Medicinal Chemistry and Chemical Biology of GPCRs

G protein-coupled receptors (GPCRs) are the most common family of receptors in the genome. The 800 members of this family comprise >1% of the coding human genome and they are expressed within every organ system. GPCRs are sensors for a wide array of extracellular stimuli, including proteins, hormones, small molecules, neurotransmitters, ions and light. As they regulate virtually every aspect of physiology, it is not surprising that GPCRs are also the target of >40% of all prescription drug sales. All GPCRs share a common architecture that consists of an extracellular N-terminal sequence, seven transmembrane domains that are connected by three extracellular and three intracellular loops, and an intracellular C-terminal domain.
Recent advances in different scientific branches have markedly changed our perception and knowledge of the physiology, physiopathology and structural biology of GPCRs. The consolidation of key concepts such as GPCR (homo/hetero) oligomerization, allosteric modulation or signaling bias provides promising and unexplored therapeutic approaches to address significant unmet medical needs. In this context, the medicinal chemist’s armamentarium to modulate these targets has expanded considerably. In addition to classical GPCR modulators [e.g., agonists (full, partial or inverse) and antagonists], contemporary drug hunters now also intensively pursue (positive/negative) allosteric modulators, (homo/hetero) bivalent ligands, bitopic ligands and biased (functionally selective) ligands.



Our group is focused on research programs aimed at discovering novel drug candidates for serious pathologies (e.g., Parkinson disease, cancer, glaucoma, diabetes, schizophrenia and neuropathic pain). In each case, the therapeutic hypothesis entails the modulation of diverse therapeutic approaches and GPCR families (adenosine, dopamine, histamine, serotonin, angiotensin and cannabinoid receptors). We are also engaged in the development and optimization of molecular probes for diverse chemical biology programs, as well as in the design and validation of synthetic methodologies that can accelerate the rational discovery of the emerging class of GPCR therapeutics.


Structural Mapping ogf Adenosine Receptor Mutations: Ligand Binding and Signaling Mechanisms.

Jespers, W., Schiedel, A. C., Heitman, L., Cooke, R., Leene, L., van Westen, G. J., Glorian, D. E., Muller, C. E., Sotelo, E., Gutiérrez de Terán, H.

Trends in Pharmacological Sciences, 2018, 39, 75-89.

Discovery of Potent and Highly Selective Adenosine A2B Receptor Antagonists Chemotypes.

El Maatougi, A., Azuaje, J., González-Gómez, M., Míguez, G., Crespo, A., García-Mera, X.,  Gutiérrez de Terán, H., Sotelo, E.*

Journal of Medicinal Chemistry, 2016, 59, 1967-1983.