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Gisela Skopp - One of the best experts on this subject based on the ideXlab platform.
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medicinal delta 9 Tetrahydrocannabinol dronabinol impairs on the road driving performance of occasional and heavy cannabis users but is not detected in standard field sobriety tests
Addiction, 2012Co-Authors: Wendy M Bosker, Gisela Skopp, Kim P C Kuypers, Eef L Theunissen, Anke Surinx, Roos J Blankespoor, W K Jeffery, H C Walls, C J Van Leeuwen, Johannes G RamaekersAbstract:Aims The acute and chronic effects of dronabinol [medicinal ?9-Tetrahydrocannabinol (THC)] on actual driving performance and the Standard Field Sobriety Test (SFST) were assessed. It was hypothesized that occasional users would be impaired on these tests and that heavy users would show less impairment due to tolerance. Design, setting and participants Double-blind, placebo-controlled, randomized, three-way cross-over study. Twelve occasional and 12 heavy cannabis users (14 males/10 females) received single doses of placebo, 10 and 20?mg dronabinol. Measurements Standard deviation of lateral position (SDLP; i.e. weaving) is the primary measure of road-tracking control. Time to speed adaptation (TSA) is the primary reaction-time measure in the car-following test. Percentage of impaired individuals on the SFST and subjective high on a visual analogue scale were secondary measures. Findings Superiority tests showed that SDLP (P?=?0.008) and TSA (P?=?0.011) increased after dronabinol in occasional users. Equivalence tests demonstrated that dronabinol-induced increments in SDLP were bigger than impairment associated with BAC of 0.5?mg/ml in occasional and heavy users, although the magnitude of driving impairment was generally less in heavy users. The SFST did not discriminate between conditions. Levels of subjective high were comparable in occasional and heavy users. Conclusions Dronabinol (medicinal Tetrahydrocannabinol) impairs driving performance in occasional and heavy users in a dose-dependent way, but to a lesser degree in heavy users due possibly to tolerance. The Standard Field Sobriety Test is not sensitive to clinically relevant driving impairment caused by oral Tetrahydrocannabinol.
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medicinal δ 9 Tetrahydrocannabinol dronabinol impairs on the road driving performance of occasional and heavy cannabis users but is not detected in standard field sobriety tests
Addiction, 2012Co-Authors: Wendy M Bosker, Gisela Skopp, Kim P C Kuypers, Eef L Theunissen, Anke Surinx, Roos J Blankespoor, W K Jeffery, C J Van Leeuwen, Chip H Walls, Johannes G RamaekersAbstract:AIMS: The acute and chronic effects of dronabinol [medicinal Δ(9) -Tetrahydrocannabinol (THC)] on actual driving performance and the Standard Field Sobriety Test (SFST) were assessed. It was hypothesized that occasional users would be impaired on these tests and that heavy users would show less impairment due to tolerance. DESIGN, SETTING AND PARTICIPANTS: Double-blind, placebo-controlled, randomized, three-way cross-over study. Twelve occasional and 12 heavy cannabis users (14 males/10 females) received single doses of placebo, 10 and 20 mg dronabinol. MEASUREMENTS: Standard deviation of lateral position (SDLP; i.e. weaving) is the primary measure of road-tracking control. Time to speed adaptation (TSA) is the primary reaction-time measure in the car-following test. Percentage of impaired individuals on the SFST and subjective high on a visual analogue scale were secondary measures. FINDINGS: Superiority tests showed that SDLP (P = 0.008) and TSA (P = 0.011) increased after dronabinol in occasional users. Equivalence tests demonstrated that dronabinol-induced increments in SDLP were bigger than impairment associated with BAC of 0.5 mg/ml in occasional and heavy users, although the magnitude of driving impairment was generally less in heavy users. The SFST did not discriminate between conditions. Levels of subjective high were comparable in occasional and heavy users. CONCLUSIONS: Dronabinol (medicinal Tetrahydrocannabinol) impairs driving performance in occasional and heavy users in a dose-dependent way, but to a lesser degree in heavy users due possibly to tolerance. The Standard Field Sobriety Test is not sensitive to clinically relevant driving impairment caused by oral Tetrahydrocannabinol.
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medicinal δ 9 Tetrahydrocannabinol dronabinol impairs on the road driving performance of occasional and heavy cannabis users but is not detected in standard field sobriety tests
Addiction, 2012Co-Authors: Wendy M Bosker, Gisela Skopp, Kim P C Kuypers, Eef L Theunissen, Anke Surinx, Roos J Blankespoor, W K Jeffery, Chip H Walls, Cees J Van Leeuwen, Johannes G RamaekersAbstract:AIMS: The acute and chronic effects of dronabinol (medicinal Tetrahydrocannabinol) on actual driving performance and the Standard Field Sobriety Test (SFST) were assessed. It was hypothesized that occasional users would be impaired on these tests and that heavy users would show less impairment due to tolerance. DESIGN, SETTING AND PARTICIPANTS: Double-blind, placebo-controlled, randomized, 3-way cross-over study. Twelve occasional and twelve heavy cannabis users (14 males/ 10 females) received single doses of placebo, 10 and 20 mg dronabinol. MEASUREMENTS: Standard deviation of lateral position (SDLP; i.e. weaving) is the primary measure of road tracking control. Time to speed adaptation (TSA) is the primary reaction time measure in the car-following test. Percentage of impaired individuals on the SFST and subjective high on a visual analogue scale were secondary measures. FINDINGS: Superiority tests showed that SDLP (p=0.008) and TSA (p=0.011) increased after dronabinol in occasional users. Equivalence tests demonstrated that dronabinol-induced increments in SDLP, were bigger than impairment associated with BAC of 0.5 mg/mL in occasional and heavy users, although the magnitude of driving impairment was generally less in heavy users. The SFST did not discriminate between conditions. Levels of subjective high were comparable in occasional and heavy users. CONCLUSIONS: Dronabinol (medicinal Tetrahydrocannabinol) impairs driving performance in occasional and heavy users in a dose-dependent way, but to a lesser degree in heavy users possibly due to tolerance. The Standard Field Sobriety Test is not sensitive to clinically relevant driving impairment caused by oral Tetrahydrocannabinol. Language: en
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partition coefficient blood to plasma ratio protein binding and short term stability of 11 nor δ9 carboxy Tetrahydrocannabinol glucuronide
Forensic Science International, 2002Co-Authors: Gisela Skopp, L Potsch, M Mauden, Barbara RichterAbstract:11-Nor-Delta(9)-carboxy Tetrahydrocannabinol glucuronide (THCCOOglu) is a major metabolite of Tetrahydrocannabinol in blood. Despite its mass spectrometric identification already in 1980, further physicochemical data of THCCOOglu have not been established. Therefore, the octanol/buffer partition coefficient P and the blood to plasma ratio b/p for THCCOOglu concentrations of 100 and 500ng/ml were investigated. Protein binding of the glucuronide was established from spiked albumin solutions at a level of 250ng/ml as well as from authentic samples. The data were compared to those of 11-nor-Delta(9)-carboxy Tetrahydrocannabinol (THCCOOH). In addition, the short-term stability of THCCOOglu in plasma at different storage temperatures was studied. Analysis was performed by LC/MS/MS. The glucuronide partition coefficient P (mean: 17.4 and 18.0 for 100 and 500ng/ml, respectively) was unexpectedly lipophilic at pH 7.4. Its blood to plasma ratios averaged 0.62 and 0.68 at 100 and 500ng/ml, respectively. THCCOOglu was highly reversibly bound to albumin (mean: 97%), and the mean fraction bound did not differ from that determined from authentic samples. THCCOOglu degraded even at a storage temperature of 4 degrees C and THCCOOH was identified as a major decomposition product.
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partition coefficient blood to plasma ratio protein binding and short term stability of 11 nor δ9 carboxy Tetrahydrocannabinol glucuronide
Forensic Science International, 2002Co-Authors: Gisela Skopp, L Potsch, M Mauden, Barbara RichterAbstract:Abstract 11-Nor-Δ 9 -carboxy Tetrahydrocannabinol glucuronide (THCCOOglu) is a major metabolite of Tetrahydrocannabinol in blood. Despite its mass spectrometric identification already in 1980, further physicochemical data of THCCOOglu have not been established. Therefore, the octanol/buffer partition coefficient P and the blood to plasma ratio b/p for THCCOOglu concentrations of 100 and 500 ng/ml were investigated. Protein binding of the glucuronide was established from spiked albumin solutions at a level of 250 ng/ml as well as from authentic samples. The data were compared to those of 11-nor-Δ 9 -carboxy Tetrahydrocannabinol (THCCOOH). In addition, the short-term stability of THCCOOglu in plasma at different storage temperatures was studied. Analysis was performed by LC/MS/MS. The glucuronide partition coefficient P (mean: 17.4 and 18.0 for 100 and 500 ng/ml, respectively) was unexpectedly lipophilic at pH 7.4. Its blood to plasma ratios averaged 0.62 and 0.68 at 100 and 500 ng/ml, respectively. THCCOOglu was highly reversibly bound to albumin (mean: 97%), and the mean fraction bound did not differ from that determined from authentic samples. THCCOOglu degraded even at a storage temperature of 4 °C and THCCOOH was identified as a major decomposition product.
Johannes G Ramaekers - One of the best experts on this subject based on the ideXlab platform.
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medicinal delta 9 Tetrahydrocannabinol dronabinol impairs on the road driving performance of occasional and heavy cannabis users but is not detected in standard field sobriety tests
Addiction, 2012Co-Authors: Wendy M Bosker, Gisela Skopp, Kim P C Kuypers, Eef L Theunissen, Anke Surinx, Roos J Blankespoor, W K Jeffery, H C Walls, C J Van Leeuwen, Johannes G RamaekersAbstract:Aims The acute and chronic effects of dronabinol [medicinal ?9-Tetrahydrocannabinol (THC)] on actual driving performance and the Standard Field Sobriety Test (SFST) were assessed. It was hypothesized that occasional users would be impaired on these tests and that heavy users would show less impairment due to tolerance. Design, setting and participants Double-blind, placebo-controlled, randomized, three-way cross-over study. Twelve occasional and 12 heavy cannabis users (14 males/10 females) received single doses of placebo, 10 and 20?mg dronabinol. Measurements Standard deviation of lateral position (SDLP; i.e. weaving) is the primary measure of road-tracking control. Time to speed adaptation (TSA) is the primary reaction-time measure in the car-following test. Percentage of impaired individuals on the SFST and subjective high on a visual analogue scale were secondary measures. Findings Superiority tests showed that SDLP (P?=?0.008) and TSA (P?=?0.011) increased after dronabinol in occasional users. Equivalence tests demonstrated that dronabinol-induced increments in SDLP were bigger than impairment associated with BAC of 0.5?mg/ml in occasional and heavy users, although the magnitude of driving impairment was generally less in heavy users. The SFST did not discriminate between conditions. Levels of subjective high were comparable in occasional and heavy users. Conclusions Dronabinol (medicinal Tetrahydrocannabinol) impairs driving performance in occasional and heavy users in a dose-dependent way, but to a lesser degree in heavy users due possibly to tolerance. The Standard Field Sobriety Test is not sensitive to clinically relevant driving impairment caused by oral Tetrahydrocannabinol.
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medicinal δ 9 Tetrahydrocannabinol dronabinol impairs on the road driving performance of occasional and heavy cannabis users but is not detected in standard field sobriety tests
Addiction, 2012Co-Authors: Wendy M Bosker, Gisela Skopp, Kim P C Kuypers, Eef L Theunissen, Anke Surinx, Roos J Blankespoor, W K Jeffery, C J Van Leeuwen, Chip H Walls, Johannes G RamaekersAbstract:AIMS: The acute and chronic effects of dronabinol [medicinal Δ(9) -Tetrahydrocannabinol (THC)] on actual driving performance and the Standard Field Sobriety Test (SFST) were assessed. It was hypothesized that occasional users would be impaired on these tests and that heavy users would show less impairment due to tolerance. DESIGN, SETTING AND PARTICIPANTS: Double-blind, placebo-controlled, randomized, three-way cross-over study. Twelve occasional and 12 heavy cannabis users (14 males/10 females) received single doses of placebo, 10 and 20 mg dronabinol. MEASUREMENTS: Standard deviation of lateral position (SDLP; i.e. weaving) is the primary measure of road-tracking control. Time to speed adaptation (TSA) is the primary reaction-time measure in the car-following test. Percentage of impaired individuals on the SFST and subjective high on a visual analogue scale were secondary measures. FINDINGS: Superiority tests showed that SDLP (P = 0.008) and TSA (P = 0.011) increased after dronabinol in occasional users. Equivalence tests demonstrated that dronabinol-induced increments in SDLP were bigger than impairment associated with BAC of 0.5 mg/ml in occasional and heavy users, although the magnitude of driving impairment was generally less in heavy users. The SFST did not discriminate between conditions. Levels of subjective high were comparable in occasional and heavy users. CONCLUSIONS: Dronabinol (medicinal Tetrahydrocannabinol) impairs driving performance in occasional and heavy users in a dose-dependent way, but to a lesser degree in heavy users due possibly to tolerance. The Standard Field Sobriety Test is not sensitive to clinically relevant driving impairment caused by oral Tetrahydrocannabinol.
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medicinal δ 9 Tetrahydrocannabinol dronabinol impairs on the road driving performance of occasional and heavy cannabis users but is not detected in standard field sobriety tests
Addiction, 2012Co-Authors: Wendy M Bosker, Gisela Skopp, Kim P C Kuypers, Eef L Theunissen, Anke Surinx, Roos J Blankespoor, W K Jeffery, Chip H Walls, Cees J Van Leeuwen, Johannes G RamaekersAbstract:AIMS: The acute and chronic effects of dronabinol (medicinal Tetrahydrocannabinol) on actual driving performance and the Standard Field Sobriety Test (SFST) were assessed. It was hypothesized that occasional users would be impaired on these tests and that heavy users would show less impairment due to tolerance. DESIGN, SETTING AND PARTICIPANTS: Double-blind, placebo-controlled, randomized, 3-way cross-over study. Twelve occasional and twelve heavy cannabis users (14 males/ 10 females) received single doses of placebo, 10 and 20 mg dronabinol. MEASUREMENTS: Standard deviation of lateral position (SDLP; i.e. weaving) is the primary measure of road tracking control. Time to speed adaptation (TSA) is the primary reaction time measure in the car-following test. Percentage of impaired individuals on the SFST and subjective high on a visual analogue scale were secondary measures. FINDINGS: Superiority tests showed that SDLP (p=0.008) and TSA (p=0.011) increased after dronabinol in occasional users. Equivalence tests demonstrated that dronabinol-induced increments in SDLP, were bigger than impairment associated with BAC of 0.5 mg/mL in occasional and heavy users, although the magnitude of driving impairment was generally less in heavy users. The SFST did not discriminate between conditions. Levels of subjective high were comparable in occasional and heavy users. CONCLUSIONS: Dronabinol (medicinal Tetrahydrocannabinol) impairs driving performance in occasional and heavy users in a dose-dependent way, but to a lesser degree in heavy users possibly due to tolerance. The Standard Field Sobriety Test is not sensitive to clinically relevant driving impairment caused by oral Tetrahydrocannabinol. Language: en
Barbara Richter - One of the best experts on this subject based on the ideXlab platform.
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partition coefficient blood to plasma ratio protein binding and short term stability of 11 nor δ9 carboxy Tetrahydrocannabinol glucuronide
Forensic Science International, 2002Co-Authors: Gisela Skopp, L Potsch, M Mauden, Barbara RichterAbstract:11-Nor-Delta(9)-carboxy Tetrahydrocannabinol glucuronide (THCCOOglu) is a major metabolite of Tetrahydrocannabinol in blood. Despite its mass spectrometric identification already in 1980, further physicochemical data of THCCOOglu have not been established. Therefore, the octanol/buffer partition coefficient P and the blood to plasma ratio b/p for THCCOOglu concentrations of 100 and 500ng/ml were investigated. Protein binding of the glucuronide was established from spiked albumin solutions at a level of 250ng/ml as well as from authentic samples. The data were compared to those of 11-nor-Delta(9)-carboxy Tetrahydrocannabinol (THCCOOH). In addition, the short-term stability of THCCOOglu in plasma at different storage temperatures was studied. Analysis was performed by LC/MS/MS. The glucuronide partition coefficient P (mean: 17.4 and 18.0 for 100 and 500ng/ml, respectively) was unexpectedly lipophilic at pH 7.4. Its blood to plasma ratios averaged 0.62 and 0.68 at 100 and 500ng/ml, respectively. THCCOOglu was highly reversibly bound to albumin (mean: 97%), and the mean fraction bound did not differ from that determined from authentic samples. THCCOOglu degraded even at a storage temperature of 4 degrees C and THCCOOH was identified as a major decomposition product.
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partition coefficient blood to plasma ratio protein binding and short term stability of 11 nor δ9 carboxy Tetrahydrocannabinol glucuronide
Forensic Science International, 2002Co-Authors: Gisela Skopp, L Potsch, M Mauden, Barbara RichterAbstract:Abstract 11-Nor-Δ 9 -carboxy Tetrahydrocannabinol glucuronide (THCCOOglu) is a major metabolite of Tetrahydrocannabinol in blood. Despite its mass spectrometric identification already in 1980, further physicochemical data of THCCOOglu have not been established. Therefore, the octanol/buffer partition coefficient P and the blood to plasma ratio b/p for THCCOOglu concentrations of 100 and 500 ng/ml were investigated. Protein binding of the glucuronide was established from spiked albumin solutions at a level of 250 ng/ml as well as from authentic samples. The data were compared to those of 11-nor-Δ 9 -carboxy Tetrahydrocannabinol (THCCOOH). In addition, the short-term stability of THCCOOglu in plasma at different storage temperatures was studied. Analysis was performed by LC/MS/MS. The glucuronide partition coefficient P (mean: 17.4 and 18.0 for 100 and 500 ng/ml, respectively) was unexpectedly lipophilic at pH 7.4. Its blood to plasma ratios averaged 0.62 and 0.68 at 100 and 500 ng/ml, respectively. THCCOOglu was highly reversibly bound to albumin (mean: 97%), and the mean fraction bound did not differ from that determined from authentic samples. THCCOOglu degraded even at a storage temperature of 4 °C and THCCOOH was identified as a major decomposition product.
Barbora Maralikova - One of the best experts on this subject based on the ideXlab platform.
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simultaneous determination of δ9 Tetrahydrocannabinol 11 hydroxy δ9 Tetrahydrocannabinol and 11 nor 9 carboxy δ9 Tetrahydrocannabinol in human plasma by high performance liquid chromatography tandem mass spectrometry
Journal of Mass Spectrometry, 2004Co-Authors: Barbora Maralikova, Wolfgang WeinmannAbstract:A rapid and sensitive method for the simultaneous confirmatory analysis of three forensic most relevant cannabinoids, Delta(9)-Tetrahydrocannabinol (THC), 11-hydroxy-Delta(9)-Tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-Delta(9)-Tetrahydrocannabinol (THC-COOH), by means of high-performance liquid chromatography/tandem mass spectrometry (LC/MS/MS) in human plasma was developed and fully validated. Sample clean-up was performed by automated silica-based solid-phase extraction and the separation was carried out using a PhenylHexyl column (50 x 2 mm i.d., 3 micro m) and acetonitrile-5 mM ammonium acetate gradient elution. Data were acquired with an API 3000 LC/MS/MS system equipped with a turboionspray interface and triple quadrupole mass analyzer using positive electrospray ionization and multiple reaction monitoring. Two MS/MS transitions for each substance were monitored and deuterated analogues of analytes were used as internal standards for quantitation. The limit of quantitation was 0.8 ng ml(-1) for THC, 0.8 ng ml(-1) for 11-OH-THC and 4.3 ng ml(-1) for THC-COOH and linearity with a correlation coefficient r(2) = 0.999 was achieved up to 100 ng ml(-1) for THC and 11-OH-THC and 500 ng ml(-1) for THC-COOH. The limits of detection were 0.2 ng ml(-1) for THC, 0.2 ng ml(-1) for 11-OH-THC and 1.6 ng ml(-1) for THC-COOH. The developed LC/MS/MS method was also successfully used for the determination of THC-COOH-glucuronide, the phase II metabolite of THC-COOH.
Castañeda Castellanos, Brian Alonso - One of the best experts on this subject based on the ideXlab platform.
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Modelo de interacción molecular de metabolitos presentes en la especie Cannabis satival con la enzima ciclooxigebasa-1 (COX1) y la enzima ciclooxigensa-2 (COX2) de homo sapines
Bogotá : Universidad de Ciencias Aplicadas y Ambientales 2019, 2019Co-Authors: Romero Salamanca, Juan Manuel, Castañeda Castellanos, Brian AlonsoAbstract:265 páginas : ilustraciones, gráficasEn el represente estudio se determinó la interacción molecular de los metabolitos conocidos en la especie Cannabis sativa L. con las dos isoformas de la enzima ciclooxigenasa (COX1 y COX2) de Homo sapiens, a partir del uso de técnicas computacionales de modelamiento por homología y acoplamiento (docking). Se modelaron por medio de homología de proteínas las dos isoformas enzimáticas COX1 y COX2 de Homo sapiens, obteniéndose modelos teóricos moleculares validos según el grafico de Ramachandran. Además, se sometieron los modelos obtenidos a un acoplamiento molecular con dos compuestos endógenos: ácido araquidónico y PGG2, y dos fármacos de actividad conocida: Flurbiprofeno y Celecoxib. Dichos acoplamientos fueron establecidos en los sitios catalíticos peroxidasa, para la enzima COX1 y ciclooxigenasa, para la enzima COX2, demostrando la idoneidad de los modelos para el posterior cribado virtual. Por otro lado, los 113 compuestos seleccionados, provenientes de la especie Cannabis sativa L. fueron evaluados a partir de los criterios establecidos por Lipinski, en donde 93 de los compuestos cumplieron con todos los criterios. El metabolito de biotransformación mayoritario de cada uno de los 93 compuestos fue determinado, por medio de revisión bibliográfica, siendo la adición de grupos hidroxilos la reacción más frecuente en todos los compuestos. Los 93 compuestos seleccionados y sus metabolitos de biotransformación fueron sometidos a un proceso de cribado virtual, en donde se establecieron cuatro categorías de estudio y se seleccionaron los primeros cuatro compuestos o metabolitos de biotransformación con el valor de energía libre de unión (ΔG) y constante de inhibición (ki) más bajo en cada una de las categorías. El primer cribado virtual fue realizado para los 93 compuestos producto de biosíntesis en la especie Cannabis sativa L y la enzima COX1 (CATEGORIA I), el segundo relacionó los mismos compuestos y la enzima COX2 (CATEGORIA II); en la tercera categoría se efectuó el cribado virtual entre los productos de biotransformación y la COX1 (CATEGORIA III), y la cuarta categoría dichos productos de biotransformación fueron evaluados frente a la COX2 (CATEGORIA IV). Para la primera categoría se seleccionaron los siguientes compuestos: Friedelin, Delta-7-cis-isotetrahidrocannabivarina, Cannabinol-C2 y Epifriedelanol. En la Categoría II fueron seleccionados los siguientes compuestos: Delta-9-tetrahidrocannabinol, Cannabiorcol, Delta-9-tetrahidrocannabivarina y 10-oxo-delta-6a-tetrahidrocannabinol. En la Categoría III los metabolitos de biotransformación que siguen fueron seleccionados: Luteolin, Friedelin, Ácido delta-9-tetrahidrocannabinolico A y 3,3’-dihydroxy-5,4’-dimethoxy bibenzyl. Finalmente, en la Categoría IV fueron seleccionados los siguientes metabolitos de biotransformación: Luteolin, Delta-9-tetrahidrocannabivarina, Delta-7- cis-iso-tetrahidrocannabivarina y Cannabinol-C2. Los cuatro compuestos y los cuatro metabolitos de biotransformación seleccionados en el cribado virtual con el modelo teórico molecular de la enzima COX1 y COX2, respectivamente fueron sometidos a un proceso de acoplamiento molecular con las enzimas correspondientes. Todos los compuestos y metabolitos de biotransformación acoplados con la enzima COX1, presentaron interacciones de tipo hidrofóbico, pi-pi y catión-pi con aminoácidos importantes en el sitio catalítico peroxidasa (GLN203, HIS207 y PHE409). En contraste, siete de los compuestos acoplados con la enzima COX2 se unieron al sitio activo ciclooxigenasa y presentaron interacciones con aminoácidos involucrados en la reacción catalítica ciclooxigenasa (TYR248, VAL349, TYR355, TYR385 y SER530) excepto el metabolito de biotransformación Luteolin-7- glucósido, quien se unió al sitio activo catalítico peroxidasa, debido a su bajo valor de coeficiente de partición octanol:agua. Además, este metabolito fue el único compuesto evaluado que mostró una interacción tipo puente de hidrógeno. El tamaño de los compuestos y su hidrofobicidad puede estar implicado en la selectividad frente a los dos sitios activos catalíticos de las isoformas estudiadas. Así, los compuestos posible candidatos a fármacos inhibidores de la enzima COX1 se ven representados en los compuestos pertenecientes a la clase terpénica (Friedelin, Epifriedelanol y el metabolito de biotransformación del Friedelin), debido a su potencia. La alta selectividad del terpeno Friedelin frente al modelo teórico de la enzima COX1 de Homo sapiens, permite que dicho compuesto sea una alternativa viable al desarrollo de un posible fármaco. La subclase cannabinoide delta-9-tetrahidrocannabinol, por otro lado, presenta una inhibición selectiva frente al modelo teórico de la enzima COX2 de Homo sapiens, con una alta afinidad de unión. Los compuestos cannabinoides han sido ampliamente estudiados frente a su acción terapéutica, sin embargo, nuestros resultados demuestran que en otras clases fitoquímicas de compuestos pueden encontrarse una alternativa al tratamiento del dolor y la inflamaciónIn the present study, the molecular interaction of the metabolites known in the Cannabis sativa L. species with the two isoforms of the enzyme cyclooxygenase (COX1 and COX2) of Homo sapiens was determined, from the use of computational techniques of modeling by homology and coupling (docking). The two COX1 and COX2 enzymatic isoforms of Homo sapiens were modeled by means of protein homology, obtaining valid molecular theoretical models according to the Ramachandran graph. In addition, the obtained models were subjected to a molecular coupling with two endogenous compounds: arachidonic acid and PGG2, and two drugs of known activity: Flurbiprofen and Celecoxib. These couplings were established in peroxidase catalytic sites, for the enzyme COX1 and cyclooxygenase, for the COX2 enzyme, demonstrating the suitability of the models for subsequent virtual screening. On the other hand, the 113 selected compounds, from the Cannabis sativa L. species were evaluated based on the criteria established by Lipinski, where 93 of the compounds met all the criteria. The major biotransformation metabolite of each of the 93 compounds was determined by means of a literature review, the addition of hydroxyl groups being the most frequent reaction in all the compounds. The 93 selected compounds and their biotransformation metabolites were subjected to a virtual screening process, where four study categories were established and the first four biotransformation compounds or metabolites were selected with the value of binding-free energy (ΔG) and constant of inhibition (ki) lower in each of the categories. The first virtual screening was performed for the 93 compounds produced by biosynthesis in the species Cannabis sativa L and the enzyme COX1 (CATEGORY I), the second related the same compounds and the enzyme COX2 (CATEGORY II); in the third category, virtual screening was carried out between the biotransformation products and the COX1 (CATEGORY III), and the fourth category said biotransformation products were evaluated against the COX2 (CATEGORY IV). For the first category, the following compounds were selected: Friedelin, Delta-7-cis-isotetrahydrocannabivarin, Cannabinol-C2 and Epifriedelanol. In Category II the following compounds were selected: Delta-9- Tetrahydrocannabinol, Cannabiorcol, Delta-9-tetrahydrocannabivarin and 10-oxo-delta-6a-Tetrahydrocannabinol. In Category III the following biotransformation metabolites were selected: Luteolin, Friedelin, Delta-9-Tetrahydrocannabinol A and 3,3'-dihydroxy-5,4'-dimethoxy bibenzyl. Finally, in Category IV the following biotransformation metabolites were selected: Luteolin, Delta-9-tetrahydrocannabivarin, Delta-7- cis-iso-tetrahydrocannabivarin and Cannabinol-C2. The four compounds and the four metabolites of biotransformation selected in the virtual screening with the theoretical molecular model of the enzyme COX1 and COX2, respectively, were subjected to a process of molecular coupling with the corresponding enzymes. All the biotransformation compounds and metabolites coupled with the COX1 enzyme showed interactions of hydrophobic type, pi-pi and cation-pi with important amino acids in the catalytic peroxidase site (GLN203, HIS207 and PHE409). In contrast, seven of the compounds coupled with the COX2 enzyme were linked to the active site cyclooxygenase and presented interactions with amino acids involved in the cyclooxygenase catalytic reaction (TYR248, VAL349, TYR355, TYR385 and SER530) except the biotransformation metabolite Luteolin-7- glucoside, who joined the peroxidase catalytic active site, due to its low partition coefficient octanol: water. In addition, this metabolite was the only compound evaluated that showed a hydrogen-bond type interaction. The size of the compounds and their hydrophobicity may be involved in the selectivity towards the two catalytic active sites of the isoforms studied. Thus, the possible candidate compounds for drugs that inhibit the COX1 enzyme are represented in the compounds belonging to the terpenic class (Friedelin, Epifriedelanol and the biotransformation metabolite of Friedelin), due to their potency. The high selectivity of the Friedelin terpene compared to the theoretical model of the COX1 enzyme of Homo sapiens, allows this compound to be a viable alternative to the development of a possible drug. The cannabinoid subclass delta-9-Tetrahydrocannabinol, on the other hand, exhibits a selective inhibition against the theoretical model of the COX2 enzyme of Homo sapiens, with a high binding affinity. The cannabinoid compounds have been widely studied against their therapeutic action, however, our results show that in other phytochemical classes of compounds an alternative to the treatment of pain and inflammation can be found.Incluye bibliografí
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Modelo de interacción molecular de metabolitos presentes en la especie Cannabis satival con la enzima ciclooxigebasa-1 (COX1) y la enzima ciclooxigensa-2 (COX2) de homo sapines
Química Farmacéutica, 2019Co-Authors: Romero Salamanca, Juan Manuel, Castañeda Castellanos, Brian AlonsoAbstract:265 páginas : ilustraciones, gráficasEn el represente estudio se determinó la interacción molecular de los metabolitos conocidos en la especie Cannabis sativa L. con las dos isoformas de la enzima ciclooxigenasa (COX1 y COX2) de Homo sapiens, a partir del uso de técnicas computacionales de modelamiento por homología y acoplamiento (docking). Se modelaron por medio de homología de proteínas las dos isoformas enzimáticas COX1 y COX2 de Homo sapiens, obteniéndose modelos teóricos moleculares validos según el grafico de Ramachandran. Además, se sometieron los modelos obtenidos a un acoplamiento molecular con dos compuestos endógenos: ácido araquidónico y PGG2, y dos fármacos de actividad conocida: Flurbiprofeno y Celecoxib. Dichos acoplamientos fueron establecidos en los sitios catalíticos peroxidasa, para la enzima COX1 y ciclooxigenasa, para la enzima COX2, demostrando la idoneidad de los modelos para el posterior cribado virtual. Por otro lado, los 113 compuestos seleccionados, provenientes de la especie Cannabis sativa L. fueron evaluados a partir de los criterios establecidos por Lipinski, en donde 93 de los compuestos cumplieron con todos los criterios. El metabolito de biotransformación mayoritario de cada uno de los 93 compuestos fue determinado, por medio de revisión bibliográfica, siendo la adición de grupos hidroxilos la reacción más frecuente en todos los compuestos. Los 93 compuestos seleccionados y sus metabolitos de biotransformación fueron sometidos a un proceso de cribado virtual, en donde se establecieron cuatro categorías de estudio y se seleccionaron los primeros cuatro compuestos o metabolitos de biotransformación con el valor de energía libre de unión (ΔG) y constante de inhibición (ki) más bajo en cada una de las categorías. El primer cribado virtual fue realizado para los 93 compuestos producto de biosíntesis en la especie Cannabis sativa L y la enzima COX1 (CATEGORIA I), el segundo relacionó los mismos compuestos y la enzima COX2 (CATEGORIA II); en la tercera categoría se efectuó el cribado virtual entre los productos de biotransformación y la COX1 (CATEGORIA III), y la cuarta categoría dichos productos de biotransformación fueron evaluados frente a la COX2 (CATEGORIA IV). Para la primera categoría se seleccionaron los siguientes compuestos: Friedelin, Delta-7-cis-isotetrahidrocannabivarina, Cannabinol-C2 y Epifriedelanol. En la Categoría II fueron seleccionados los siguientes compuestos: Delta-9-tetrahidrocannabinol, Cannabiorcol, Delta-9-tetrahidrocannabivarina y 10-oxo-delta-6a-tetrahidrocannabinol. En la Categoría III los metabolitos de biotransformación que siguen fueron seleccionados: Luteolin, Friedelin, Ácido delta-9-tetrahidrocannabinolico A y 3,3’-dihydroxy-5,4’-dimethoxy bibenzyl. Finalmente, en la Categoría IV fueron seleccionados los siguientes metabolitos de biotransformación: Luteolin, Delta-9-tetrahidrocannabivarina, Delta-7- cis-iso-tetrahidrocannabivarina y Cannabinol-C2. Los cuatro compuestos y los cuatro metabolitos de biotransformación seleccionados en el cribado virtual con el modelo teórico molecular de la enzima COX1 y COX2, respectivamente fueron sometidos a un proceso de acoplamiento molecular con las enzimas correspondientes. Todos los compuestos y metabolitos de biotransformación acoplados con la enzima COX1, presentaron interacciones de tipo hidrofóbico, pi-pi y catión-pi con aminoácidos importantes en el sitio catalítico peroxidasa (GLN203, HIS207 y PHE409). En contraste, siete de los compuestos acoplados con la enzima COX2 se unieron al sitio activo ciclooxigenasa y presentaron interacciones con aminoácidos involucrados en la reacción catalítica ciclooxigenasa (TYR248, VAL349, TYR355, TYR385 y SER530) excepto el metabolito de biotransformación Luteolin-7- glucósido, quien se unió al sitio activo catalítico peroxidasa, debido a su bajo valor de coeficiente de partición octanol:agua. Además, este metabolito fue el único compuesto evaluado que mostró una interacción tipo puente de hidrógeno. El tamaño de los compuestos y su hidrofobicidad puede estar implicado en la selectividad frente a los dos sitios activos catalíticos de las isoformas estudiadas. Así, los compuestos posible candidatos a fármacos inhibidores de la enzima COX1 se ven representados en los compuestos pertenecientes a la clase terpénica (Friedelin, Epifriedelanol y el metabolito de biotransformación del Friedelin), debido a su potencia. La alta selectividad del terpeno Friedelin frente al modelo teórico de la enzima COX1 de Homo sapiens, permite que dicho compuesto sea una alternativa viable al desarrollo de un posible fármaco. La subclase cannabinoide delta-9-tetrahidrocannabinol, por otro lado, presenta una inhibición selectiva frente al modelo teórico de la enzima COX2 de Homo sapiens, con una alta afinidad de unión. Los compuestos cannabinoides han sido ampliamente estudiados frente a su acción terapéutica, sin embargo, nuestros resultados demuestran que en otras clases fitoquímicas de compuestos pueden encontrarse una alternativa al tratamiento del dolor y la inflamaciónIn the present study, the molecular interaction of the metabolites known in the Cannabis sativa L. species with the two isoforms of the enzyme cyclooxygenase (COX1 and COX2) of Homo sapiens was determined, from the use of computational techniques of modeling by homology and coupling (docking). The two COX1 and COX2 enzymatic isoforms of Homo sapiens were modeled by means of protein homology, obtaining valid molecular theoretical models according to the Ramachandran graph. In addition, the obtained models were subjected to a molecular coupling with two endogenous compounds: arachidonic acid and PGG2, and two drugs of known activity: Flurbiprofen and Celecoxib. These couplings were established in peroxidase catalytic sites, for the enzyme COX1 and cyclooxygenase, for the COX2 enzyme, demonstrating the suitability of the models for subsequent virtual screening. On the other hand, the 113 selected compounds, from the Cannabis sativa L. species were evaluated based on the criteria established by Lipinski, where 93 of the compounds met all the criteria. The major biotransformation metabolite of each of the 93 compounds was determined by means of a literature review, the addition of hydroxyl groups being the most frequent reaction in all the compounds. The 93 selected compounds and their biotransformation metabolites were subjected to a virtual screening process, where four study categories were established and the first four biotransformation compounds or metabolites were selected with the value of binding-free energy (ΔG) and constant of inhibition (ki) lower in each of the categories. The first virtual screening was performed for the 93 compounds produced by biosynthesis in the species Cannabis sativa L and the enzyme COX1 (CATEGORY I), the second related the same compounds and the enzyme COX2 (CATEGORY II); in the third category, virtual screening was carried out between the biotransformation products and the COX1 (CATEGORY III), and the fourth category said biotransformation products were evaluated against the COX2 (CATEGORY IV). For the first category, the following compounds were selected: Friedelin, Delta-7-cis-isotetrahydrocannabivarin, Cannabinol-C2 and Epifriedelanol. In Category II the following compounds were selected: Delta-9- Tetrahydrocannabinol, Cannabiorcol, Delta-9-tetrahydrocannabivarin and 10-oxo-delta-6a-Tetrahydrocannabinol. In Category III the following biotransformation metabolites were selected: Luteolin, Friedelin, Delta-9-Tetrahydrocannabinol A and 3,3'-dihydroxy-5,4'-dimethoxy bibenzyl. Finally, in Category IV the following biotransformation metabolites were selected: Luteolin, Delta-9-tetrahydrocannabivarin, Delta-7- cis-iso-tetrahydrocannabivarin and Cannabinol-C2. The four compounds and the four metabolites of biotransformation selected in the virtual screening with the theoretical molecular model of the enzyme COX1 and COX2, respectively, were subjected to a process of molecular coupling with the corresponding enzymes. All the biotransformation compounds and metabolites coupled with the COX1 enzyme showed interactions of hydrophobic type, pi-pi and cation-pi with important amino acids in the catalytic peroxidase site (GLN203, HIS207 and PHE409). In contrast, seven of the compounds coupled with the COX2 enzyme were linked to the active site cyclooxygenase and presented interactions with amino acids involved in the cyclooxygenase catalytic reaction (TYR248, VAL349, TYR355, TYR385 and SER530) except the biotransformation metabolite Luteolin-7- glucoside, who joined the peroxidase catalytic active site, due to its low partition coefficient octanol: water. In addition, this metabolite was the only compound evaluated that showed a hydrogen-bond type interaction. The size of the compounds and their hydrophobicity may be involved in the selectivity towards the two catalytic active sites of the isoforms studied. Thus, the possible candidate compounds for drugs that inhibit the COX1 enzyme are represented in the compounds belonging to the terpenic class (Friedelin, Epifriedelanol and the biotransformation metabolite of Friedelin), due to their potency. The high selectivity of the Friedelin terpene compared to the theoretical model of the COX1 enzyme of Homo sapiens, allows this compound to be a viable alternative to the development of a possible drug. The cannabinoid subclass delta-9-Tetrahydrocannabinol, on the other hand, exhibits a selective inhibition against the theoretical model of the COX2 enzyme of Homo sapiens, with a high binding affinity. The cannabinoid compounds have been widely studied against their therapeutic action, however, our results show that in other phytochemical classes of compounds an alternative to the treatment of pain and inflammation can be found.Incluye bibliografíaPregradoQuímico(a) Farmacéutic
