Background and Purpose Hydrogen sulphide (H2S) is synthesised endogenously through cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST). Although exogenous H2S is known to produce vasodilatation, the vascular effect of H2S produced through 3-MST is unknown. In this study we demonstrate the effect of a novel inhibitor of 3-MST, DPHE, and determined the effect of this compound on contractile responses in porcine coronary artery. Experimental Approach Synthesis of H2S through 3-MST, and CBS/CSE was determined in rat liver cytosols. Effects of 3-MST inhibitors DPHE, 3-PAB, or I3MT-3, or CBS/CSE inhibitors AOAA and PPG on contractile responses in porcine coronary arteries were determined using isolated tissue baths. Key Results DPHE inhibited the production of H2S from 3-meraptopyruvate (IC50 ~8 µM). The 3-MST inhibitors DPHE, I3MT-3, and 3-PAB all inhibited contractions to U46619 in porcine coronary artery segments through an endothelium-independent mechanism. DPHE and 3MT-3 reduced the U46619 contractions in the absence of extracellular calcium and inhibited the contraction to the L-type calcium channel opener BAY K8644. The combination of AOAA (100 µM) and PPG (10 µM) had no effect on the U46619 contractions. The inhibitory effect of the 3-MST inhibitors does not appear to involve Rho kinase, ERK-MAP kinase, or the mitochondrial electron transport chain. Conclusions and Implications Inhibition of 3-MST in coronary arteries leads to an inhibition of both calcium-dependent and -independent contractions, whereas CBS/CSE inhibitors had no effect on receptor mediated contractions. These data suggest that 3-MST, not CBS/CSE, regulates vascular tone in porcine coronary artery.

In the past year, the FDA, the EMA or the MHRA authorised fifty-three (53) novel drugs. While this 2024 harvest is not as rich as that of 2023, when 70 new chemical entities were approved, the number of “orphan” drug authorisations in 2024 (21) is similar to that of 2023 (24), illustrating the very dynamic development of therapeutics in areas of high unmet need. Clearly, the most striking characteristic of the 2024 drug yield is the creative pharmacological design, which allows these medicines to employ a novel approach to target a disease. Some such 2024 notable examples are: the first drug successfully using a ”dock-and-block” mechanism of inhibition (zenocutuzumab), the first approved drug for schizophrenia designed as an agonist of M1/M4 muscarinic receptors (xanomeline), the first biparatopic antibody (zanidatamab), binding two distinct epitopes of the same molecule, the first haemophilia therapy that instead of relying on external supplementation of clotting factors, restores Factor Xa activity by inhibiting TFPI (marstacimab), or the first ever authorized direct telomerase inhibitor (imetelstat) that reprogrammes the tumour cells’ oncogenic drive. In addition, in 2024 an impressive percentage of the novel drugs were first-in-class (28 out of 53, or 53% of the total) and a substantial number of them can be considered disease-agnostic, indicating the possibility of future approved extension of their use into additional indications. Overall, the 2024 harvest demonstrates the therapeutic potential of innovative pharmacological design, which allows the effective targeting of intractable disorders and addresses crucial, unmet therapeutic needs

G protein-coupled receptors modulate a plethora of physiological processes and mediate the effects of one-third of FDA-approved drugs. Notably, depending on which ligand has activated a particular receptor, it can engage different intracellular transducers. This paradigm of ligand-dependent ‘biased signaling’ dictates a need to advance beyond the level of receptors to consider the combined ligand-receptor pair in order to understand physiological signaling. Bias signaling also has the potential to improve medicines by reducing adverse effects. However, this is challenged by inconsistent interpretation of results and lack of commonly agreed guidelines. Here, we present recommended terminology and guidelines to conduct, report and quantify bias in a comparable and reproducible fashion. We expect these recommendations will facilitate a common understanding of experiments and findings across basic receptor research and drug discovery, while the area and the analytical methods to measure bias are still evolving, especially in complex cellular, tissue and organismal systems.

In this review, we identify opportunities for drug discovery in the treatment of COVID-19 and in so doing, provide a rational roadmap whereby pharmacology and pharmacologists can mitigate against the global pandemic. We assess the scope for targetting key host and viral targets in the mid-term, by first screening these targets against drugs already licensed; an agenda for drug re-purposing, which should allow rapid translation to clinical trials. A simultaneous, multi-pronged approach using conventional drug discovery methodologies aimed at discovering novel chemical and biological means targetting a short-list of host and viral entities should extend the arsenal of anti-SARS-CoV-2 agents. This longer-term strategy would provide a deeper pool of drug choices for future-proofing against acquired drug resistance. Second, there will be further viral threats, which will inevitably evade existing vaccines. This will require a coherent therapeutic strategy which pharmacology and pharmacologists are best placed to provide.