Discovery[ edit perdi peso con le ovaie policistiche In the late s, non-selective serotonin receptor antagonists demonstrated a relationship between serotonin receptors and food intake.
Later, animal studies showed that serotonin receptor agonists might act as a mediator of satiety. Subsequently, these receptors became a promising pharmacotherapeutic target for further investigation for the treatment of obesity.
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These knockout mice were hyperphagicwhich led to obesity, partial Leptin resistance, increased adipose deposition, insulin resistance, and impaired glucose tolerance. As a result of these symptoms, the researchers identified a functional role for the receptors in serotonergic regulation of food intake and body weight.
Prior to the discovery of fenfluramine, amphetamines were the primary form of anorectic drugs available, however the side 5ht2c perdita di peso made them difficult to use. Fenfluramine's anorectic effect is achieved through an increase in serotonin levels, imparting a sensation of fullness, which leads to a lower intake of food.
Fenfluramine was sold as a racemic mixture of two enantiomersdexfenfluramine and levofenfluramine. Subsequently, reports of severe side effects associated with heart valve abnormalities and an increased risk of pulmonary hypertension resulted in a decision to remove products containing fenfluramine from the U. S market, and then from other markets around the world. Indexfenfluramine became the first long-term treatment anti-obesity medication approved in the US; adverse effects observed during clinical trials included dry mouth, diarrhea and drowsiness.
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After several reports of adverse cardiovascular effects, the FDA banned dexfenfluramine in The absence of the hypophagic reduced food consumption effect of mCPP in 5-HT2C receptor knockout mice suggests that this effect is mediated through 5-HT2C receptor activation.
Repeated administration of mCPP to humans might result in decreased food intake and weight loss. Please help improve it to make it understandable to non-expertswithout removing the technical details.
Perdita di peso 5ht2c
January Learn how and when to remove this template message Figure 1 — Mechanism of action. A hypothetical model for the agonist activation of 5-HT2C receptor. PLC metabolizes phosphatidylinositol 4,5-bisphosphate into inositol 1,4,5-triphosphate IP3. The 5-HT2C receptors can also stimulate the extracellular signal-regulated kinase ERK pathway which is activated by neurotrophins and other neuroactive chemicals. Production of these chemicals effects neuronal differentiation, survival, regenerationand structural and functional plasticity.
Early studies of the ERK pathway showed that mood stabilizers for the treatment of manic-depressive illness stimulated the pathway. This led to the understanding that stimulation of the 5-HT2C receptors could regulate manic-depressive conditions in a manner similar to mood stabilizers.
The highest density of receptor expression is within the choroid plexus. Other brain locations include the nucleus of the solitary tractdorsomedial hypothalamusparaventricular hypothalamic nucleus and the amygdalaall of which are associated with regulation of food intake.
This distribution pattern may explain the effect they have in integral function in the control of many physiological and behavioral responses, such as feeding, anxiety, temperature regulation, locomotionsexual behavior, and the occurrence of seizures. Ligands that preferentially bind to and stabilize the R state are termed inverse agonists and reduce the effector activity.
Neutral antagonists show equal affinity for both conformations and do not alter the equilibrium between the two states, however they occupy the receptor and can block the effect of both agonists and inverse agonists. This gene product undergoes an RNA editing process leading to a decrease in agonist binding affinity, however antagonist binding remains unaltered. This process of RNA editing generates 14 unique receptor isoforms of the 5-HT2C receptor that differ in three amino acids in the second intracellular loop.
When serotonin binds to the receptors, the most important contacts are in TM helixes 3, 5 and 6 Figure 3while the other four TM helixes do not interact directly with the serotonin compound.
When binding of serotonin takes place, the protonated primary amine site forms a salt bridge with D residue in TM 3, as well as forming a hydrogen bond with 5ht2c perdita di peso S in TM 3.
The ring falls tight into the receptor pocket, stacked between two phenylalanines. Amine of the indole group forms a hydrogen bond with S residue in TM 5 and hydroxide substituent of the indole forms hydrogen bonds both with residue S in TM 3 and I in TM 6.
Outline of the 5-HT2C receptor. The most important contacts when serotonin binds are with residues in TM helixes 3, 5, and 6. Pharmacophore[ edit ] Figure 4.
The best fit mapped with the four features 5ht2c perdita di peso the pharmacophore. In the drug discovery process of a 5-HT2C agonist, a pharmacophore module has been used to discover novel 5-HT2C receptor ligands.
The pharmacophore has four features; one aromatic ring, two hydrophobic features and one positive ionizable feature. Figure 4 shows an example of a compound that fits the agonist pharmacophore perfectly.
The nitrogen atom of piperazine fits the positive ionizable feature, the benzofuran part fits the aromatic ring and one hydrophobic, and the trifluoromethane part fits another hydrophobic feature of the pharmacophore. Compounds with maximum potency featured two substituents linked to the core structure. Addition of aromatic groups to the piperazine ring reduces potency derivative 4 in figure 5 and the absence of the piperazine ring or substitution with other aliphatic - or cyclic groups reduces potency as well derivatives 5 and 6 in figure 5.