Discovery of an Ortho-Substituted N-Cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaine Derivative as a Selective and Potent Kappa Opioid Receptor Agonist with Subsided Sedative Effect.

Research into kappa opioid receptor (KOR) agonists with attenuated central-nervous-system side effects is a critical focus for developing productive and safe analgesics. Herein, a series of ortho-substituted N-cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaines were designed, synthesized, and subjected to bioassays. Compound 7a exhibited high subtype selectivity and potent agonistic activity toward KOR (KOR, Ki = 3.9 nM, MOR/KOR = 270, DOR/KOR = 1075; [35S]GTPγS binding, EC50 = 3.4 nM). Additionally, this compound exhibited robust and persistent antinociceptive effects in rodent models with different animal strains (hot plate test, ED50 = 0.20-0.30 mg/kg, i.p.; abdominal constriction test, ED50 = 0.20-0.60 mg/kg, i.p.), with its KOR-mediated mechanism for antinociception firmly established. Notably, compound 7a, unlike conventional KOR agonists, displayed minimal sedation and aversion at the antinociceptive ED50 dose. This feature addresses a crucial limitation in existing KOR agonists, positioning compound 7a as a promising novel therapeutic agent.

Effects of whey protein complex combined with low-intensity exercise in elderly inpatients with COPD at a stable stage.

BACKGROUND AND OBJECTIVES: Previous literature mostly has demonstrated the efficacy of pulmonary rehabilitation (PR) combined with whole nutrition powder in patients with chronic obstructive pulmonary disease (COPD). However, the benefits of whey protein as an oral nutritional supplement (ONS) during PR are not clear. METHODS AND STUDY DESIGN: It took 12 weeks to complete the trial, we divided 90 elderly patients with stable-stage COPD into a low-intensity exercise group (n= 30, PR group), PR plus whey proteins complex group (n= 30, PRWP group), and a control group (n= 30) randomly, and assessed index such as exercise capacity, mental health status, lung function, and body composition. Eventually, 84 people persisted until the end of the trial. RESULTS: Compared with the control group, hand grip strength (HGS)(1.4 ± 0.6 kg, and 1.0 ± 0.2 kg respectively, p< 0.05) in the PRWP and PR group, 6 minutes of walking distance (6MWD)(14.1 ± 3.8m, p< 0.05) in PRWP group improved. Furthermore, compared with the PR group, Medical Research Council Dyspnea Scale (MRC)(-0.2 ± 0.1, p< 0.01), anxiety score (-1.2 ± 0.4, p< 0.01), and body weight (2.0 ± 0.8kg, p< 0.05) improved in the PRWP group. There were no inter-group differences in a fat-free mass index or appendicular skeletal muscle mass index. CONCLUSIONS: Muscle strength could be enhanced in both intervention models. Adding whey protein complex was additionally successful in rectifying dyspnea, anxiety, and weight loss caused by exercise. This rehabilitation pattern might be valuable in elderly patients with COPD.

Reversal of subtype-selectivity and function by the introduction of a para-benzamidyl substituent to N-cyclopropylmethyl nornepenthone.

The discovery and development of novel µ-opioid receptor (MOR) antagonists is a significant area to combat Opioid Use Disorder (OUD). In this work, a series of para-substituted N-cyclopropylmethyl-nornepenthone derivatives were designed and synthesized and pharmacologically assayed. Compound 6a was identified as a selective MOR antagonist both in vitro and in vivo. Its molecular basis was elucidated using molecular docking and MD simulations. A subpocket on the extracellular side of the TM2 domain of MOR, in particular the residue Y2.64, was proposed to be responsible for the reversal of subtype selectivity and functional reversal of this compound.