The synthesis and preliminary pharmacological evaluation of the racemic cis and trans 3-alkylfentanyl analogues

A general, five step method for the synthesis of 3-alkylfentanyl analogues (i.e., cis and trans 3-alkyl-4-anilidopiperidines 6.16.6) has been developed. The starting N-phenethyl-4-piperidone 1 was first converted into the cyclohexylimine derivative 2, a-deprotonated with butyllithium and the resulting imine anion efficiently monoalkylated with primary and secondary alkyl halides. After mild acid hydrolysis, the obtained 3-alkyl-4-piperidones 3.13.6 were isolated in good yields (7985 %), then condensed with aniline to form imines 4.14.6. Subsequent reduction of the imines (LiAlH4/THF) yielded cis/trans mixtures of 3-alkyl-4-anilinopiperidines 5.15.6. Quantitative separation of the diastereoisomers by column chromatography of Al2O3 gave pure cis 5.15.6 (2951 % yield) and trans 5.15.6 (1927 % yield), with the cis/trans ratio in the range 7/36/4. The synthesis was concluded by N-acylation of the purified 5.15.6, with propionyl chloride, to afford cis and trans 3-alkyl-4-anilidopiperidines 6.16.6 (~95 % yield, as monooxalate salts). No enatioseparation was attempted at any stage. The relative cis/trans stereochemistry was provisionally assigned from the 1H-NMR spectra. Of the twelve synthesized 3-alkylfentanyls, ten compounds (two known and eight novel derivatives, all as the monooxalate salts) were preliminarily tested as analgesics in rats, comparing the potency to fentanyl. Except for the known (±)-cis-3-Me fentanyl 6.1cis, (8 × fentanyl), and the novel (±)-cis-3-Et fentanyl 6.2cis, (1.5 × fentanyl), all of the others were less active than fentanyl or inactive. Some tentative conclusions on the structure-activity relationship (SAR) in this series of derivatives have been made

The synthesis and pharmacological evaluation of (±)-2,3-seco-fentanyl analogues

An efficient, five-step synthetic approach to various acyclic 1,3-diamines has been developed and applied to the preparation of a novel class of open-chained fentanyl analogues. The acyclic derivatives 5.15.5 (all new compounds) were synthesized with the aim of estimating the significance of the piperidine ring for the opioid analgesic activity of anilido-piperidines. The starting b-keto-amide 1.1, prepared by the aminolysis of methyl acetoacetate with methylphenethylamine, (93 % yield), was successively reacted with NaH and BuLi, to form the highly reactive a,g-dienolate anion 1.1a. Regio and chemoselective g-alkylation of the dienolate with various primary and secondary alkyl halides furnished the b-keto-amides 1.21.5 (7691 %). Reductive amination of the keto-amides 1.11.5 with aniline and Zn powder in acetic acid, via the enamine intermediates 2.12.5, afforded the b-anilino amides 3.13.5 (7485 %). After reductive deoxygenation of the tertiary amide group, using in situ generated diborane, the corresponding 1,3-diamines 4.14.5 were obtained (8797 %). The synthesis of (±)-2,3-seco-fentanyls 5.15.5 was completed by N-acylation of the diamines 4.14.5 with propionyl chloride, followed by precipitation of the monooxalate salts (8695 %). The parent compound, 2,3-seco-fentanyl 5.1, was found to be a 40 times less potent narcotic analgesic than fentanyl but still 56 times more active than morphine in rats, while i-Pr derivative 5.3 was inactive. Apart from the pharmacological significance, the general procedure described herein may afford various functionalized, 1,3-diamines as potential complexing agents and building blocks for the synthesis of aza-crown ethers

The effects of N-acetyl-L-cysteine on subchronic methionine load in male wistar rats: Focus on standard biochemical parameters and markers of homocysteine metabolism in blood

86th Congress of the European-Atherosclerosis-Society (EAS), Lisbon,PORTUGAL, MAY 05-08, 201

Effect of Menopause, Anthropometry, Nutrition and Lifestyle on Bone Status of Women in the Northern Mediterranean

Objective: The purpose of this study was to explore the influence of age, menopause, anthropometry, nutrition and lifestyle on bone status of women of the Northern Mediterranean Region of Croatia, which is considered the Adriatic Coast of Southeast Europe. Methods: Quantitative ultrasound measurement was performed on the women‘s right heel and the values of the primary parameters (the Broad Ultrasonic Attenuation and the Speed of Sound [BUA and SOS]) were obtained. Dietary data were assessed with specially designed semi-quantitative food frequency questionnaire. Multiple regression analysis was employed to examine the influence of age and anthropometry, as well as hormonal and nutritional factors on BUA and SOS. Results: In all female subjects, both primary parameters were predicted by menopause. Among nutrition and lifestyle factors, carbohydrates were significant predictors for BUA (β = -0.151, p < 0.05), and smoking is significant predictor for SOS (β = -0.113, p < 0.05). In premenopausal women, BUA is significantly predicted by body height (β = 0.71, p < 0.05) and body mass index (β = 1.44, p < 0.05). In postmenopausal women, both primary parameters are strongly predicted by age and anthropometric parameters. Besides, SOS is significantly predicted by smoking (β = -0.18, p < 0.01) and alcohol (β = -0.13, p < 0.05). Besides, SOS is significantly predicted by smoking (β = -0.18, p < 0.01) and alcohol (β = -0.13, p < 0.05). Conclusion: Bone quality in women from the Croatian Mediterranean Region mostly depends on their hormonal status. When the effect of menopause is controlled, bone status becomes dependent on age and anthropometry. Keywords: Anthropometry, lifestyle, menopause, nutrition, quantitative ultrasound "Efecto de la Menopausia, la Antropometría, la Nutrición y el Estilo de Vida Sobre la Condición Ósea de las Mujeres en el Mediterráneo Norte" S Pavicic Zezelj, O Cvijanovic, V Micovic, D Bobinac, Z Crncevic-Orlic, G Malatestinic RESUMEN Objetivo: El propósito de este estudio fue explorar la influencia de la edad, la menopausia, la antropometría, la nutrición y el estilo de vida en la condición ósea de las mujeres de la región mediterránea norteña de Croacia, que es considerada la Costa Adriática del Sudeste de Europa. Métodos: Se realizó una medicación cuantitativa mediante ultrasonido en el talón derecho de las mujeres y se obtuvieron los valores de los parámetros primarios (la atenuación del ultrasonido de banda ancha y la velocidad del sonido [AUB y VDS]). Los datos dietéticos fueron evaluados mediante un cuestionario semi-cuantitativo de frecuencia de alimentos, especialmente diseñado. Se empleo el análisis de regresión múltiple para examinar la influencia de la edad y la antropometría, así como los factores hormonales y nutritivos sobre AUB y VDS. Resultados: En todas las sujetos hembras, ambos parámetros primarios fueron predichos por la menopausia. Entre los factores nutrición y estilo de vida, los carbohidratos fueron predictores significativas de para AUB (ß = -0.151, p < 0.05), y fumar es el predictor significativo para VDS (ß = -0.113, p < 0.05). En las mujeres premenopáusicas, la AUB es predicha significativamente por la altura del cuerpo (ß = 0.71, < 0.05) y el índice de masa corporal (ß = 1.44, p < 0.05). En las mujeres postmenopáusicas, ambos parámetros primarios son fuertemente predichos por la edad y los parámetros antropométricos. Además, la VDS es predicha significativamente por el hábito de fumar (ß = -0.18, p < 0.01) y el alcohol (ß = -0.13, p < 0.05). Conclusión: La calidad ósea de las mujeres de la región mediterránea croata depende principalmente de su estado hormonal. Cuando el efecto de la menopausia se controla, la condición ósea se hace dependiente de la edad y la antropometría. Palabras claves: Antropometría, estilo de vida, menopausia, nutrición, ultrasonido cuantitativ

Higher environmental temperature potentiates cataleptic effect of fentanyl in rats

The influence of higher environmental temperature (HET=30+/-1 degrees C) on fentanyl-induced behavior was studied in unrestrained rats. Subacute exposure (3 days) of rats to HET significantly (P lt 0.01) increased the cataleptic effect of fentanyl citrate (0.5 mg/kg), in comparison to the corresponding exposure to normal environmental temperature (NET=22+/-1 degrees C). Also, the hyperthermic response of rats to a low dose of fentanyl citrate (0.2-0.5 mg/kg) was significantly (P lt 0.01) potentiated, and the hypothermic response to a high dose of fentanyl citrate (1.5 mg/kg) was significantly (P lt 0.05) attenuated after exposure to HET. Fentanyl-induced hyperexcitability, loss of righting reflex, loss of corneal reflex and analgesia were not significantly affected by HET. This study provides the first evidence on the influence of environmental temperature on drug-induced catalepsy. MET-induced potentiation of the cataleptic response to fentanyl could be the result of an interference with behavioral thermoregulation.Free full text: [https://doi.org/10.1254/jjp.78.523

The effects of acutely and subchronically applied DL-methionine on plasma oxidative stress markers and activity of acetylcholinesterase in rat cardiac tissue

© 2020 Inst. Sci. inf., Univ. Defence in Belgrade. All rights reserved. Background/Aim. Chronically induced hypermethioninemia leads to hyperhomocysteinemia which causes oxidative stress, atherogenesis, neurodegeneration and cancer. However, little is known about the acute and subchronic effects of DL-methionine (Met). The aim of study was to assess the effects of acutely and subchronically applied Met on oxidative stress parameters in rat plasma [enzymes: catalase (CAT), glutathione peroxidise (GPx), superoxide dismutase (SOD) and index of lipid peroxidation, malondialdehyde (MDA)], and acetylcholinesterase (AChE) activity in rat cardiac tissue. Methods. The enzymes activities, as well as MDA concentration were evaluated following acute (n = 8) and subchronic (n = 10) application of Met [i.p. 0.8 mmoL/kg body weight (b.w.) in a single dose in the acute overload or daily during three weeks in the subchronic overload]. The same was done in the control groups following application of physiological solution [i.p. 1 mL 0.9% NaCl (n = 8) in the acute overload and 0.1–0.2 mL 0.9% NaCl, daily during three weeks (n =10) in the subchronic overload]. Tested parameters were evaluated 60 minutes after application in acute experiments and after three weeks of treatment in subchronic experiments. Results. There were no difference in homocysteine values between the groups treated with Met for three weeks and the control group. Met administration significantly increased the activity of CAT and GPx after 1 h compared to the control group (p = 0.008 for both enzymes), whereas the activity of SOD and MDA concentrations were unchanged. Subchronically applied Met did not affect activity of antioxidant enzymes and MDA level. AChE activity did not show any change in rat cardiac tissue after 1 h, but it was significantly decreased after the subchronic treatment (p = 0.041). Conclusion. Results of present research indicate that Met differently affects estimated parameters during acute and subchronic application. In the acute treatment Met mobilizes the most part of antioxidant enzymes while during the subchronic treatment these changes seems to be lost. On the contrary, the acute Met overload was not sufficient to influence on the AChE activity, while longer duration of Met loading diminished function of the enzyme. These findings point out that methionine can interfere with antioxidant defense system and cholinergic control of the heart function