrazole, and sec-butanol, interfere with GABAA Rα1. TBPS binds to the picrotoxin site, preventing chloride flow, while thujone acts as a noncompetitive inhibitor likely within the channel pore. Pentylenetetrazole inhibits by antagonizing the modulatory site of GABA, and sec-butanol disrupts the receptor's lipid environment, affecting its conformation and function. Lastly, flumazenil competes at the benzodiazepine site, blocking the enhancement of GABAA Rα1 response by positive allosteric modulators.