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

Gupta, Pradeep Kumar; Yadav, Shiv Kumar; Bhutia, Yangchen Doma; Singh, Poonam; Rao, P. Venkata; Gujar, Niranjan L.; Ganesan, K.; Bhattacharya, Rahul

doi:10.1007/s00044-012-0390-6

Cited by 16 publications

(26 citation statements)

References 23 publications

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“…Moreover, N-allyl substitution on the piperidine ring does not confer antagonist activity as in the case of morphinan derivatives. N -(1-propyl), N -(1-(2-phenoxyethyl)-, N -(1-(3-phenoxypropyl)- and N -(1-(2-cyanoethyl)-4-piperidinyl)-propionanilides ( 101 ), displayed activity similar to fentanyl [11,168,169]. Replacement of the nitrogen atom for oxygen, sulfur or carbon ( 102–104 ) resulted in loss of activity [Vardanyan RS, Unpublished Data].…”

Section: Replacement Of 2-arylethylsubstituents At Piperidine Ringmentioning

confidence: 99%

Fentanyl-Related Compounds and Derivatives: Current Status and Future Prospects for Pharmaceutical Applications

2014

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Fentanyl and its analogs have been mainstays for the treatment of severe to moderate pain for many years. In this review, we outline the structural and corresponding synthetic strategies that have been used to understand the structure–biological activity relationship in fentanyl-related compounds and derivatives and their biological activity profiles. We discuss how changes in the scaffold structure can change biological and pharmacological activities. Finally, recent efforts to design and synthesize novel multivalent ligands that act as mu and delta opioid receptors and NK-1 receptors are discussed.

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Section: Replacement Of 2-arylethylsubstituents At Piperidine Ringmentioning

confidence: 99%

Fentanyl-Related Compounds and Derivatives: Current Status and Future Prospects for Pharmaceutical Applications

2014

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“…We also reported on the synthesis and bioefficacy of fentanyl and its 1-substituted analogs ( 1 – 4 ), where the phenethyl chain of fentanyl was replaced by alkyl, ethereal and nitrile functional groups (Gupta et al ., 2013 ). Compared to fentanyl and its four analogs, 2 exhibited the lowest median effective dose (ED 50 ) and highest potency ratio.…”

Section: Introductionmentioning

confidence: 99%

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

Yadav

Maurya

Gupta

et al. 2014

Interdisciplinary Toxicology

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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-t-butyl-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.

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“…Moreover, these cytokines are associated with the development of septic shock and organ dysfunction 10 . Synthesis and comparative bioassay of fentanyl and its 1-substituted analogues (1)(2)(3)(4)(5)(6)(7)(8) in mice were earlier reported by us 11,12 . Out of these eight compounds, N-(1-(2-phenoxyethyl)-4-piperidinyl)propionanilide (2), N-isopropyl-3-(4-(Nphenylpropionamido)piperidin-1-yl)propanamide (5), and…”

Section: Introductionmentioning

confidence: 92%

“…The doses of fentanyl and its analogues were equivalent to their respective 0.50 LD 50 (i.p.) values, which were 8.75 mg/kg (fentanyl), 56.10 mg/kg (analogue 2), 56.90 mg/kg (analogue 5), and 53.65 mg/kg (analogue 6) 11,12 . Six animals were randomly selected from each group for each time point IL-6 is produced by both immune and non-immune tissues and hence has numerous different biological effects.…”

Section: Treatmentmentioning

confidence: 99%

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Acute Immunomodulatory Effects of Fentanyl and its Three New Analogues in Swiss Albino Mice

Yadav

Bhattacharya

2017

Def. Life. Sc. Jl.

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Fentanyl is a potent synthetic opioid analgesic. However, due to its several limitations, new analogues are being synthesised for better pain management. We have earlier reported the synthesis and bio-efficacy of fentanyl and its eight new analogues (1-8) in mice. Among eight analogues tested, 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. Therapeutic efficacy of fentanyl and its analogues are known to be compromised due to many adverse effects, including alterations in the immune system. Therefore, the present study was undertaken to assess the acute effect of fentanyl and its three analogues (2, 5, and 6) on plasma levels of different pro-inflammatory cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and anti-inflammatory cytokines such as interleukin-10 (IL-10) at different time points. Mice were intraperitoneally treated with 0.50 LD 50 of the compounds and cytokines were measured 1 h, 2 h, 4 h, and 24 h post-exposure. Compared to control, none of the treatments produced any change in TNF-α and IL-1β levels. However, IL-6 levels were significantly elevated between 1 h to 2 h post-exposure in fentanyl and analogue 2 treated groups. Further, IL-10 levels were found to be significantly increased in fentanyl, analogue 2, and 6 treated groups at 1 h and 2 h post-exposure. Pretreatment of naltrexone (opioid receptor antagonist) blocked the effects of fentanyl, confirming that its effects were opioid receptor-dependent. However, effect of naltrexone on analogue 2 and 6 was not conclusively evidenced, indicating that immunomodulatory changes caused by the analogues could have some additional implications as well. The present study reveals undesirable effects of fentanyl and its new analogues on cytokines homeostasis, thereby limiting their use in pain management.

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

Cited by 16 publications

References 23 publications

Fentanyl-Related Compounds and Derivatives: Current Status and Future Prospects for Pharmaceutical Applications

Fentanyl-Related Compounds and Derivatives: Current Status and Future Prospects for Pharmaceutical Applications

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

Acute Immunomodulatory Effects of Fentanyl and its Three New Analogues in Swiss Albino Mice

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