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, α 2 -adrenergic, and I 2 imidazoline receptors in 1c antinociception were studied. Also examined was the effect of an endothelin ET A 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 (α 2 -adrenoceptor antagonist), idazoxan (α 2 -adrenoceptor/I 2 -imidazoline antagonist), BU224 (I 2 -imidazoline antagonist) or BQ123 (endothelin ET A receptor antagonist) to study the involvement of these receptors. Compound 1c produced a dose-dependent increase in antinociceptive latencies; ED 50 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 α 2 -adrenergic, I 2 -imidazoline and endothelin ET A receptors are not involved in 1c antinociception.