Synthesis and evaluation of κ-opioid receptor agonistic activity and antinociceptive effect of novel morphine analogues, 7α-phenyl-6α,14α-endo-etheno-tetrahydrothebaine with substituted o-, m- and p-amino group

• DOI: 10.1007/s00044-010-9471-6
• Publication Date: 2010-11-16T00:32:46Z
• Authors: Hong Qi; Wei Li; Yu Qiu; Yong-yao Cui; Jian Ma; Xiao-ling Gao; Yi-bin Zeng; Jie Yang; Yun Tang; Xing-hai Wang; Wei Sheng; Qiong Xie; Jing-geng Liu; Zhui-bai Qiu; Hong-zhuan Chen
• Keywords: 0303 health sciences; 03 medical and health sciences; 3. Good health

7α-Phenyl-6α,14α-endo-etheno-tetrahydrothebaine is an analogue of morphine but with much weaker affinity and efficacy to opioid receptors. Three compounds with o-, m- and p-amino substitution on its 7α-phenyl group were designed and synthesized to evaluate their κ-opioid receptor agonistic activity and antinociceptive effect. The introduction of amino group greatly increased the binding activity to κ-opioid receptor but only compound with p-substitution showed agonistic activity with potency similar to the marketed κ agonist butorphanol. In vivo antinociceptive test showed that compound with p-amino substitution displayed highest antinociceptive activity while compounds with o-, m-amino substitution showed partial or little analgesia effects. All these data indicate that p-amino substitution conferred κ agonist activity, suggesting that 7α-phenyl-6α,14α-endo-etheno-tetrahydrothebaines with a p-amino substitution may contain a novel pharmacophore component and could be considered as a leading compound for novel antinociceptive agents.