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Modulation of opioid receptor affinity and efficacy via N-substitution of 9?-hydroxy-5-(3-hydroxyphenyl)morphan: Synthesis and computer simulation study.

ABSTRACT: The enantiomers of a variety of N-alkyl-, N-aralkyl-, and N-cyclopropylalkyl-9?-hydroxy-5-(3-hydroxyphenyl)morphans were synthesized employing cyanogen bromide and K2CO3 to improve the original N-demethylation procedure. Their binding affinity to the ?-, ?-, and ?-opioid receptors (ORs) was determined and functional (GTP?35S) assays were carried out on those with reasonable affinity. The 1R,5R,9S-enantiomers (1R,5R,9S)-(-)-5-(3-hydroxyphenyl)-2-(4-nitrophenethyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S-16), (1R,5R,9S)-(-) 2-cinnamyl-5-(3-hydroxyphenyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S-20), and (1R,5R,9S)-(-)-5-(3-hydroxyphenyl)-2-(4-(trifluoromethyl)phenethyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S-15), had high affinity for the ?-opioid receptor (e.g., 1R,5R,9S-16: Ki=0.073, 0.74, and 1.99nM, respectively). The 1R,5R,9S-16 and 1R,5R,9S-15 were full, high efficacy ?-agonists (EC50=0.74 and 18.5nM, respectively) and the former was found to be a partial agonist at ?-OR and an antagonist at ?-OR, while the latter was a partial agonist at ?-OR and ?-OR in the GTP?35S assay. The enantiomer of 1R,5R,9S-16, (+)-1S,5S,9R-16 was unusual, it had good affinity for the ?-OR (Ki=26.5nM) and was an efficacious ?-antagonist (Ke=29.1nM). Molecular dynamics simulations of the ?-OR were carried out with the 1R,5R,9S-16 ?-agonist and the previously synthesized (1R,5R,9S)-(-)-5-(9-hydroxy-5-(3-hydroxyphenyl-2-phenylethyl)-2-azabicyclo[3.3.1]nonane (1R,5R,9S-(-)-NIH 11289) to provide a structural basis for the observed high affinities and efficacies. The critical roles of both the 9?-OH and the p-nitro group are elucidated, with the latter forming direct, persistent hydrogen bonds with residues deep in the binding cavity, and the former interacting with specific residues via highly structured water bridges.

SUBMITTER: Truong PM

PROVIDER: S-EPMC5407189 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Modulation of opioid receptor affinity and efficacy via N-substitution of 9β-hydroxy-5-(3-hydroxyphenyl)morphan: Synthesis and computer simulation study.

Truong Phong M PM Hassan Sergio A SA Lee Yong-Sok YS Kopajtic Theresa A TA Katz Jonathan L JL Chadderdon Aaron M AM Traynor John R JR Deschamps Jeffrey R JR Jacobson Arthur E AE Rice Kenner C KC

Bioorganic & medicinal chemistry 20170301 8

The enantiomers of a variety of N-alkyl-, N-aralkyl-, and N-cyclopropylalkyl-9β-hydroxy-5-(3-hydroxyphenyl)morphans were synthesized employing cyanogen bromide and K2CO3 to improve the original N-demethylation procedure. Their binding affinity to the μ-, δ-, and κ-opioid receptors (ORs) was determined and functional (GTPγ35S) assays were carried out on those with reasonable affinity. The 1R,5R,9S-enantiomers (1R,5R,9S)-(-)-5-(3-hydroxyphenyl)-2-(4-nitr ...[more]

PMID: 28314512

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Project description:BackgroundOpioid-related mortality is high and increasing in the Western world, and interventions aimed at reducing opioid-related deaths represent an important area of study. In Skåne County, Sweden, a patient choice reform resulted in increased access to opioid substitution treatment (OST). In addition, a gradual shift towards less restrictive terms for exclusion from OST has been implemented. The aim of this study was to assess the impact of these policy changes on opioid-related deaths.MethodsDetailed data on opioid-related deaths in Skåne during the 2 years prior to and following the policy change were obtained from forensic records and from health care services. Data on overdose deaths for Skåne and the rest of Sweden were obtained using publicly available national register data. Time periods were used as the predictor for opioid-related deaths in the forensic data. The national level data were used in a natural experiment design in which rates of overdose deaths were compared between Skåne and the rest of Sweden before and after the intervention.ResultsThere was no significant difference in the number of deaths in Skåne between the data collection periods (RR: 1.18 95% CI:0.89-1.57, p= 0.251). The proportion of deaths among patients enrolled in OST increased between the two periods (2.61, 1.12-6.10, p= 0.026). There was no change in deaths related to methadone or buprenorphine in relation to deaths due to the other opioids included in the study (0.92, 0.51-1.63, p= 0.764). An analysis of national mortality data showed an annual relative decrease in unintentional drug deaths in Skåne compared to the rest of Sweden following the onset of the reform (0.90, 0.84-0,97, p= 0.004).ConclusionsOpioid-related deaths, as assessed using forensic data, has not changed significantly in Skåne following a change to lower-threshold OST. By contrast, national level data indicate that the policy change has been associated with decreased overdose deaths. The discrepancy between these results highlights the need for more research to elucidate this issue. The result that more patients die during ongoing OST following an increase in access to treatment underlines the need for further preventive interventions within the OST treatment setting.

Project description:Syringomyelia is a pathological condition in which fluid-filled cavities (syringes) form and expand in the spinal cord. Syringomyelia is often linked with obstruction of the craniocervical junction and a Chiari malformation, which is similar in both humans and animals. Some brachycephalic toy breed dogs such as Cavalier King Charles Spaniels (CKCS) are particularly predisposed. The exact mechanism of the formation of syringomyelia is undetermined and consequently with the lack of clinical explanation, engineers and mathematicians have resorted to computer models to identify possible physical mechanisms that can lead to syringes. We developed a computer model of the spinal cavity of a CKCS suffering from a large syrinx. The model was excited at the cranial end to simulate the movement of the cerebrospinal fluid (CSF) and the spinal cord due to the shift of blood volume in the cranium related to the cardiac cycle. To simulate the normal condition, the movement was prescribed to the CSF. To simulate the pathological condition, the movement of CSF was blocked.For normal conditions the pressure in the SAS was approximately 400 Pa and the same applied to all stress components in the spinal cord. The stress was uniformly distributed along the length of the spinal cord. When the blockage between the cranial and spinal CSF spaces forced the cord to move with the cardiac cycle, shear and axial normal stresses in the cord increased significantly. The sites where the elevated stress was most pronounced coincided with the axial locations where the syringes typically form, but they were at the perimeter rather than in the central portion of the cord. This elevated stress originated from the bending of the cord at the locations where its curvature was high.The results suggest that it is possible that repetitive stressing of the spinal cord caused by its exaggerated movement could be a cause for the formation of initial syringes. Further consideration of factors such as cord tethering and the difference in mechanical properties of white and grey matter is needed to fully explore this possibility.

Project description:Despite major advances in the study of glioma, the quantitative links between intra-tumor molecular/cellular properties, clinically observable properties such as morphology, and critical tumor behaviors such as growth and invasiveness remain unclear, hampering more effective coupling of tumor physical characteristics with implications for prognosis and therapy. Although molecular biology, histopathology, and radiological imaging are employed in this endeavor, studies are severely challenged by the multitude of different physical scales involved in tumor growth, i.e., from molecular nanoscale to cell microscale and finally to tissue centimeter scale. Consequently, it is often difficult to determine the underlying dynamics across dimensions. New techniques are needed to tackle these issues. Here, we address this multi-scalar problem by employing a novel predictive three-dimensional mathematical and computational model based on first-principle equations (conservation laws of physics) that describe mathematically the diffusion of cell substrates and other processes determining tumor mass growth and invasion. The model uses conserved variables to represent known determinants of glioma behavior, e.g., cell density and oxygen concentration, as well as biological functional relationships and parameters linking phenomena at different scales whose specific forms and values are hypothesized and calculated based on in vitro and in vivo experiments and from histopathology of tissue specimens from human gliomas. This model enables correlation of glioma morphology to tumor growth by quantifying interdependence of tumor mass on the microenvironment (e.g., hypoxia, tissue disruption) and on the cellular phenotypes (e.g., mitosis and apoptosis rates, cell adhesion strength). Once functional relationships between variables and associated parameter values have been informed, e.g., from histopathology or intra-operative analysis, this model can be used for disease diagnosis/prognosis, hypothesis testing, and to guide surgery and therapy. In particular, this tool identifies and quantifies the effects of vascularization and other cell-scale glioma morphological characteristics as predictors of tumor-scale growth and invasion.

Dataset Information

Modulation of opioid receptor affinity and efficacy via N-substitution of 9?-hydroxy-5-(3-hydroxyphenyl)morphan: Synthesis and computer simulation study.

Publications

Modulation of opioid receptor affinity and efficacy via N-substitution of 9β-hydroxy-5-(3-hydroxyphenyl)morphan: Synthesis and computer simulation study.

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