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Multicomponent reactions (MCRs) are extremely popular owing to their facile execution, high atom-efficiency and the high diversity of products. MCRs can be used to access various heterocycles and highly functionalized scaffolds, and thus have been invaluable tools in total synthesis, drug discovery and bioconjugation. Traditional isocyanide-based MCRs utilize an external nucleophile attacking the reactive nitrilium ion, the key intermediate formed in the reaction of the imine and the isocyanide. However, when reactants with multiple nucleophilic groups (bisfunctional reactants) are used in the MCR, the nitrilium intermediate can be trapped by an intramolecular nucleophilic attack to form various heterocycles. The implications of nitrilium trapping along with widely applied conventional isocyanide-based MCRs in drug design are discussed in this review. [ABSTRACT FROM AUTHOR]

3-Iodobenzoylnaltrexamide 1(IBNtxA) isa potent analgesicacting through a novel receptor target that lack many side-effectsof traditional opiates composed, in part, of exon 11-associated truncatedsix transmembrane domain MOR-1 (6TM/E11) splice variants. To betterunderstand the SAR of this drug target, a number of 4,5-epoxymorphinananalogues were synthesized. Results show the importance of a free3-phenolic group, a phenyl ring at the 6 position, an iodine at the3′or 4′ position of the phenyl ring, and an N-allyl or c-propylmethyl group to maintainhigh 6TM/E11 affinity and activity. 3-Iodobenzoylnaloxamide 15(IBNalA) with a N-allyl group displayedlower δ opioid receptor affinity than its naltrexamine analogue,was 10-fold more potent an analgesic than morphine, elicited no respiratorydepression or physical dependence, and only limited inhibition ofgastrointestinal transit. Thus, the aryl-naloxamide scaffold can generatea potent analgesic acting through the 6TM/E11 sites with advantageousside-effect profile and greater selectivity. [ABSTRACT FROM AUTHOR]

The generation of potent opioid analgesics that lack the side effects of traditional opioids may be possible by targeting truncated splice variants of the μ-opioid receptor. μ-Opioids act through GPCRs that are generated from the Oprml gene, which undergoes extensive alternative splicing. The most abundant set of Oprml variants encode classical full-length 7 transmembrane domain (7TM) μ-opioid receptors that mediate the actions of the traditional μ-opioid drugs morphine and methadone. In contrast, 3-iodobenzoyl-6β-naltrexamide (IBNtxA) is a potent analgesic against thermal, inflammatory, and neuropathic pain that acts independently of 7TM μ-opioid receptors but has no activity in mice lacking a set of 6TM truncated μ-opioid receptor splice variants. Unlike traditional opioids, IBNtxA does not depress respiration or result in physical dependence or reward behavior, suggesting it acts through an alternative μ-opioid receptor target. Here we demonstrated that a truncated STM splice variant, mMOR-IG, can rescue IBNtxA analgesia in a μ-opioid receptor-deficient mouse that lacks all Oprml splice variants, ablating μ-opioid activity in these animals. Intrathecal administration of lentivirus containing the STM variant mMOR-ID restored IBNtxA, but not morphine, analgesia in Oprm7-deficient animals. Together, these results confirm that a truncated 6TM GPCR is both necessary and sufficient for IBNtxA analgesia. [ABSTRACT FROM AUTHOR]

The persistence of chronic pain and continuing overdose deaths from pain-relieving opioids targeting μ opioid receptor (μOR) have fueled the need for reliable long-term analgesics which use different targets and mechanisms. The δ opioid receptor (δOR) is a potential alternative target for non-addictive analgesics to alleviate chronic pain, made more attractive by its lack of respiratory depression associated with μOR agonists. However, early δOR full agonists were found to induce seizures, precluding clinical use. Partial δOR agonists may offer more controlled activation of the receptor compared to full agonists, but the development of such ligands has been hindered by uncertainty over the molecular mechanism mediating partial agonism. Using a structure-based approach, we explored the engagement of the sodium binding pocket in δOR and developed a bitopic ligand, C6-Quino, predicted to be a selective δOR partial agonist. Functional studies of C6-Quino revealed that it displayed δOR partial agonist activity at both G-protein and arrestin pathways. Its interaction with the sodium pocket was confirmed and analyzed using a single particle cryo-EM. Additionally, C6-Quino demonstrated favorable chemical and physiological properties like oral activity, and analgesic activity in multiple chronic pain models. Notably, μOR-related hyperlocomotion and respiratory depression, and δOR-related convulsions, were not observed at analgesic doses of C6-Quino. This fundamentally new approach to designing δOR ligands provides a blueprint for the development of partial agonists as safe analgesics and acts as a generic method to optimize signaling profiles of other Class A GPCRs., Competing Interests: Competing financial interests The authors declare no competing financial interests.

The µ-opioid receptor (µOR) is a well-established target for analgesia 1 , yet conventional opioid receptor agonists cause serious adverse effects, notably addiction and respiratory depression. These factors have contributed to the current opioid overdose epidemic driven by fentanyl 2 , a highly potent synthetic opioid. µOR negative allosteric modulators (NAMs) may serve as useful tools in preventing opioid overdose deaths, but promising chemical scaffolds remain elusive. Here we screened a large DNA-encoded chemical library against inactive µOR, counter-screening with active, G-protein and agonist-bound receptor to 'steer' hits towards conformationally selective modulators. We discovered a NAM compound with high and selective enrichment to inactive µOR that enhances the affinity of the key opioid overdose reversal molecule, naloxone. The NAM works cooperatively with naloxone to potently block opioid agonist signalling. Using cryogenic electron microscopy, we demonstrate that the NAM accomplishes this effect by binding a site on the extracellular vestibule in direct contact with naloxone while stabilizing a distinct inactive conformation of the extracellular portions of the second and seventh transmembrane helices. The NAM alters orthosteric ligand kinetics in therapeutically desirable ways and works cooperatively with low doses of naloxone to effectively inhibit various morphine-induced and fentanyl-induced behavioural effects in vivo while minimizing withdrawal behaviours. Our results provide detailed structural insights into the mechanism of negative allosteric modulation of the µOR and demonstrate how this can be exploited in vivo., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Clinical treatment of acute to severe pain relies on the use of opioids. While their potency is significant, there are considerable side effects that can negatively affect patients. Their rise in usage has correlated with the current opioid epidemic in the United States, which has led to more than 70,000 deaths per year (Volkow and Blanco, 2021). Opioid-related drug development aims to make target compounds that show strong potency but with diminished side effects. Research into pharmaceuticals that could act as potential alternatives to current pains medications has relied on mechanistic insights of opioid receptors, a class of G-protein coupled receptors (GPCRs), and biased agonism, a common phenomenon among pharmaceutical compounds where downstream effects can be altered at the same receptor via different agonists. Opioids function typically by binding to an active site on the extracellular portion of opioid receptors. Once activated, the opioid receptor initiates a G-protein signaling pathway and/or the β-arrestin2 pathway. The proposed concept for the development of safe analgesics around mu and kappa opioid receptor subtypes has focused on not recruiting β-arrestin2 (biased agonism) and/or having low efficacy at the receptor (partial agonism). By altering chemical motifs on a common scaffold, chemists can take advantage of biased agonism as well as create compounds with low intrinsic efficacy for the desired treatments. This review will focus on ligands with bias profile, signaling aspects of the receptor and probe into the structural basis of receptor that leads to bias and/or partial agonism., (Copyright © 2023 Elsevier Inc. All rights reserved.)

W-18 (4-chloro-N-[1-[2-(4-nitrophenyl)ethyl]-2-piperidinylidene]-benzenesulfonamide) and W-15 (4-chloro-N-[1-(2-phenylethyl)-2-piperidinylidene]-benzenesulfonamide) represent two emerging drugs of abuse chemically related to the potent opioid agonist fentanyl (N-(1-(2-phenylethyl)-4-piperidinyl)-N-phenylpropanamide). Here, we describe the comprehensive pharmacological profiles of W-18 and W-15, as examination of their structural features predicted that they might lack opioid activity. We found W-18 and W-15 to be without detectible activity at μ, δ, κ, and nociception opioid receptors in a variety of assays. We also tested W-18 and W-15 for activity as allosteric modulators at opioid receptors and found them devoid of significant positive or negative allosteric modulatory activity. Comprehensive profiling at essentially all the druggable GPCRs in the human genome using the PRESTO-Tango platform revealed no significant activity. Weak activity at the sigma receptors and the peripheral benzodiazepine receptor was found for W-18 (Ki = 271 nM). W-18 showed no activity in either the radiant heat tail-flick or the writhing assays and also did not induce classical opioid behaviors. W-18 is extensively metabolized, but its metabolites also lack opioid activity. Thus, although W-18 and W-15 have been suggested to be potent opioid agonists, our results reveal no significant activity at these or other known targets for psychoactive drugs.

Receptor binding provides a valuable approach for characterization of drugs and their receptors. There are three major families of opioid receptors: mu, delta, and kappa. Highly selective radioligands are available for all three classes of traditional receptors. Of the three, the mu receptor undergoes extensive alternative splicing, generating a number of traditional mu receptor subtypes as well as a nontraditional, truncated set of variants associated with exon 11. These exon 11-associated truncated variants are not readily labeled with current radioligands. Here we describe the synthesis of a radioiodinated ligand suitable for carrying out binding studies for this target.

It would be useful to develop a surrogate for animal skin, which could be use to predict flux through human skin. The fluxes (and physicochemical properties) of sunscreens and other compounds from propylene glycol (PG):water (AQ), 30:70, through human skin have previously been reported. We measured the fluxes of several of those sunscreens and other compounds from PG:AQ, 30:70, through silicone membrane and fit both sets of data to the Roberts-Sloan (RS) equation to determine any similarities. For both sets of data, the fluxes were directly dependent on their solubilities in a lipid solvent [octanol (OCT), in this case] and in a polar solvent (PG:AQ, 30:70, or AQ in this case) and inversely on their molecular weights. The fit of the experimental (EXP) fluxes through human skin in vivo to RS was excellent: r² = 0.92 if the vehicle (VEH) PG:AQ, 30:70 was the polar solvent (RS¹) or r² = 0.97 if water was the polar solvent (RS²). The fit of the EXP fluxes through silicone membrane to RS was good: r² = 0.80 if the VEH PG:AQ, 30:70, was the polar solvent (RS¹) or r² = 0.81 if water was the polar solvent (RS²). The correlations between their EXP fluxes through human skin in vivo and their EXP fluxes through silicone membrane were good (r² = 0.85). In addition, the correlation between EXP fluxes from PG:AQ, 30:70, through human skin in vivo and their fluxes calculated from the coefficients of the fit of solubilities, molecular weights and fluxes from water through silicone membranes from a previous n = 22 database to RS was even better (r² = 0.94). These results suggest that flux through human skin can be calculated from flux through a silicone membrane.