The 5-HT2 receptors mediate many of the central and peripheral physiologic functions of serotonin. Cardiovascular effects include contraction of blood vessels and shape changes in platelets; central nervous system effects include neuronal sensitization to tactile stimuli and mediation of some of the effects of hallucinogenic substituted amphetamines. The 5-HT2B receptor is highly expressed in the liver and kidney, with lower levels of expression being seen in the cerebral cortex, whole brain, pancreas, and spleen - with no expression in the heart, despite its cardiovascular effects. The 5-HT2B receptor subtype is involved in:
Cardiac: The 5-HT2B receptor regulates cardiac structure and functions as demonstrated by the abnormal cardiac development observed in 5-HT2B receptor null mice. The 5-HT2B receptor stimulation can also lead to pathological proliferation of cardiac valve fibroblasts, which with chronic overstimulation of 5-HT2B can lead to a severe valvulopathy. Moreover, 5-HT2B receptors were recently shown to be overexpressed in human failing heart and antagonists of 5-HT2B receptors were uncovered to prevent both angiotensin II or beta-adrenergic agonist-induced pathological cardiac hypertrophy in mouse.
Serotonin transporter: 5-HT2B receptors regulate serotonin release via the serotonin transporter, and are important both to normal physiological regulation of serotonin levels in blood plasma, and with the abnormal acute serotonin release produced by drugs such as MDMA. Surprisingly however 5-HT2Breceptor activation appears to be protective against the development of serotonin syndrome following elevated extracellular serotonin levels, despite its role in modulating serotonin release.
Clinical significance
5-HT2B receptors have also been strongly implicated in drug-induced valvular heart disease. In this context, it is generally considered to be an antitarget. The structure of the 5-HT2B receptor was resolved in a complex with the valvulopathogenic drug ergotamine.
Ligands
As of 2009, few highly selective 5-HT2Breceptor ligands have been discovered, although numerous potent non-selective compounds are known, particularly agents with concomitant 5-HT2C binding. Research in this area has been limited due to the cardiotoxicity of 5-HT2B agonists, and the lack of clear therapeutic application for 5-HT2B antagonists, but there is still a need for selective ligands for scientific research.
Agonists
;Selective
BW-723C86: fair functional subtype selectivity; almost full agonist. Anxiolytic in vivo.
Ro60-0175 functionally selective over 5-HT2A, potent agonist at both 5-HT2B/C
5-HT2B antagonists have previously been proposed as treatment for migraine headaches, and RS-127,445 was trialled in humans up to Phase I for this indication, but development was not continued. More recent research has focused on possible application of 5-HT2B antagonists as treatments for chronic heart disease. Research claims serotonin 5-HT2B receptors have effect on liver regeneration.
