Binding and signaling kinetics have previously proven important in validation of biased agonism at GPCRs. Here we provide a comprehensive kinetic pharmacological comparison of clinically relevant μ-opioid receptor agonists, including the novel biased agonist oliceridine (TRV130) which is in clinical trial for pain management. We demonstrate that the bias profile observed for the selected agonists is not time-dependent and that agonists with dramatic differences in their binding kinetic properties can display the same degree of bias. Binding kinetics analyses demonstrate that buprenorphine has 18-fold higher receptor residence time than oliceridine. This is thus the largest pharmacodynamic difference between the clinically approved drug buprenorphine and the clinical candidate oliceridine, since their bias profiles are similar. Further, we provide the first pharmacological characterization of (S)-TRV130 demonstrating that it has a similar pharmacological profile as the (R)-form, oliceridine, but displays 90-fold lower potency than the (R)-form. This difference is driven by a significantly slower association rate. Finally, we show that the selected agonists are differentially affected by G protein-coupled receptor kinase 2 and 5 (GRK2 and GRK5) expression. GRK2 and GRK5 overexpression greatly increased μ-opioid receptor internalization induced by morphine, but only had modest effects on buprenorphine and oliceridine-induced internalization. Overall, our data reveal that the clinically available drug buprenorphine displays a similar pharmacological bias profile in vitro compared to the clinical candidate drug oliceridine and that this bias is independent of binding kinetics suggesting a mechanism driven by receptor-conformations. This article is part of the Special Issue entitled 'New Vistas in Opioid Pharmacology'.

Introduction Statins may reduce the severity of psoriasis, but the available evidence is unclear. We conducted a meta-analysis of randomized controlled studies (RCTs) that investigated the effect of statins on psoriasis severity assessed with the Psoriasis Area and Severity Index (PASI)....

With the aging of the population, treatment of conditions emerging in old age, such as neurodegenerative disorders, has become a major medical challenge. Of these, Alzheimer’s disease, leading to cognitive dysfunction, is of particular interest. Neuronal loss plays an important role in the pathophysiology of this condition, and over the years, a great effort has been made to determine the role of various factors in this process. Unfortunately, until now, the exact pathomechanism of this condition remains unknown. However, the most popular theories associate AD with abnormalities in the Tau and β-amyloid (Aβ) proteins, which lead to their deposition and result in neuronal death. Neurons, like all cells, die in a variety of ways, among which pyroptosis, apoptosis, and necroptosis are associated with the activation of various caspases. It is worth mentioning that Tau and Aβ proteins are considered to be one of the caspase activators, leading to cell death. Moreover, the protease activity of caspases influences both of the previously mentioned proteins, Tau and Aβ, converting them into more toxic derivatives. Due to the variety of ways caspases impact the development of AD, drugs targeting caspases could potentially be useful in the treatment of this condition. Therefore, there is a constant need to search for novel caspase inhibitors and evaluate them in preclinical and clinical trials. Graphical Abstract

The growing number of studies on G protein-coupled receptors (GPCRs) family are a source of noticeable improvement in our understanding of the functioning of these proteins. GPCRs are responsible for a vast part of signaling in vertebrates and, as such, invariably remain in the spotlight of medicinal chemistry. A deeper insight into the underlying mechanisms of interesting phenomena observed in GPCRs, such as biased signaling or allosteric modulation, can be gained with experimental and computational studies. The latter play an important role in this process, since they allow for observations on scales inaccessible for most other methods. One of the key steps in such studies is proper computational reconstruction of actual ligand-receptor or protein-protein interactions, a process called molecular docking. A number of improvements and innovative applications of this method were documented recently. In this review, we focus particularly on innovations in docking to GPCRs.