Abstract
Opioid drugs, including morphine, primarily act on μ-opioid receptors, produce antinociceotive effect with some unacceptable side effects. Recent studies indicated that drugs possess μ/κ-opioid receptor dual agonism or the dual function of μ-opioid receptor agonism/δ-opioid receptor antagonism functional activity could reduce side effects. This study described the identification of the tetrahydroisoquinoline compounds 4 as a μ-opioid receptor agonist by high-throughput screening. The consequent chemical structural modification of the benzenesulfonyl and cyclohexanecarbonyl moieties for the structure-activity relationship study. Finally, a number of potent these compounds 21、51‒55、58、59、63、64、66、68‒71 were designed and synthesized, and ability of new compounds in affecting forskoline-stimulated adenylyl cyclase activity in HEK293 cells stably and expressing the μ-、κ- and δ-opioid receptors, respectively. In which compounds 21 and 69‒71 displayed partial to excellent inhibitory activities against adenylyl cyclase in HEK293 cells stably expressing μ- and κ- opioid receptors, respectively. In other words, compounds 21 and 69‒71 can activate both μ- and κ-opioid receptors. The compound 21 and 69‒71 were carried out quick tail-flick tests in mice to verify their analgesic effect. Among them, compound 69 demonstrated medium analgesic effect at a low dosage (3 mg/kg), however, compounds 21, 70 and 71 exhibited toxicity at a high dosage (20 mg/kg).