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| Formula | C16H21BrN2 |
| Molar mass | 321.262 g·mol−1 |
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Desformylflustrabromine (dFBr) is a monomethyltryptamine derivative which was first isolated as a secondary metabolite of the marine bryozoan Flustra foliacea . [1]
dFBr has been identified as a novel positive allosteric modulator of neuronal nicotinic acetylcholine receptor with sub-type specificity for heteromeric receptor with no effect on homomeric sub-type. [2] A recent study has been published which describes the synthesis of water-soluble salts of dFBr and its action has been confirmed as selective potentiator of α4β2 nicotinic acetylcholine receptor responses by using two-electrode voltage clamp whole cell recordings. [3] In the year 2002 it was reported that dFBr was cytotoxic on human colon cancer cell line HCT 116. [4]
Desformylflustrabromine has also been found to be a positive allosteric modulator for the α2β2 subtype of neuronal nicotinic acetylcholine receptor. Additionally it relieves the inhibition of both α2β2 and α4β2 nicotinic acetylcholine receptors by β-Amyloid (1–42) Peptide. [5] Thus desformylflustrabromine can potentially be used in the treatment of Alzheimer's disease. Many of the analogues and derivatives of dFBr are reported to have a potentiating effect on the α4β2 receptors. [6] [7]
Modulation of nicotonic acetylcholine receptor function by desformylflustrabromine has also been found to produce analgesic and anti-allodynic effects in animal models, which could potentially make it of interest for the treatment of neuropathic pain. [8] [9] Anti-addictive and pro-cognitive actions have also been demonstrated. [10] [11] Furthermore, limited experimental data suggests a potential use in treating the compulsive behaviors seen in OCD. [12]
Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral nervous system, muscle, and many other tissues of many organisms. At the neuromuscular junction they are the primary receptor in muscle for motor nerve-muscle communication that controls muscle contraction. In the peripheral nervous system: (1) they transmit outgoing signals from the presynaptic to the postsynaptic cells within the sympathetic and parasympathetic nervous system, and (2) they are the receptors found on skeletal muscle that receive acetylcholine released to signal for muscular contraction. In the immune system, nAChRs regulate inflammatory processes and signal through distinct intracellular pathways. In insects, the cholinergic system is limited to the central nervous system.
Galantamine is used for the treatment of cognitive decline in mild to moderate Alzheimer's disease and various other memory impairments. It is an alkaloid that has been isolated from the bulbs and flowers of Galanthus nivalis, Galanthus caucasicus, Galanthus woronowii, and some other members of the family Amaryllidaceae, such as Narcissus (daffodil), Leucojum aestivum (snowflake), and Lycoris including Lycoris radiata. It can also be produced synthetically.
The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Upon opening, the GABAA receptor on the postsynaptic cell is selectively permeable to chloride ions (Cl−) and, to a lesser extent, bicarbonate ions (HCO3−). Depending on the membrane potential and the ionic concentration difference, this can result in ionic fluxes across the pore. If the membrane potential is higher than the equilibrium potential (also known as the reversal potential) for chloride ions, when the receptor is activated Cl− will flow into the cell. This causes an inhibitory effect on neurotransmission by diminishing the chance of a successful action potential occurring at the postsynaptic cell. The reversal potential of the GABAA-mediated inhibitory postsynaptic potential (IPSP) in normal solution is −70 mV, contrasting the GABAB IPSP (-100 mV).
Allopregnanolone is a naturally occurring neurosteroid which is made in the body from the hormone progesterone. As a medication, allopregnanolone is referred to as brexanolone, sold under the brand name Zulresso, and used to treat postpartum depression. It is used by injection into a vein over a 60-hour period under medical supervision.
The muscle-type nicotinic receptor is a type of nicotinic acetylcholine receptor consisting of the subunit combination (α1)2β1δε (adult receptor) or (α1)2β1δγ (fetal receptor). These receptors are found in neuromuscular junctions, where activation leads to an excitatory postsynaptic potential (EPSP), mainly by increased Na+ and K+ permeability.
The alpha-4 beta-2 nicotinic receptor, also known as the α4β2 receptor, is a type of nicotinic acetylcholine receptor implicated in learning, consisting of α4 and β2 subunits. It is located in the brain, where activation yields post- and presynaptic excitation, mainly by increased Na+ and K+ permeability.
The alpha-7 nicotinic receptor, also known as the α7 receptor, is a type of nicotinic acetylcholine receptor implicated in long-term memory, consisting entirely of α7 subunits. As with other nicotinic acetylcholine receptors, functional α7 receptors are pentameric [i.e., (α7)5 stoichiometry].
Neuronal acetylcholine receptor subunit alpha-2, also known as nAChRα2, is a protein that in humans is encoded by the CHRNA2 gene. The protein encoded by this gene is a subunit of certain nicotinic acetylcholine receptors (nAchR).
In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimulus. Some of them, like benzodiazepines, are drugs. The site that an allosteric modulator binds to is not the same one to which an endogenous agonist of the receptor would bind. Modulators and agonists can both be called receptor ligands.
UB-165 is a drug which acts as an agonist at neuronal nicotinic acetylcholine receptors being a full agonist of the α3β2 isoform and a partial agonist of the α4β2* isoform. It is used to study the role of this receptor subtype in the release of dopamine and noradrenaline in the brain, and has also been used as a lead compound to derive a number of other selective nicotinic receptor ligands.
PNU-120596 is a drug that acts as a potent and selective positive allosteric modulator for the α7 subtype of neural nicotinic acetylcholine receptors. It is used in scientific research into cholinergic regulation of dopamine and glutamate release in the brain.
PNU-282,987 is a drug that acts as a potent and selective agonist for the α7 subtype of neural nicotinic acetylcholine receptors. In animal studies, it shows nootropic effects, and derivatives may be useful in the treatment of schizophrenia, although PNU-282,987 is not suitable for use in humans because of excessive inhibition of the hERG antitarget. PNU-282987 has been shown to initiate signaling that leads to adult neurogeneis in mammals.
PHA-543,613 is a drug that acts as a potent and selective agonist for the α7 subtype of neural nicotinic acetylcholine receptors, with a high level of brain penetration and good oral bioavailability. It is under development as a possible treatment for cognitive deficits in schizophrenia. It reduces excitotoxicity and protects striatal dopaminergic neurons in rat models. It also potentiates cognitive enhancement from memantine, decreases dynorphin release and inhibits GSK-B3.
The alpha-3 beta-4 nicotinic receptor, also known as the α3β4 receptor and the ganglion-type nicotinic receptor, is a type of nicotinic acetylcholine receptor, consisting of α3 and β4 subunits. It is located in the autonomic ganglia and adrenal medulla, where activation yields post- and/or presynaptic excitation, mainly by increased Na+ and K+ permeability.
Coronaridine, also known as 18-carbomethoxyibogamine, is an alkaloid found in Tabernanthe iboga and related species, including Tabernaemontana divaricata for which it was named.
SB-206553 is a drug which acts as a mixed antagonist for the 5-HT2B and 5-HT2C serotonin receptors. It has anxiolytic properties in animal studies and interacts with a range of other drugs. It has also been shown to act as a positive allosteric modulator of α7 nicotinic acetylcholine receptors. Modified derivatives of SB-206553 have been used to probe the structure of the 5-HT2B receptor.
In pharmacology, GABAA receptor positive allosteric modulators are positive allosteric modulator (PAM) molecules that increase the activity of the GABAA receptor protein in the vertebrate central nervous system.
The alpha-3 beta-2 nicotinic receptor, also known as the α3β2 receptor, is a type of nicotinic acetylcholine receptor, consisting of α3 and β2 subunits.
JNJ-39393406 is an experimental medication which is under development by Janssen Pharmaceutica, a division of Johnson & Johnson, for the treatment of depressive disorders and smoking withdrawal. It acts as a selective positive allosteric modulator of the α7 nicotinic acetylcholine receptor (nAChR). It does not act on the α4β2 or α3β4 nAChRs or the serotonin 5-HT3 receptor, and does not interact with a panel of 62 other receptors and enzymes. The drug has been found to lower the agonist and nicotine threshold for activation of the α7 nAChR by 10- to 20-fold and to increase the maximum agonist response of the α7 nAChR by 17- to 20-fold.
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