With focus on fibrosis

5-HT<sub>2B</sub> BIOLOGY


Serotonin or 5-hydroxytryptamine (5-HT) is mainly found in the periphery where it is involved in e.g. regulation of vascular tone, platelet aggregation and bowel peristalsis. Peripheral 5-HT is mainly produced by the enterochromaffin cells of the gut and extracellular 5-HT is effectively transported into platelets. When platelets encounter, e.g. endothelial damage they become activated and aggregate, and release 5-HT resulting in an increase in local concentration.

With the exception of the 5-HT3 receptor (ligand-gated ion channel), 5-HT exerts its biological functions through interactions with specific cell-surface G-protein coupled receptors (GPCR). The 5-HT2 receptor family consists of 3 subtypes, 5-HT2A, 5-HT2B and 5-HT2C. The 5-HT2B receptor is expressed in major organ systems and has been shown to be involved in many pathophysiological mechanisms, see below.

Treatment opportunities. Examples of pathophysiological mechanism with known involvement of the 5-HT2B receptor.

Under normal conditions, wound healing or tissue repair is a tightly regulated process. Damaged connective tissue is replaced through synthesis of extracellular matrix (ECM) proteins produced by e.g. activated fibroblasts or myofibroblasts. Platelet derived 5-HT is critical for normal wound healing where it stimulates both vasoconstriction and vasodilation, influences inflammatory responses, cell proliferation, remodeling and promotes formation of a temporary scar. A dysregulated 5-HT activity can have detrimental effects and promote aberrant wound healing resulting in excessive ECM synthesis and tissue fibrosis. The fibrotic tissue disrupts the physiological tissue structure, leading to organ dysfunction and contributes to morbidity and increased mortality of affected patients.

Emerging research reveals an important role of peripheral 5-HT2B receptors in diseases associated with tissue fibrosis. Activation of peripheral 5-HT2B receptors has been linked to development of tissue fibrosis in humans and the receptor is upregulated in lungs of patients with idiopathic lung fibrosis and in dermal fibroblasts isolated from patients with systemic sclerosis. Furthermore, mice deficient in the 5-HT2B receptor are almost completely protected from experimental fibrosis. The 5-HT2B receptors modify cell differentiation and activation and are involved in the regulation and production of pro-fibrotic mediators such as TGF-β.

AnaMar’s first-in-class 5-HT2B receptor antagonists target the extracellular matrix producing myofibroblast resulting in decreased matrix production and attenuation of tissue fibrosis. AnaMar’s approach has been validated in Proof of Principle studies using both human cells and disease models of fibrosis.