Descriptive molecular pharmacology of the δ opioid receptor (DOR): A computational study with structural approach.

This work focuses on the δ receptor (DOR), a G protein-coupled receptor (GPCR) belonging to the opioid receptor group. DOR is expressed in numerous tissues, particularly within the nervous system. Our study explores computationally the receptor's interactions with various ligands, including opiates and opioid peptides. It elucidates how these interactions influence the δ receptor response, relevant in a wide range of health and pathological processes. Thus, our investigation aims to explore the significance of DOR as an incoming drug target for pain relief and neurodegenerative diseases and as a source for novel opioid non-narcotic analgesic alternatives. We analyze the receptor's structural properties and interactions using Molecular Dynamics (MD) simulations and Gaussian-accelerated MD across different functional states. To thoroughly assess the primary differences in the structural and conformational ensembles across our different simulated systems, we initiated our study with 1 µs of conventional Molecular Dynamics. The strategy was chosen to encompass the full activation cycle of GPCRs, as activation processes typically occur within this microsecond range. Following the cMD, we extended our study with an additional 100 ns of Gaussian accelerated Molecular Dynamics (GaMD) to enhance the sampling of conformational states. This simulation approach allowed us to capture a comprehensive range of dynamic interactions and conformational changes that are crucial for GPCR activation as influenced by different ligands. Our study includes comparing agonist and antagonist complexes to uncover the collective patterns of their functional states, regarding activation, blocking, and inactivation of DOR, starting from experimental data. In addition, we also explored interactions between agonist and antagonist molecules from opiate and opioid classifications to establish robust structure-activity relationships. These interactions have been systematically quantified using a Quantitative Structure-Activity Relationships (QSAR) model. This research significantly contributes to our understanding of this significant pharmacological target, which is emerging as an attractive subject for drug development.

Synthesis and Evaluation of Antioxidant, Anti-Edematogenic and Antinociceptive Properties of Selenium-Sulfa Compounds.

Herein we describe results for the synthesis and synthetic application of 4-amino-3-(arylselenyl)benzenesulfonamides, and preliminary evaluation of antioxidant, anti-edematogenic and antinociceptive properties. This class of compounds was synthesized in good yields by a reaction of commercially available sulfanilamide and diorganyl diselenides in the presence of 10 mol% of I2 . Furthermore, the synthesized compound 4-amino-3-(phenylselenyl)benzenesulfonamide (3 a) was evaluated on complete Freund's adjuvant (CFA)-induced acute inflammatory pain. Dose- and time-response curves of antinociceptive effect of compound 3 a were performed using this experimental model. Also, the effect of compound 3 a was monitored in a hot-plate test to evaluate the acute non-inflammatory antinociception. The open-field test was performed to evaluate the locomotor and exploratory behaviors of mice. Oxidative stress markers, such as glutathione peroxidase activity; reactive species, non-protein thiols, and lipid peroxidation levels were performed to investigate the antioxidant action of compound 3 a. Our findings suggest that the antioxidant effect of compound 3 a may contribute to reducing the nociception and suppress the signaling pathways of inflammation on the local injury induced by CFA. Thus, compound 3 a reduced the paw edema as well as the hyperalgesic behavior in mice, being a promising therapeutic agent for the treatment of painful conditions.

Synthesis of a PVA drug delivery system for controlled release of a Tramadol-Dexketoprofen combination.

The local administration of analgesic combinations by means of degradable polymeric drug delivery systems is an alternative for the management of postoperative pain. We formulated a Tramadol-Dexketoprofen combination (TDC) loaded in poly(vinyl alcohol) (PVA) film. Films were prepared by the solvent casting method using three different molecular weights of PVA and crosslinking those films with citric acid, with the objective of controlling the drug release rate, which was evaluated by UV-vis spectrometry. Non-crosslinked PVA films were also evaluated in the experiments. Differential scanning calorimetry (DSC) analysis of samples corroborated the crosslinking of PVA by the citric acid. Blank and loaded PVA films were tested in vitro for its impact on blood coagulation prothrombin time (PT) and partial thromboplastin time (PTT). The swelling capacity was also evaluated. Crosslinked PVA films of higher-molecular weight showed a prolonged release rate compared with that of the lower-molecular-weight films tested. Non-crosslinked PVA films released 11-14% of TDC. Crosslinked PVA films released 80% of the TDC loaded (p < 0.05). This suggests that crosslinking films can modify the drug release rate. The blank and loaded PVA films induced PT and PTT in the normal range. The results showed that the polymeric films evaluated here have the appropriate properties to allow films to be placed directly on surgical wounds and have the capacity for controlled drug release to promote local analgesia for the control of postoperative pain.

Miniaturized extraction method for analysis of synthetic opioids in urine by microextraction with packed sorbent and liquid chromatography-tandem mass spectrometry.

Synthetic opioids are responsible for numerous overdoses and fatalities worldwide. Currently, fentanyl and its analogs are also mixed with heroin, cocaine and methamphetamine, or sold as oxycodone, hydrocodone and alprazolam in counterfeit medications. Microextraction techniques became more frequent in analytical toxicology over the last decade. A method to simultaneously quantify nine synthetic opioids, fentanyl, sufentanil, alfentanil, acrylfentanyl, thiofentanyl, valerylfentanyl, furanylfentanyl, acetyl fentanyl and carfentanil, and two metabolites, norfentanyl and acetyl norfentanyl, in urine samples by microextraction with packed sorbent (MEPS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed and validated. A multivariate optimization was performed to establish the number and speed (stroke) of draw-eject sample cycles and the extraction solvent. The best extraction condition was eight draw-eject sample cycles, with a velocity of 3.6 µL/sec and acetonitrile as elution solvent. Linearity was achieved between 1 to 100 ng/mL, with a limit of detection (LOD) of 0.1 ng/mL and limit of quantification (LOQ) of 1 ng/mL. Imprecision (% relative standard deviation) and bias (%) were less than 12.8% and 5.7%, respectively. The method had good specificity and selectivity when challenged with 10 different matrix sources and 36 pharmaceuticals and drugs of abuse at concentrations of 100 or 500 ng/mL. The method was successfully applied to authentic urine samples. MEPS was an efficient semi-automatic extraction technique, requiring small volumes of organic solvents (640 µL) and sample (200 µL). The cartridges can be cleaned and reused (average of 150 sample extractions/barrel inside and needle).

Pharmacokinetics and Pharmacodynamics Evaluation of Tramadol in Thermoreversible Gels.

We evaluated pharmacokinetics (PK) and pharmacodynamics (PD) induced by new formulations of tramadol (TR) in thermoreversible gels. The poloxamer- (PL-) tramadol systems were prepared by direct dispersion of the drug in solutions with PL 407 and PL 188. The evaluated formulations were as follows: F1: TR 2% in aqueous solution and F2: PL 407 (20%) + PL 188 (10%) + TR 2%; F3: PL 407 (25%) + PL 188 (5%) + TR 2%; F4: PL 407 (20%) + TR 2%. New Zealand White rabbits were divided into four groups (n = 6) and treated by subcutaneous route with F1, F2, F3, or F4 (10 µg·kg-1). PK evaluation used TR and M1 plasma levels. PD evaluation was performed with the measurement of both pupils' diameters. F2 showed higher TR plasma concentration after 180 minutes and presented lower M1 concentrations at almost all evaluated periods. Areas under the curve (ASC0-480 and ASC0-∞ ) and clearance of F2 presented differences compared to F1. F2 presented significant correlation (Pearson correlation) between the enhancement of TR and M1 concentrations and the decrease of pupil size (miosis). Thus, F2 was effective in altering pharmacokinetics and pharmacodynamics effects of TR.

Single-molecular diodes based on opioid derivatives.

We propose an efficient single-molecule rectifier based on a derivative of opioid. Electron transport properties are investigated within the non-equilibrium Green's function formalism combined with density functional theory. The analysis of the current-voltage characteristics indicates obvious diode-like behavior. While heroin presents rectification coefficient R>1, indicating preferential electronic current from electron-donating to electron-withdrawing, 3 and 6-acetylmorphine and morphine exhibit contrary behavior, R<1. Our calculations indicate that the simple inclusion of acetyl groups modulate a range of devices, which varies from simple rectifying to resonant-tunneling diodes. In particular, the rectification rations for heroin diodes show microampere electron current with a maximum of rectification (R=9.1) at very low bias voltage of ∼0.6 V and (R=14.3)∼1.8 V with resistance varying between 0.4 and 1.5 M Ω. Once most of the current single-molecule diodes usually rectifies in nanoampere, are not stable over 1.0 V and present electrical resistance around 10 M. Molecular devices based on opioid derivatives are promising in molecular electronics.

El significado del capital social "individual" en diabéticos receptores de cuidado en un contexto urbano colombiano / The meaning of "individual" social capital for diabetics receiving care in a Colombian city / O significado do capital social "individual" em diabéticos que precisam de cuidados dentro de um contexto urbano colombiano

Comprender el significado del capital social de la diabetes tipo 2 según género, dentro un contexto urbano colombiano. Investigación cualitativa del interaccionismo simbólico. 25 mujeres y 16 hombres, diabéticos, familiares, vecinos y personal asistencial participaron en seis grupos focales. Emergieron 850 códigos que se integraron en un set de 142 códigos de códigos para el ego, el alter y alter ego. Tres categorías y veinte subcategorías fueron identificadas para el diseño del "paradigma de la codificación". El significado no es igual para hombres y mujeres. Los vínculos sociales de las redes sociales, creados cotidianamente por la confianza y la solidaridad para el cuidado, son valorados de manera diferente, debido a experiencias y hechos sociales resultantes de la autoconfianza, la autoeficacia para el apoyo social principalmente y, la autoestima frente al manejo y control de la enfermedad. Los recursos sociales de un individuo son reificados para el manejo y cuidado de la enfermedad como estrategia para disminuir las inequidades en salud.

The aim of this study was to understand the meaning of social capital in relation to type 2 diabetes according to gender, within an urban setting in Colombia, based on a qualitative design for symbolic interactionism. Twenty-four women and 16 men with diabetes, family members, and healthcare personnel participated in six focus groups. A total of 850 codes emerged that comprised a set of 142 codes for ego, alter, and alter ego. Three categories and 20 subcategories were identified for the "coding paradigm design". The meaning differed between men and women. Social ties in social networks, created daily through trust and solidarity for care, were valued differently due to the social experiences and events resulting from self-confidence, self-efficacy for social support, and mainly self-esteem vis-à-vis management and control of the disease. An individual's social resources are reified for the management and care of the disease as a strategy to mitigate health inequalities. .

Compreender o significado do capital social, diabetes tipo 2 por sexo, um contexto urbano da Colômbia. pesquisa qualitativa do interacionismo simbólico. 25 mulheres e 16 homens, diabéticos, familiares, vizinhos e cuidadores participaram seis grupos focais. 850 códigos se que foram integrados em um conjunto de 142 codes para o ego, o alter e alter ego. Três categorias e vinte subcategorias foram identificados para o projeto de "codificação de paradigma". O significado não é o mesmo para homens e mulheres. Laços sociais das redes sociais criadas diariamente pela confiança e solidariedade são valorizados cuidado diferente, porque as experiências sociais e fatos resultantes da auto-confiança, auto-eficácia e de apoio social, principalmente, auto-gestão e controle em relação a doença. Os recursos sociais de um indivíduo são reificadas para a gestão o cuidado da doença como uma estratégia para reduzir as desigualdades na saúde.

Antinociceptive effects of a chloroform extract and the alkaloid dicentrine isolated from fruits of Ocotea puberula.

The present work describes the chemical characterization of a chloroform fraction (CF) obtained from an extract of Ocotea puberula (Lauraceae) fruits, and preliminary antinociceptive analysis of CF and the alkaloid dicentrine, isolated from this fraction. CF (30-300 mg/kg, p. o.) caused dose-related inhibition of abdominal constrictions caused by acetic acid and also inhibited both phases of formalin-induced nociception. However, hexane or ethyl acetate fractions did not produce any effect. Antinociception caused by CF (100 mg/kg, p. o.) in the acetic acid test was not affected either by caffeine, an adenosine receptor antagonist, or by naloxone, an opioid receptor antagonist, and neither was associated with nonspecific effects such as muscle relaxation or sedation. Furthermore, dicentrine (30-300 mg/kg, p. o.) produced dose-related inhibition of acetic acid-induced pain without causing changes in the motor performance of mice. The results show, for the first time, that CF from Ocotea puberula fruits produced marked antinociception in different models of chemical pain, and this effect appears to be, at least in part, due to the presence of dicentrine. The mechanism by which CF and the alkaloid produced antinociception still remains unclear, but the adenosinergic or opioid system seems unlikely to be involved in this action.

Merging ethnoppharmacology with chemotaxonomy: An approach to unveil bioactive natural products. The case of Psychotria alkaloids as potential analgesics

Psychotria colorata (Will ex R&S) Muell.Arg. flowers are used by "caboclos" in the Amazon as the basis for a homemade analgesic. The study of P. colorata revealed the presence of several pyrrolidinoindoline alkaloids, some with opioid-like analgesic activity in vivo. Neurochemical studies of active alkaloids proved their capability of inhibiting [3H] naloxone binding, confirming the opioid nature of the analgesic activity. These data launched a broader screening of Psychotria species, including P. carthagenensis, P. brachyceras, P. leiocarpa, P. myriantha, P. suterella and P. brachypoda. The analysis of the analgesic activity of several Psychotria species, as well as of specific isolated compounds, allowed a tentative structure/activity relationship and opened a promising research avenue in the search for new analgesic drugs.