title: 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-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.
authors.affiliation: Pharmacology and Toxicology Division, Defence Research and Development Establishment, Jhansi Road, Gwalior 474 002, (M.P.), India.
authors.forename: Shiv Kumar
authors.initials: SK
authors.lastname: Yadav
authors.affiliation: Synthetic Chemistry Division, Defence Research and Development Establishment, Jhansi Road, Gwalior 474 002, (M.P.), India.
authors.forename: Chandra Kant
authors.initials: CK
authors.lastname: Maurya
authors.affiliation: Synthetic Chemistry Division, Defence Research and Development Establishment, Jhansi Road, Gwalior 474 002, (M.P.), India.
authors.forename: Pradeep Kumar
authors.initials: PK
authors.lastname: Gupta
authors.affiliation: School of Studies in Zoology, Jiwaji University, Gwalior 474 011, (M.P.), India.
authors.forename: Ajai Kumar
authors.initials: AK
authors.lastname: Jain
authors.affiliation: Synthetic Chemistry Division, Defence Research and Development Establishment, Jhansi Road, Gwalior 474 002, (M.P.), India.
authors.forename: Kumaran
authors.initials: K
authors.lastname: Ganesan
authors.affiliation: Pharmacology and Toxicology Division, Defence Research and Development Establishment, Jhansi Road, Gwalior 474 002, (M.P.), India.
authors.forename: Rahul
authors.initials: R
authors.lastname: Bhattacharya
keywords: efficacy; fentanyl analogs; opioids; synthesis; toxicity