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6,7‐Benzomorphans have been investigated in medicinal chemistry for developing new drugs. This nucleus could be considered a versatile scaffold. The physicochemical properties of benzomorphan N‐substituent are crucial in achieving a definite pharmacological profile at opioid receptors. Thus, the dual‐target MOR/DOR ligands LP1 and LP2 were obtained through N‐substituent modifications. Specifically, LP2, bearing as N‐substituent the (2R/S)‐2‐methoxy‐2‐ phenylethyl group, is a dual‐target MOR/DOR agonist and is successful in animal models of inflammatory and neuropathic pain. To obtain new opioid ligands, we focused on the design and synthesis of LP2 analogs. First, the 2‐methoxyl group of LP2 was replaced by an ester or acid functional group. Then, spacers of different lengths were introduced at N‐substituent. In‐vitro, their affinity profile versus opioid receptors has been performed through competition binding assays. Molecular modeling studies were conducted to deeply analyze the binding mode and the interactions between the new ligands and all opioid receptors. [ABSTRACT FROM AUTHOR]

Sigma receptor is a transmembrane non‐GPCR protein expressed mainly in the endoplasmic reticulum membrane associated with mitochondria. It is classified into two types: Sigma‐1 (S1R) and Sigma‐2 (S2R) based on their biological functions. S1R has been implicated in many neurological disorders such as anxiety, schizophrenia, and depression. Therefore, S1R ligands possess a variety of potential clinical applications with a great interest in the treatment of neuropathic pain. In this study, we report the discovery of a novel lead compound for S1R binding, based on the thiazolidine‐2,4‐dione nucleus. We have explored hydrophobic groups of different sizes on both sides of the five‐membered ring scaffold guided by the crystal structure of S1R. Six compounds showed more than 50% displacement of the radioligand at 10 µM concentration with compound 6c resulting in 100% displacement and a Ki of 95.5 nM. Moreover, compounds 6c and 6e showed a significant selectivity over S2R. In addition, molecular docking predicted that all the compounds showed the critical salt bridge with Glu172 with variable degrees of π‐stacking interaction with Tyr103. Upon optimization, this series of compounds could represent potential clinically useful S1R ligands for pain management. [ABSTRACT FROM AUTHOR]

In this paper, we investigated the hypothesis that pseudouridine isoxazolidinyl nucleoside analogues could act as potential inhibitors of the pseudouridine 5ʹ‐monophosphate glycosidase. This purpose was pursued using molecular modeling and in silico ADME‐Tox profiling. From these studies emerged that the isoxazolidinyl derivative 1 5ʹ‐monophosphate can be effectively accommodated within the active site of the enzyme with a ligand efficiency higher than that of the natural substrate. In this context, the poor nucleofugality of the N‐protonated isoxazolidine prevents or slows down, the first mechanistic step proposed for the degradation of the pseudouridine 5ʹ‐monophosphate glycosidase, leading to the enzyme inhibition. Finally, the results of the physicochemical and ADME‐Tox informative analysis pointed out that compound 1 is weakly bounded to plasma protein, only moderately permeate the blood–brain barrier, and is non‐carcinogen in rat and mouse. To the best of our knowledge, this is the first paper that introduces the possibility of inhibition of pseudouridine 5ʹ‐monophosphate glycosidase by a molecule that competing with the natural substrate hinders the glycosidic C–C bond cleavage. [ABSTRACT FROM AUTHOR]

In this paper, we investigated the hypothesis that pseudouridine isoxazolidinyl nucleoside analogues could act as potential inhibitors of the pseudouridine 5'-monophosphate glycosidase. This purpose was pursued using molecular modeling and in silico ADME-Tox profiling. From these studies emerged that the isoxazolidinyl derivative 1 5'-monophosphate can be effectively accommodated within the active site of the enzyme with a ligand efficiency higher than that of the natural substrate. In this context, the poor nucleofugality of the N-protonated isoxazolidine prevents or slows down, the first mechanistic step proposed for the degradation of the pseudouridine 5'-monophosphate glycosidase, leading to the enzyme inhibition. Finally, the results of the physicochemical and ADME-Tox informative analysis pointed out that compound 1 is weakly bounded to plasma protein, only moderately permeate the blood-brain barrier, and is non-carcinogen in rat and mouse. To the best of our knowledge, this is the first paper that introduces the possibility of inhibition of pseudouridine 5'-monophosphate glycosidase by a molecule that competing with the natural substrate hinders the glycosidic C-C bond cleavage., (© 2017 John Wiley & Sons A/S.)