Pradeep Kumar Gupta

A quantitative NMR protocol for the simultaneous analysis of atropine and obidoxime in parenteral injection devices

A rapid selective and accurate quantitative (1)H NMR method was developed for the simultaneous analysis of obidoxime chloride and atropine sulfate, the active components in parenteral injection devices (PID) used for the emergency treatment of poisoning by toxic organophosphates. The spectra were acquired in 90% H(2)O-10% D(2)O using sodium 3-(trimethylsilyl)-1-propane sulfonate hydrate as the internal standard. Both synthetic mixtures and dosage forms were assayed. The results were compared with those obtained from a reported HPLC method.

A convenient one pot synthesis of fentanyl

Fentanyl, N-(1-phenethyl-4-piperidyl) propionanilide, was prepared by performing three successive one pot reactions at room temparature.

Synthesis and comparative bioefficacy of N -(1-phenethyl-4-piperidinyl)propionanilide (fentanyl) and its 1-substituted analogs in Swiss albino mice

Fentanyl [N-(1-phenethyl-4-piperidinyl)propionanilide] is a popular narcotic analgesic agent that is clinically used worldwide. However, fentanyl and its several analogs have caused abuse and fatalities in humans due to overdosing and narrow therapeutic index. The present study reports the synthesis and comparative bioefficacy of fentanyl and its four analogs, viz., N-(1-propyl-4-piperidinyl)propionanilide (1), N-(1-(2-phenoxyethyl)-4-piperidinyl)propionanilide (2), N-(1-(3-phenoxypropyl)-4-piperidinyl)propionanilide (3) and N-(1-(2-cyanoethyl)-4-piperidinyl)propionanilide (4), where the phenethyl chain of fentanyl was replaced by different functional groups, viz., alkyl, ethereal, and nitrile moieties. The median lethal dose (LD50) of the compounds was determined by three different routes and all the analogs were found to be safer than fentanyl. Observational assessment on spontaneous activities of the central nervous system, peripheral nervous system, and autonomic nervous system revealed that all the analogs were similar to fentanyl. Further, the neurotoxic effects of all the analogs were reversed by naloxone hydrochloride (opioid antagonist), confirming that their effects were mediated through opioid receptors. Antinociceptive activity was displayed by all the compounds and their median effective dose (ED50) and analgesic potency ratio were more or less similar to fentanyl. The lowest ED50 (23.7) and the highest potency ratio (1.18) was observed in the case of 2. However, the maximum therapeutic index was afforded by 4. The study indicates the promising role of some new opioid analgesics.

Synthesis and biological evaluation of some novel 1-substituted fentanyl analogs in Swiss albino mice.

ABSTRACT Fentanyl [N-(1-phenethyl-4-piperidinyl)propionanilide] is a potent opioid analgesic agent, but a has narrow therapeutic index. We reported earlier on the synthesis and bioefficacy of fentanyl and its 1-substituted analogs (1-4) in mice. Here we report the synthesis and biological evaluation of four additional analogs, viz. N-isopropyl-3-(4-(N-phenylpropionamido)piperidin-1-yl)propanamide (5), N-tbutyl- 3-(4-(N-phenylpropionamido)piperidin-1-yl)propanamide (6), isopropyl 2-[4-(N-phenylpropionamido)piperidin-1-yl]propionate (7) and t-butyl 2-[4-(N-phenylpropionamido)piperidin-1-yl]propionate (8). The median lethal dose (LD50) determined by intravenous, intraperitoneal and oral routes suggests these analogs to be comparatively less toxic than fentanyl. On the basis of observational assessment on spontaneous activities of the central, peripheral, and autonomic nervous systems, all the analogs were found to be similar to fentanyl. Naloxone hydrochloride abolished the neurotoxic effects of these analogs, thereby ascertaining their opioid receptor-mediated effects. All the analogs displayed significant analgesic effects, measured by formalin-induced hind paw licking and tail immersion tests at their respective median effective dose (ED50). They also exhibited 8-12 fold increase in therapeutic index over fentanyl. However, 5 and 6 alone produced lower ED50 (20.5 and 21.0 μg/kg, respectively) and higher potency ratio (1.37 and 1.33, respectively) compared to fentanyl. They could thus be considered for further studies on pain management

Effect of exposure to fentanyl aerosol in mice on breathing pattern and respiratory variables

The breathing pattern of mice that were exposed to fentanyl aerosol was studied (2.7, 5.7, 6.0, 10.0, and 23.6 μg/m3; for 1 hour), using dimethyl sulfoxide as a vehicle. This study was conducted in a head-only exposure assembly. Body plethysmographs connected to a volumetric pressure transducer were used to capture the respiratory signals, and an on-line computer program capable of recognizing the changes in the breathing pattern was used for monitoring the respiratory pattern. The response of mice to fentanyl exposure was found to be concentration dependent. A lower concentration (2.7 μg/m3) showed fast recovery and no mortality, while 100% mortality was observed at a higher concentration (23.6 μg/m3). No sensory, pulmonary irritation, and airway limitation in mice was observed, and death occurred probably due to respiratory depression. The concentration that decreased 50% of the respiratory frequency (RD50) was estimated to be 6.4 μg/m3. The extrapolated human threshold limit value, calculated from the RD50 value, was found to be 0.192 μg/m3. The concentration that caused 50% mortality in exposed mice (LC50) was estimated to be 8.8 μg/m3. This study shows that aerosolized fentanyl does not cause sensory and pulmonary irritation, and since the RD50 and LC50 are very close with a low safety margin, this type of sedative should not be used as an incapacitating agent.

Biochemical, Oxidative, and Physiological Changes Caused by Acute Exposure of Fentanyl and Its 3 Analogs in Rodents

Synthesis and bioefficacy of fentanyl and its 8 new 1-substituted analogs (1-8) were earlier reported by us. Of these 8 compounds, N-(1-(2-phenoxyethyl)-4-piperidinyl)propionanilide (2), N-isopropyl-3-(4-(N-phenylpropionamido)piperidin-1-yl)propanamide (5), and N-t-butyl-3-(4-(N-phenylpropionamido)piperidin-1-yl) propanamide (6) were found to be more effective and less toxic compared to fentanyl. The present study reports the acute effect of fentanyl (0.50 Median Lethal Dose (LD50); intraperitoneal) and its 3 analogs (2, 5, and 6) on various biochemical and oxidative parameters in mice and various physiological parameters in rats. Blood alkaline phosphatase (1 hour and 7 days) and urea levels (1 hour) were significantly elevated by fentanyl, while alanine aminotransferase levels (1 hour) were increased by both fentanyl and analog 2 compared to the corresponding control. Increase in partial pressure of carbon dioxide and decrease in partial pressure of oxygen were also caused by fentanyl and analog 2 (1 hour). Analog 6 alone elevated malondialdehyde levels in the brain, liver, and kidney tissues (7 days). The LD50 of fentanyl and analogs 2, 5, and 6 were found to be 0.879, 87.88, 69.80, and 55.44 mg/kg, respectively, in rats. Significant decrease in heart rate, mean arterial pressure, respiratory rate (RR), and neuromuscular transmission was produced by fentanyl and analog 2, while analog 5 decreased the RR alone. The changes, particularly the respiratory depression, were found to be reversed by naloxone, a μ-receptor antagonist. Thereby, indicating involvement of μ-receptor mediated effects of the compounds. To conclude, all the analogs were found to be less toxic compared to fentanyl, suggesting their possible role in pain management.

Phosphorus pentasulfide mediated conversion of organic thiocyanates to thiols

In this paper we report an efficient and mild procedure for the conversion of organic thiocyanates to thiols in the presence of phosphorus pentasulfide (P2S5) in refluxing toluene. The method avoids the use of expensive and hazardous transition metals and harsh reducing agents, as required by reported methods, and provides an attractive alternative to the existing methods for the conversion of organic thiocyanates to thiols.