Effective and safe analgesics represent an unmet medical need for the treatment of acute and chronic pain. A series of N-cyclopropylmethyl-7α-phenyl-6,14-endoethano­tetrahydro­northebaines were designed, synthesized, and assayed, leading to the discovery of a benzylamine derivative (compound 4, SLL-039) as a highly selective and potent κ opioid agonist (κ, K i = 0.47 nM, κ/μ = 682, κ/δ = 283), which was confirmed by functional assays in vitro and antinociceptive assays in vivo. The in vivo effect could be blocked by pretreatment with the selective κ antagonist nor-BNI. Moreover, this compound did not induce sedation, a common dose limiting effect of κ opioid receptor agonists, at its analgesic dose compared to U50,488H. The dissociation of sedation/antinociception found in SLL-039 was assumed to be correlated with the occupation of its benzamide motif in a unique subsite involving V1182.63, W124EL1, and E209EL2.

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Pain was implicated in many diseases. Despite effectiveness to treat moderate to severe pain, opioid analgesics elicited many side effects, greatly limiting their prescription in clinics. Based on M1, an active metabolite of tramadol, 3-((dimethylamino)methyl)-4-(3-hydroxyphenyl)piperidin-4-ol analogues were designed, synthesized, and evaluated in vitro. Among all the compounds tested, compound 23 was found to be a novel, highly selective, and potent MOR agonist (K i MOR = 0.0034 nM, EC 50 MOR = 0.68 nM, E max = 206.5%; K i DOR = 41.67 nM; K i KOR = 7.9 nM). Structure−activity relationship exploration showed that the linker between the piperidine ring and the phenyl ring as well as substituent pattern of the phenyl ring played a pivotal role in binding affinity and selectivity. (3R, 4S)-23 (K i MOR = 0.0021 ± 0.0001 nM, EC 50 MOR = 0.0013 ± 0.0001 nM, E max = 209.1 ± 1.4%; K i DOR = 18.4 ± 0.7 nM, EC 50 DOR = 74.5 ± 2.8 nM, E max = 267.1 ± 1.4%; K i KOR = 25.8 ± 0.2 nM, EC 50 DOR = 116.2 ± 4.4 nM, E max = 209.5 ± 1.4%) had more potent activity for opioid receptors than its enantiomer (3S, 4R)-23 and was found to be a potent, highly selective MOR agonist with novel scaffold. High binding affinity and selectivity of (3R, 4S)-23 for MOR over KOR and DOR and its mechanism of activating MOR were proposed by docking and molecular dynamics simulations, respectively.

BackgroundArterial stiffness is a significant determinant and evaluation of cardio-cerebrovascular disease and all-cause mortality risk in the stroke population. Estimated pulse wave velocity (ePWV) is a well-established indirect measure of arterial stiffness. We examined the association of ePWV with all-cause and cardio-cerebrovascular disease (CCD) mortality in the stroke population in a large sample of US adults.MethodsThe study design was a prospective cohort study with data from the National Health and Nutrition Examination Survey (NHANES) from 2003 to 2014, between the ages of 18–85 years, with follow-up through December 31, 2019. 1,316 individuals with stroke among 58,759 participants were identified and ultimately, 879 stroke patients were included in the analysis. ePWV was calculated from a regression equation using age and mean blood pressure according to the following formula: ePWV = 9.587 − (0.402 × age) + [4.560 × 0.001 × (age2)] − [2.621 × 0.00001 × (age2) × MBP] + (3.176 × 0.001 × age × MBP) − (1.832 × 0.01 × MBP). Survey-weighted Cox regression models were used to assess the association between ePWV and all-cause and CCD mortality risk.ResultsThe high ePWV level group had a higher increased risk of all-cause mortality and CCD mortality compared to the low ePWV level group after fully adjusting for covariates. With an increase in ePWV of 1 m/s, the risk of all-cause and CCD mortality increased by 44%–57% and 47%–72% respectively. ePWV levels were linearly correlated with the risk of all-cause mortality (P for nonlinear = 0.187). With each 1 m/s increase in ePWV, the risk of all-cause mortality increased by 44% (HR 1.44, 95% CI: 1.22–1.69; P < 0.001). When ePWV was <12.1 m/s, an increase in ePWV per 1 m/s was associated with a 119% (HR 2.19, 95% CI: 1.43–3.36; P < 0.001) increase in CCD mortality risk; when ePWV was ≥12.1 m/s, an increase in ePWV per 1 m/s was not associated with in CCD mortality risk.ConclusionePWV is an independent risk factor for all-cause and CCD mortality in stroke patients. Higher levels of ePWV are associated with higher all-cause mortality and CCD mortality in stroke patients.

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