receptor complex and modulate the effect of first order modulators. open channel blockers: prolong ligand-receptor occupancy, activation kinetics and cl ion flux in a subunit configuration-dependent and sensitization-state dependent manner. non-competitive channel blockers: bind to or near the central pore of the receptor complex and directly block cl− conductance through the ion channel. examples orthosteric agonists: gaba, gaboxadol, isoguvacine, muscimol, progabide, beta-alanine, taurine, piperidine-4-sulfonic acid (partial agonist). orthosteric antagonists: bicuculline, gabazine. positive allosteric modulators: barbiturates, benzodiazepines, certain carbamates (ex. carisoprodol, meprobamate, lorbamate), honokiol, magnolol, baicalin, baicelin, thienodiazepines, alcohol (ethanol), etomidate, glutethimide, kavalactones, meprobamate, quinazolinones (ex. methaqualone, etaqualone, diproqualone), neuroactive steroids, niacin/niacinamide, nonbenzodiazepines (ex. zolpidem, eszopiclone), propofol, stiripentol, theanine, valerenic acid, volatile/inhaled anesthetics, lanthanum, and riluzole. negative allosteric modulators: flumazenil, ro15-4513, sarmazenil, pregnenolone sulfate, amentoflavone, and zinc. inverse allosteric agonists: beta-carbolines (ex. harmine, harmaline, tetrahydroharmine). second-order modulators: (−)‐epigallocatechin‐3‐gallate. non-competitive channel blockers: cicutoxin, oenanthotoxin, pentylenetetrazol, picrotoxin, thujone, and lindane. effects ligands which contribute to receptor activation typically have anxiolytic, anticonvulsant, amnesic, sedative, hypnotic, euphoriant, and muscle relaxant properties. some such as muscimol and the z-drugs may also be hallucinogenic. ligands which decrease receptor activation usually have opposite effects, including anxiogenesis and convulsion. some of the subtype-selective negative allosteric modulators such as α5ia are being investigated for their nootropic effects, as well as treatments for the unwanted side effects of other gabaergic drugs. novel drugs a useful property of the many benzodiazepine site allosteric modulators is that they may display selective binding to particular subsets of receptors comprising specific subunits. this allows one to determine which gabaa receptor subunit combinations are prevalent in particular brain areas and provides a clue as to which subunit combinations may be responsible for behavioral effects of drugs acting at gabaa receptors. these selective ligands may have pharmacological advantages in that they may allow dissociation of desired therapeutic effects from undesirable side effects. few subtype selective ligands have gone into clinical use as yet, with the exception of zolpidem which is reasonably selective for α1, but several more selective compounds are in development such as the α3-selective drug adipiplon. there are many examples of subtype-selective compounds which are widely used in scientific research, including: cl-218,872 (highly α1-selective agonist) bretazenil (subtype-selective partial agonist) imidazenil and l-838,417 (both partial agonists at some subtypes, but weak antagonists at others) qh-ii-066 (full agonist highly selective for α5 subtype) α5ia (selective inverse agonist for α5 subtype) sl-651,498 (full agonist at α2 and α3 subtypes, and as a partial agonist at α1 and α5 3-acyl-4-quinolones: selective for α1 over α3 paradoxical reactions there are multiple indications that paradoxical reactions upon – for example – benzodiazepines, barbiturates, inhalational anesthetics, propofol, neurosteroids, and alcohol are associated with structural deviations of gabaa receptors. the combination of the five subunits of the receptor (see images above) can be altered in such a way that for example the receptor's response to gaba remains unchanged but the response to one of the named substances is dramatically different from the normal one. there are estimates that about 2–3 % of the general population may suffer from serious emotional disorders due to such receptor deviations, with up to 20% suffering from moderate disorders of this kind. it is generally assumed that the receptor alterations are, at least partly, due to genetic and also epigenetic deviations. there are indication that the latter may be triggered by, among other factors, social stress or occupational burnout.