Allosteric modulators of glycoprotein hormone receptors: discovery and therapeutic potential

Abstract

The glycoprotein hormones, luteinizing hormone, follicle-stimulating hormone and thyroid stimulating hormone, are important regulators of reproductive and metabolic processes. However, because of the nature of their ligand-receptor interactions that contain multiple contact sites, classical small molecule drug discovery strategies have not been successful. However, recent advances in screening and combinatorial chemistry strategies have identified chemical series that act allosterically as positive, negative or mixed modulators of the glycoprotein hormone receptors. This review will discuss the discovery and highlight the currently known series of allosteric modulators to this therapeutically important family of G-protein coupled receptors. Lastly, we will present potential mechanisms whereby the different series could modulate receptor function in the context of currently held theory and known structure of G protein-coupled receptors.

Are circulating gonadotropin isoforms naturally occurring biased agonists? Basic and therapeutic implications

“…Whether these molecules are capable of activating the IP3 signaling pathway or other cascades associated with FSH signal transduction is not currently known. Overall, these observations demonstrate that one can design allosteric modulators of the same core structure that can selectively target signaling pathways associated with a given receptor producing biased signaling [37,73]. Since these compounds activate the receptor in different ways, we refer to them pharmacologically as allosteric biased agonists, but they can be perceived as functional agonists and antagonists in order to reflect the overall effects they have on the biology of the target cell.…”

“…Using a similar approach as Yanofsky et al [74], van Koppen et al [82] demonstrated that the thienopyrimidine class of LH/hCGR allosteric modulators interact in a similar region as the thiazolidinone FSH allosteric modulators and the pyridine/pyrimidine class of calciumsensing receptor antagonists (the P2 pocket [73]) on their respective receptors. This confirms that the P2 pocket of GPCRs is an important site for directing therapeutically relevant functional agonists and antagonists [73,83,84]. These data suggest that these compounds are negative allosteric modulators/allosteric antagonists of the FSHR.…”

“…With the onset of improved screening technology, the application of new synthetic mechanisms and access to larger, more diverse chemical libraries, the last decade has seen numerous reports describing the identification of novel chemical series of synthetic small molecules modulating activity of gonadotropin receptors. Interestingly, these small molecule synthetic ligands have been found to possess a range of pharmacological activities; however, they are devoid of competitive binding with the gonadotropins themselves [73]. Therefore, these agents do not appear to alter the orthosteric site, eliciting their modulatory activities via allosteric sites present in the receptor.…”

Novel pathways in gonadotropin receptor signaling and biased agonism

“…Three classes of biased ligands have been described for gonadotropin hormone receptors: 1) small molecules binding at either the orthosteric site on the ECD or at allosteric sites located in the transmembrane region; 2) hormone/antibody complexes and 3) glycosylation variants of the hormone. All three classes can induce selective cellular responses compounds have exhibited very good potency and in vivo efficacy in animal models [90]. Even though these compounds have been screened and characterized within the classical conceptual framework of linear efficacy, generally using reporters of Gs-coupling as read-outs, they raise intriguing possibilities for the development of biased agonists at gonadotropin receptors.…”

“…The surface is colored according to the electrostatic potential. Electrostatic potentials and images were generated using PyMol I, II, III and VII [90,93,94]. The P1 pocket is a common binding site for native small molecule ligands of GPCRs such as the β-adrenergic receptor [94].…”