ABSTRACT
In recent years, synthetic opioids have emerged as a predominant cause of drug-overdose-related fatalities, causing the "opioid crisis." To design safer therapeutic agents, we accidentally discovered µ-opioid receptor (MOR) antagonists based on fentanyl with a relatively uncomplicated chemical composition that potentiates structural modifications. Here, we showed the development of novel atropisomeric fentanyl analogues that exhibit more potent antagonistic activity against MOR than naloxone, a morphinan MOR antagonist. Derivatives displaying stable axial chirality were synthesized based on the amide structure of fentanyl. The aS- and aR-enantiomers exerted antagonistic and agonistic effects on the MOR, respectively, and each atropisomer interacted with the MOR by assuming a distinct binding mode through molecular docking. These findings suggest that introducing atropisomerism into fentanyl may serve as a key feature in the molecular design of future MOR antagonists to help mitigate the opioid crisis.
Subject(s)
Fentanyl , Receptors, Opioid, mu , Receptors, Opioid, mu/antagonists & inhibitors , Receptors, Opioid, mu/metabolism , Fentanyl/pharmacology , Fentanyl/analogs & derivatives , Fentanyl/chemistry , Stereoisomerism , Humans , Molecular Docking Simulation , Structure-Activity Relationship , Animals , Narcotic Antagonists/chemistry , Narcotic Antagonists/pharmacology , Molecular Conformation , Analgesics, Opioid/pharmacology , Analgesics, Opioid/chemistry , Analgesics, Opioid/chemical synthesis , CHO Cells , CricetulusABSTRACT
PURPOSE: This study aimed to clarify age-related changes in the iliocapsularis (IC) using indicators of quantity, quality, and mechanical properties. We also compared the age-related changes in the IC and other hip muscles. METHODS: Eighty-seven healthy women (ages: 21-82 years, mean age: 45.9 ± 15.7 years) participated in the experiment. We measured thickness, echo intensity, and shear modulus of the IC, iliacus muscle, rectus femoris, and the thickness and shear modulus of the hip joint capsule. Spearman's rank correlation coefficient was used to measure the association of age with variables measured in the muscles and joint capsule. RESULTS: Thickness of the iliacus muscle and rectus femoris decreased significantly with age, but the thickness of the IC and hip joint capsule showed no significant correlation. The echo intensities of the IC, iliacus muscle, and rectus femoris were positively correlated, which increased with age. Furthermore, the shear modulus of the iliacus, rectus femoris, and hip joint capsule showed an increase with age, whereas the shear modulus of the IC exhibited no correlation with age. CONCLUSION: The muscle quality of the IC changed significantly, unlike that of the iliacus or rectus femoris. Additionally, the correlation with echo intensity was relatively weaker in the IC compared with the iliacus or rectus femoris.
Subject(s)
Hip Joint , Muscle, Skeletal , Humans , Female , Adult , Middle Aged , Young Adult , Aged , Aged, 80 and over , Hip Joint/diagnostic imaging , Muscle, Skeletal/diagnostic imaging , Muscle, Skeletal/physiology , Quadriceps Muscle/physiology , ThighABSTRACT
PURPOSE: This study aimed to examine the effect of age on the mechanical properties, muscle size, and muscle quality in the upper and lower limb and trunk muscles. METHODS: We evaluated the shear modulus (G), muscle thickness (MT), and echo intensity (EI) of the upper and lower limb and trunk muscles of 83 healthy women (21-83-year-old). The G values of some limb muscles were measured in relaxed and stretched positions. RESULTS: Regarding the effect of age on G at the distinct positions, the G of the upper limb muscles were not significantly correlated with age in the relaxed and stretched positions. In contrast, the G of the iliacus showed a significant negative correlation in both positions. Additionally, the G of the rectus femoris had a significant negative correlation only in the relaxed position. Regarding differences among body parts, the G of the lower limb and oblique abdominal muscles showed a significant negative correlation, but no correlation in the upper limb, rectus abdominis, and back muscles. Moreover, MT showed a significant negative correlation with age in the lower limb, abdominal, and erector spinae muscles, but no correlation was detected in the upper limb and lumbar multifidus muscles. EI had a significant positive correlation in all the muscles. CONCLUSION: The effect of age on G depended on body parts, and the G of the lower limb and oblique abdominal muscles negatively associated with age. Additionally, G in the relaxed position may be more susceptible to aging than G in the stretched position.
