This MechoA is related to substances which modify activity of ion channels or ionotropic receptors except for nicotinic acetylcholine receptors (nAChRs) for which a dedicated MechoA class (MechoA 6.2) exists.
Substances with MechoA 6.6 may disrupt the functioning of receptors to γ-aminobutyric acid (GABA), a neurotransmitter. There are two types of GABA receptors, GABAAR and GABABR, which are directly (GABAAR) or indirectly (GABABR) responsible of the influx of chloride ions. Activation of GABAergic neurons leads to antidepressant effects like anticonvulsants, anxiolytics, sedatives and hypnotics effects (Olsen and DeLorey, 1999).
2,2,2-trichloroethanol has a GABAergic activity by binding to GABA receptors which are then more sensitive to GABA.
Neurons have also G protein-coupled receptors to opioids which trigger the opening of channels for potassium efflux and calcium influx. The activation of the opioids receptors leads to the reduction of action potential and nerve signal propagation.
Morphine and derivatives are the most known of the opioids with MechoA 6.6 (Chahl, 1996).
Some substances prevent the closing of sodium channels in neurons thus prolonging their excitation.
These are basically DDT (dichlorodiphenyltrichloroethane) and analogues like methoxychlor and pyrethroids like resmethrin, cypermethrin or tefluthrin, etc. (figure below).
Figure: Structure of DDT derivatives and pyrethroids derivatives.
Besides having impact on sodium channels, type II pyrethroids also inhibit the opening of GABAergic chloride channels and Ca-Mg-ATPase thus resulting in a modification of calcium concentration in the neuron (Coats, 1990). Moreover, various substances can modulate GABAergic calcium channels which have several different binding sites with a broad range of potential modulations (see figure below).
Figure: GABA receptor and binding sites (Olsen and DeLorey, 1999).
The binding site of 2,2,2-trichloroethanol and ethanol is uncertain (Olsen and DeLorey, 1999). Pyrethroids seem to bind to the picrotoxin site (Coats, 1990). Chlorinated alicyclic insecticides are also binding to the picrotoxin site thus preventing the channel to open and the neuron to recover its resting state. These insecticides cause death by respiratory arrest (Coats, 1990). They have various structures with a non-aromatic cycle (i.e. alicyclic) and several chlorine substituents as a common point. Some of them are presented in the figure below.
Figure: chlorinated alicyclic insecticides and picrotoxinin.
Caffeine is another example of substance which have a MechoA 6.6 because it binds to GABA receptor at benzodiazepine sites. However, this mechanism is minor for caffeine (and methylxanthines, in general) which modulates several calcium channels by activating or disactivating them depending on the dose.
Furthermore, caffeine is an antagonist of adenosine receptors leading to repression of the spontaneous neuronal electric activity, the synaptic transmission inhibition and the neurotransmitter release (Nehlig et al., 1992). Caffeine would also disrupt calcium regulation in plants, but these mechanisms are not well studied (IAC Publishing Labs, n.d.).