5-HT2C receptor agonist
They have been investigated for the treatment of a number of conditions including obesity, psychiatric disorders, sexual dysfunction and urinary incontinence.
The development of 5-HT2C agonists has been a major obstacle, because of severe side effects due to a lack of selectivity over 5-HT2A and 5-HT2B receptors.
[8] Serotonin has been implicated as a critical factor in the short-term regulation of food intake and in promoting loss of weight associated with hyperphagia.
[9] Studies using pharmacological and genetic tools demonstrated that the 5-HT2C receptor subtype was one of the principal mediators through which serotonin exerts its anorectic effects in rodents.
As a result of these symptoms, the researchers identified a functional role for the receptors in serotonergic regulation of food intake and body weight.
[9] The 5-HT2c receptor agonist Fenfluramine (market names Pondimin, Ponderax and Adifax) was discovered in 1972 as a result of research performed to identify anorectic compounds lacking the effects of psycho-stimulants and sympathomimetic agents (such as amphetamines).
Prior to the discovery of fenfluramine, amphetamines were the primary form of anorectic drugs available, however the side effects 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.
In 1996, dexfenfluramine 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.
In addition, the activation of PLA2 also results in recruitment of a RhoA/PLD pathway through RhoA, an enzyme that regulates a wide spectrum of cellular functions through PLD (phospholipase D) target protein.
The 5-HT2C receptors can also stimulate the extracellular signal-regulated kinase (ERK) pathway which is activated by neurotrophins and other neuroactive chemicals.
This led to the understanding that stimulation of the 5-HT2C receptors could regulate manic-depressive conditions in a manner similar to mood stabilizers.
Ligands that preferentially bind to and stabilize the R state are termed inverse agonists and reduce the effector activity.
Both receptors couple the same cellular signal transduction pathways, PLC and PLA2, that lead to an accumulation of inositol phosphate and Ca2+ within the postsynaptic cell.
[clarification needed] These hits contained a pyrazolo[3,4-d]pyrimidine core (shown in figure 5), which is important for potency toward the 5-HT2C receptors.
Derivatives lacking the arylpiperazine core, such as 4-aryl-1,2,3,6-tetrahydropyridinum chlorine analogues, are more favorable for potency and selectivity over the other two receptors (Figure 7).
[36] Obesity is a global epidemic health problem and has received considerable attention as a major public hazard.
Lorcaserin is the only agent that has completed phase III clinical trials, and achieved US Food and Drug Administration (FDA) approval.
[7] Lorcaserin is a potent and selective 5-HT2C agonist with rapid oral absorption that shows dose-dependent decrease in food intake and body weight.
This functional selectivity is critical to prevent potential side effects and suggests that the theoretical risk of cardiac valvulopathy is very low.
Clinical trials have supported this theory since they have not revealed any side effects on heart valves or pulmonary artery pressure like the former obesity drugs.
Vabicaserin is a full agonist with approximately 4-fold greater selectivity for 5-HT2C over these related receptors, in terms of binding affinity.
Many potent compounds with high selectivity for 5-HT2C receptors have been synthesized and are promising candidates for further development for the treatment of stress urinary incontinence (SUI).
Evidence supports a therapeutic potential of 5-HT2C receptor modulation in the treatment of a variety of pathological conditions, including schizophrenia, obesity, urinary incontinence and sexual dysfunction.
