Bispecific sigma-1 receptor antagonism and mu-opioid receptor partial agonism: WLB-73502, an analgesic with improved efficacy and safety profile compared to strong opioids

Opioids are the most effective painkillers, but their benefit-risk balance often hinder their therapeutic use. WLB-73502 is a dual, bispecific compound that binds sigma-1 (S1R) and mu-opioid (MOR) receptors. WLB-73502 is an antagonist at the S1R. It behaved as a partial MOR agonist at the G-protein pathway and produced no/unsignificant β-arrestin-2 recruitment, thus demonstrating low intrinsic efficacy on MOR at both signalling pathways. Despite its partial MOR agonism, WLB-73502 exerted full antinociceptive efficacy, with potency superior to morphine and similar to oxycodone against nociceptive, inflammatory and osteoarthritis pain, and superior to both morphine and oxycodone against neuropathic pain. WLB-73502 crosses the blood-brain barrier and binds brain S1R and MOR to an extent consistent with its antinociceptive effect. Contrary to morphine and oxycodone, tolerance to its antinociceptive effect did not develop after repeated 4-week administration. Also, contrary to opioid comparators, WLB-73502 did not inhibit gastrointestinal transit or respiratory function in rats at doses inducing full efficacy, and it was devoid of proemetic effect (retching and vomiting) in ferrets at potentially effective doses. WLB-73502 benefits from its bivalent S1R antagonist and partial MOR agonist nature to provide an improved antinociceptive and safety profile respect to strong opioid therapy.

Oliceridine - Breakthrough in the Management of Pain

Oliceridine an intravenous opioid approved in 2020 by the Food and Drug Administration (FDA) to treat moderate-to-severe pain. Oliceridin developed with a novel mechanism that is biased agonism toward G-protein-coupled receptors pathway. Being biased agonist, it does not activate beta arrestin pathway responsible for opioid-related adverse events (ORAE), especially respiratory depression. Because of the novel mechanism, oliceridine has paved a pathway to decrease ORAE. Oliceridine has received breakthrough status by FDA. However, FDA denied oliceridine approval and withdrew breakthrough status by 2019. FDA made this decision because of the inadequacy of the safety data. Abuse potential and QT prolongation studies are conducted as per FDA recommendation in the year 2019; oliceridine was approved for moderate to severe pain in adults. This review will briefly summarize the pharmacological properties and study results of oliceridine in the management of pain. Thorough literature search was done for the efficacy and safety of oliceridine, search was done in electronic database of PubMed and Cochrane from inception till June 2021. Oliceridine was found to be effective in acute severe pain with less OREA when compared to morphine. Oliceridine has many drawbacks than what is hypothesized earlier, but this approach has opened new options for patients suffering from severe pain. Long?term effect of oliceridine has to be monitored to assess the effects of biased agonism.

Sweet Taste-Sensing Receptors Expressed in Pancreatic beta-Cells: Sweet Molecules Act as Biased Agonists

The sweet taste receptors present in the taste buds are heterodimers comprised of T1R2 and T1R3. This receptor is also expressed in pancreatic beta-cells. When the expression of receptor subunits is determined in beta-cells by quantitative reverse transcription polymerase chain reaction, the mRNA expression level of T1R2 is extremely low compared to that of T1R3. In fact, the expression of T1R2 is undetectable at the protein level. Furthermore, knockdown of T1R2 does not affect the effect of sweet molecules, whereas knockdown of T1R3 markedly attenuates the effect of sweet molecules. Consequently, a homodimer of T1R3 functions as a receptor sensing sweet molecules in beta-cells, which we designate as sweet taste-sensing receptors (STSRs). Various sweet molecules activate STSR in beta-cells and augment insulin secretion. With regard to intracellular signals, sweet molecules act on STSRs and increase cytoplasmic Ca2+ and/or cyclic AMP (cAMP). Specifically, when an STSR is stimulated by one of four different sweet molecules (sucralose, acesulfame potassium, sodium saccharin, or glycyrrhizin), distinct signaling pathways are activated. Patterns of changes in cytoplasmic Ca2+ and/or cAMP induced by these sweet molecules are all different from each other. Hence, sweet molecules activate STSRs by acting as biased agonists.