GABAA receptor positive allosteric modulator
GABAA PAMs increase the effect of GABA by making the channel open more frequently or for longer periods.
Examples of GABAA PAMs include ethanol, benzodiazepines such as diazepam (Valium) and alprazolam (Xanax), Z-drugs such as zolpidem (Ambien) and the barbiturate drugs.
Several efficient benzodiazepines offer choices about dosage form, length of action, metabolic interaction and safety.
[3] Certain metabolites of progesterone and deoxycorticosterone are potent and selective positive allosteric modulators of the γ-aminobutyric acid type A (GABAA) receptor.
[4] Hans Selye demonstrated in 1940 that certain pregnane steroids could cause both anesthesia and sedation,[5] but 40 years later the molecular mechanism emerged to explain their depressant effect.
In a rat brain slice preparation, the synthetic steroidal anesthetic alphaxalone (5α-pregnan-3α-ol-11,20 dione) enhanced both stimulus-evoked inhibition and the effects of exogenously applied muscimol, which is a GABAA selective agonist.
Humans have 19 receptor subunits and are classified into α (1–6), β (1–3), γ (1–3), δ, ε, π, θ, and ρ (1−3).
[14] In 2013 the barbiturates phenobarbital and butabarbital are still used as sedatives in certain cases as well as to antagonize the effects of drugs as ephedrine and theophylline.
[2] Synaptic action of benzodiazepines: GABAA receptors located at synapses are activated when they are exposed to high concentration of GABA.
Benzodiazepines enhance the receptor affinity for GABA by increasing the decay of spontaneous miniature inhibitory postsynaptic currents (mIPSC).
Additionally, studies in α5 mice showed that the spinal α5-containing GABAA receptor has a minor role in inflammatory pain.
An α2, α3 and/or α5 selective positive allosteric agonist, like L-838,417 for example, might be useful as an analgesic drug against inflammatory or neuropathic pain.
[3] Further studies in animal neuropathic pain models have shown that stabilizing the potassium chloride cotransporter 2 (KCC2) at neuronal membranes could not only potentiate the L-838,417-induced analgesia but also rescue its analgesic potential at high doses, revealing a novel strategy for analgesia in pathological pain, by combined targeting of the appropriate GABAA receptor subtypes (i.e. α2, α3) and restoring Cl− homeostasis.
Clinical studies have shown that alprazolam and adinazolam have antidepressant activities in patients with major depressive disorder.
Studies in y2 knockout mice have shown that they display increased anxiety and depressive-like symptoms in despair-based tests.
Other studies with α2 knockout mice have displayed increased anxiety and depression-like symptoms in conflict-based feeding tests.
Barbiturates were synthesized in 1864 by Adolf von Baeyer by combining urea and malonic acid (Figure 5).
In general, the more lipid-soluble the barbiturate, the more rapid its onset, the shorter its duration and the greater the degree of hypnotic activity.
[33] According to research performed by Maddalena et al., using artificial neural networks, position 7 has the most effect on receptor affinity.
If the group in position 1 is changed to N-alkyl, haloalkyl, alkynyl and small cycle or aminoalkyl the activity is increased.
[34] In the mid 1980s, the neuroactive steroids 3α,5α-tetrahydroprogesterone or allopregnanolone (3α,5α-THP) and 3α,5α-tetrahydrodeoxycorticosterone (3α,5α-THDOC) were shown to modulate neuronal excitability via their interaction with GABAA receptors.
The four steroid rings form a rigid framework for positioning these hydrogen groups in three-dimensional space.
