title: Synthesis and antinociceptive properties of N-phenyl-N-(1-(2-(thiophen-2-yl)ethyl)azepane-4-yl)propionamide in the mouse tail-flick and hot-plate tests.
abstract: The goals of this study, were to synthesize N-phenyl-N-(1-(2-(thiophen-2-yl)ethyl)azepane-4-yl)propionamide (1c) and determine its antinociceptive properties. The effect of clonidine on 1c antinociception and the involvement of opioid, α2-adrenergic, and I2 imidazoline receptors in 1c antinociception were studied. Also examined was the effect of an endothelin ETA receptor antagonist on 1c antinociception. Synthesis of 1c was accomplished in two steps using modifications of previously reported methods. Antinociceptive (tail-flick and hot-plate) latencies were measured in male Swiss Webster mice treated with 1c; antagonists+1c; clonidine+1c; or antagonists+clonidine+1c. Mice were pretreated with naloxone (opioid antagonist), yohimbine (α2-adrenoceptor antagonist), idazoxan (α2-adrenoceptor/I2-imidazoline antagonist), BU224 (I2-imidazoline antagonist) or BQ123 (endothelin ETA receptor antagonist) to study the involvement of these receptors. Compound 1c produced a dose-dependent increase in antinociceptive latencies; ED50 values were 0.15 mg/kg and 0.16 mg/kg, respectively, in the tail flick and hot plate tests. Naloxone, but not yohimbine, idazoxan or BU224, blocked 1c antinociception. Neither clonidine nor BQ123 potentiated 1c antinociception. Results demonstrate that 1c is 15-times more potent than morphine. The antinociceptive effect of 1c is mediated through opioid receptors. The α2-adrenergic, I2-imidazoline and endothelin ETA receptors are not involved in 1c antinociception.
authors.affiliation: Department of Pharmaceutical Sciences, Midwestern University, Chicago College of Pharmacy, 555 31st Street, Downers Grove, IL 60515, USA. Electronic address: sandur@midwestern.edu.
authors.forename: Shridhar V
authors.initials: SV
authors.lastname: Andurkar
authors.affiliation: Department of Pharmaceutical Sciences, Midwestern University, Chicago College of Pharmacy, 555 31st Street, Downers Grove, IL 60515, USA.
authors.forename: Madhu Shaw J
authors.initials: MS
authors.lastname: Reniguntala
authors.affiliation: Department of Pharmaceutical Sciences, Midwestern University, Chicago College of Pharmacy, 555 31st Street, Downers Grove, IL 60515, USA.
authors.forename: Anil
authors.initials: A
authors.lastname: Gulati
authors.affiliation: Department of Pharmacal Sciences, Auburn University Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: DeRuiter
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology*; D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006358:Hot Temperature / Q000009:adverse effects; D008297:Male; D051379:Mice; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D010812:Physical Stimulation / Q000009:adverse effects
chemical_list: D000577:Amides; D000700:Analgesics; C034666:propionamide
keywords: Adrenergic receptor; Antinociception; Clonidine; Fentanyl; Imidazoline receptor; Opioid receptor