Molecular mechanisms of inverse agonism via κ-opioid receptor-G protein complexes.

Opioid receptors, a subfamily of G protein-coupled receptors (GPCRs), are key therapeutic targets. In the canonical GPCR activation model, agonist binding is required for receptor-G protein complex formation, while antagonists prevent G protein coupling. However, many GPCRs exhibit basal activity, allowing G protein association without an agonist.

Know your molecule: pharmacological characterization of drug candidates to enhance efficacy and reduce late-stage attrition.

Despite advances in chemical, computational and biological sciences, the rate of attrition of drug candidates in clinical development is still high. A key point in the small-molecule discovery process that could provide opportunities to help address this challenge is the pharmacological characterization of hit and lead compounds, culminating in the selection of a drug candidate. Deeper characterization is increasingly important, because the 'quality' of drug efficacy, at least for G protein-coupled receptors (GPCRs), is now understood to be much more than activation of commonly evaluated pathways such as cAMP signalling, with many more 'efficacies' of ligands that could be harnessed therapeutically.

A Pharmacological perspective on the temporal properties of sweeteners.

Several non-caloric sweeteners exhibit a delay in sweetness onset and a sweetness linger after sampling. These temporal properties are thought to be the result of non-specific interactions with cell membranes and proteins in the oral cavity. Data and analysis presented in this report also support the potential involvement of receptor affinity and binding kinetics to this phenomenon.

Intracellular Allosteric Antagonist of the Olfactory Receptor OR51E2.

Olfactory receptors are members of class A (rhodopsin-like) family of G protein-coupled receptors (GPCRs). Their expression and function have been increasingly studied in nonolfactory tissues, and many have been identified as potential therapeutic targets. In this manuscript, we focus on the discovery of novel ligands for the olfactory receptor family 51 subfamily E2 (OR51E2).

Bias translation: The final frontier?

Biased signalling is a natural result of GPCR allosteric function and should be expected from any and all synthetic and natural agonists. Therefore, it may be encountered in all agonist discovery projects and must be considered as a beneficial (or possible detrimental) feature of new candidate molecules. While bias is detected easily, the synoptic nature of GPCR signalling makes translation of simple in vitro bias to complex in vivo systems problematic.