Endocrine Abstracts

The LH receptor (LHR) together with the FSH receptor (FSHR) and TSH receptor (TSHR) constitute a highly conserved subgroup of G protein-coupled receptors. Activation of these receptors requires the binding of the glycoprotein hormones to the long and divergent N-terminus of the receptor and the intramolecular signal transduction from the hormone-receptor complex to the transmembrane domain of the receptor. The main signaling pathway of the LHR, TSHR and FSHR is stimulation of adenylyl cyclase via Gs proteins but they may couple to phospholipase C via Gq proteins as well. Interaction of activated receptors with β-arrestin has also been demonstrated but this coupling mechanism has been studied in much less detail.

Research and development within various pharmaceutical companies have been focused on developing low molecular weight (LMW) agonists and antagonists for these receptors. Such LMW allosteric receptor modulators offer increased homogeneity and consistency, better compound stability compared to glycoprotein hormones and, preferably can be administered orally to improve patient convenience and compliance. At MSD (formerly Organon), allosteric nanomolar potent and orally active LMW agonists and antagonists of the LHR, TSHR and FSHR have been developed. These compounds have been shown to interact with the transmembrane domains instead of the N-terminus of the receptor.

In this presentation, the allosteric profile of two nanomolar potent, orally active LHR and FSHR agonists (Org 42599 and Org 214444-0 respectively), and one TSHR antagonist (Org 274179-0) will be presented. Highlighted will be i) biased signaling and rescue of expression and signaling of intracellularly retained mutant receptors identified in human patients with impaired reproductive function (Org 42599), ii) full inhibition of receptor signaling without affecting hormone binding (Org 274179-0) and iii) enhancement of binding and signaling of the glycoprotein hormone (Org 214444-0).

Declaration of interest

The presenting author (CVK) has been employee of MSD (Oss, The Netherlands).

Declaration of funding

This work was supported by MSD (Organon, The Netherlands).