- Pradeep Kumar Gupta1,
- Shiv Kumar Yadav2,
- Yangchen Doma Bhutia2,
- Poonam Singh2,
- Pooja Rao2,
- Niranjan Laxman Gujar2,
- Kumaran Ganesan1 &
- …
- Rahul Bhattacharya2
- 2006Accesses 
- 18Citations 
- 6 Altmetric 
Abstract
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) andN-(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 of2. However, the maximum therapeutic index was afforded by4. The study indicates the promising role of some new opioid analgesics.
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Acknowledgments
The authors thank Prof. (Dr.) M.P. Kaushik, Director, DRDE, Gwalior, for his support and encouragement.
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- Division of Synthetic Chemistry, Defence Research and Development Establishment, Jhansi Road, Gwalior, 474 002, Madhya Pradesh, India - Pradeep Kumar Gupta & Kumaran Ganesan 
- Division of Pharmacology and Toxicology, Defence Research and Development Establishment, Jhansi Road, Gwalior, 474 002, Madhya Pradesh, India - Shiv Kumar Yadav, Yangchen Doma Bhutia, Poonam Singh, Pooja Rao, Niranjan Laxman Gujar & Rahul Bhattacharya 
- Pradeep Kumar GuptaSearch author on:PubMed Google Scholar 
- Shiv Kumar YadavSearch author on:PubMed Google Scholar 
- Yangchen Doma BhutiaSearch author on:PubMed Google Scholar 
- Poonam SinghSearch author on:PubMed Google Scholar 
- Pooja RaoSearch author on:PubMed Google Scholar 
- Niranjan Laxman GujarSearch author on:PubMed Google Scholar 
- Kumaran GanesanSearch author on:PubMed Google Scholar 
- Rahul BhattacharyaSearch author on:PubMed Google Scholar 
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Correspondence toRahul Bhattacharya.
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Gupta, P.K., Yadav, S.K., Bhutia, Y.D.et al. Synthesis and comparative bioefficacy ofN-(1-phenethyl-4-piperidinyl)propionanilide (fentanyl) and its 1-substituted analogs in Swiss albino mice.Med Chem Res22, 3888–3896 (2013). https://doi.org/10.1007/s00044-012-0390-6
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