GABAA receptor positive allosteric modulator

The GABAA receptors have historically been a target of drug treatment research. The earliest compounds were ionic compounds, such as bromide. Barbiturates In 1903, the first psychoactive derivative of barbituric acid was synthesized and marketed for headaches. Within 30 years, many other barbiturates were developed and found use as sedatives, sleep aids and general anesthetics. Although barbiturates fell out of favor, they continue to serve as a short-acting anesthetic and anti-epileptic drugs. Benzodiazepines Benzodiazepines were discovered in 1955 and largely replaced the barbiturates because of their larger therapeutic index. Neurosteroids Certain metabolites of progesterone and deoxycorticosterone are potent and selective positive allosteric modulators of the γ-aminobutyric acid type A (GABAA) receptor. Hans Selye demonstrated in 1940 that certain pregnane steroids could cause both anesthesia and sedation, 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. ==Receptor==

The GABAA receptors are made up of subunits which form a receptor complex. 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). The function of the receptor is different according to how the pentameric complex is put together. The most common complex that includes around 40% of the GABAA receptors is the α1β2γ2 combination. The expression of the subunits can be very different depending on brain region. The combination of the subunits influences how the receptor acts. For example, if the α1 and β2 subunits are expressed together they have high sensitivity to GABA, but low channel conductance. But if the γ2 is expressed with α1 and β2 the sensitivity is low and channel conductance is high. γ2 subunit has to be present for high affinity binding of benzodiazepine. Little is known about where different complexes are located in the brain, complicating drug discovery. and barbiturates bind at a beta subunit that is distinct from the benzodiazepine binding site. ==Available agents==

• Chloral hydrate (and related trichloroethanol prodrugs) • Barbiturates (e.g., barbital, phenobarbital, pentobarbital, thiopental, photoswitchable DASA-barbital) • Benzodiazepines • Nonbenzodiazepines (e.g., zaleplon, zolpidem, zopiclone) • Inhalational anesthetics (e.g., diethyl ether, halothane, isoflurane) • Etomidate • Propofol • Fluoxetine • Neurosteroids (e.g., brexanolone, zuranolone, alphaxalone (veterinary)) • Kavalactones • Ethanol • Abecarnil • Azocarnil (photoswitchable) • Caleicine (As a theorised pro-drug in Calea ternifolia) • Quinazolinone-type sedatives (methaqualone) == Applications ==

Barbiturates Barbiturates' precise action sites have not yet been defined. The second and third transmembrane domains of the β subunit appear to be critical; binding may involve a pocket formed by β-subunit methionine 286 as well as α-subunit methionine 236. Insomnia Barbiturates were introduced as hypnotics for patients with schizophrenia. It induced a state of deep and prolonged sleep. But this was not used for long because of adverse side effects. Anticonvulsant Phenobarbital was the first truly effective drug against epilepsy. It was discovered by accident when given to epileptic patients to help them sleep. The positive side effects were anticonvulsant properties that reduced seizure number and intensity. 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. Phenobarbital is used in cases of drug withdrawal syndromes. It is used as normal and emergency treatment in some cases of epilepsy. Analgesia Sedative actions of benzodiazepines limit their usefulness as analgesic agents and they are therefore generally not considered to be appropriate. This limitation can be bypassed by intrathecal administration. GABAA receptors in the periaqueductal gray are pro-nociceptive at supraspinal sites while GABAA that are found in the spinal cord are anti-hyperalgesic. Spinal α2 and α3 containing GABAA receptors are responsible for the anti-hyperalgesic action of intrathecal diazepam. This was shown when the anti-hyperalgesic action was reduced when administered in α2 and α3 mice in inflammatory pain and in neuropathic pain. 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. Schizophrenia Benzodiazepines are used as a supporting treatment in patients with schizophrenia. NMDA, and sigma receptors. The neurosteroid progesterone (PROG) that activates progesterone receptors expressed in peripheral and central glial cells. Additionally it has been surmised that the 3α-hydroxy ring A-reduced pregnane steroids allopregnanolone and tetrahydrodeoxycorticosterone increase the GABA-mediated chloride currents while pregnenolone sulfate and dehydroepiandrosterone (DHEA) sulfate on the other hand display antagonistic properties at the GABAA receptors. ==Synthesis==

Barbituric acid Barbituric acid is the parent compound of barbiturate drugs although barbituric acid itself is not pharmacologically active. Barbiturates were synthesized in 1864 by Adolf von Baeyer by combining urea and malonic acid (Figure 5). A synthesis process was later developed and perfected by French chemist Edouard Grimaux in 1879, making possible the subsequent widespread development of barbiturate derivatives. Malonic acid was later replaced by diethyl malonate, as using the ester avoids the need to deal with the acidity of the carboxylic acid and its unreactive carboxylate (see figure 6). Barbituric acid can form a large variety of barbiturate drugs by using the Knoevenagel condensation reaction. Benzodiazepines The structure that the first benzodiazepine is based on was discovered by Leo H. Sternbach. He thought the compound had a heptoxdiazine structure (Figure 7) but it was later determined to be a quinazoline-3-oxide. Possible drug candidates were then synthesized from that compound and screened for activity. One of these compounds was active, chlordiazepoxide. It was marketed in 1960 and became the first benzodiazepine drug. Biosynthesis of neurosteroids Neurosteroids are synthesized in the central nervous system (CNS) and the peripheral nervous system (PNS) from cholesterol and steroidal precursors that are imported from the peripheral sources. These sources include 3β-hydroxy-Δ5 derivatives, such as pregnenolone (PREG) and dehydroepiandrosterone (DHEA), their sulfates, and reduced metabolites such as the tetrahydro derivative of progesterone 3α-hydroxy-5α-pregnane-20-one (3α,5α-THPROG). After the local synthesis or from metabolism of adrenal of gonadal steroids many neurosteroids accumulate in the brain. ==Structure-activity relationship==

Barbiturates Barbiturates have special uses and are organized into 4 classes: ultrashort-, short-, intermediate- and long-acting. Empirically SARs of barbiturants are based on thousands of (animal) tested compounds. They have shown that R and R' may not be H in position 5 (see figure 8). Also, position 5 confer sedative-hypnotic properties. Benzodiazepines According to research performed by Maddalena et al., using artificial neural networks, position 7 has the most effect on receptor affinity. When the active group in position 7 is made more lipophilic and the electronic charge is increased the receptor affinity increases. In the same study position 2´ was found to be the second-most important in affecting the affinity, but the group in that position needs to be electrophilic to have an effect. Positions 3, 6' and 8 are of less importance. Changes to 6, 8, 9 or 4´ decrease activity. If the group in position 1 is changed to N-alkyl, haloalkyl, alkynyl and small cycle or aminoalkyl the activity is increased. Position 3 hydroxylation can cause rapid conjugation and decrease duration and potency, which can be clinically useful. Structure- activity studies (SAR) showed that the 3alpha-OH group is essential for the anesthetic actions of these steroids, they also have an optimally-placed hydrogen bond accepting group on the β face of the steroid at the C-17 position. The four steroid rings form a rigid framework for positioning these hydrogen groups in three-dimensional space. Analogues 5 and 6 (Figure 10) are weak modulators of GABAA receptor function because the flexible side chains in these analogues do not have the conformations required for high biological activity. == See also ==