Vizi E S, Foldes F F, Rich J, Knoll J
Pharmacology. 1976;14(1):76-85. doi: 10.1159/000136582.
The isolated longitudinal muscle preparation (with attached Auerbach plexus) of the guinea pig ileum was used to investigate the structure activity relationship and kinetics of some naloxone and naltrexone derivatives and that of cyclazocine. The agonist used for the investigation of the antagonistic effect of these compounds was 6-azidomorphine (AM). AM was found to be an about 20 times more potent agonist than morphine. In contrast to cyclazocine, which also was found to be approximately 15 times more potent agonist than morphine, naloxone had no demonstrable agonistic activity and naltrexone and the various naloxone and naltrexone derivatives had only insignificant agonistic activity with ED50/Ke ratios ranging from 2,000 to about 120,000. All compounds tested were competitive reversible antagonists of AM. 6-Methylene substitution caused an approximate 50 and 100% increase of the antagonistic activity of naloxone and naltrexone, respectively, and decreased the duration of action of naloxone. 3-Acetate or 3-nicotinate substitution decreased potency and had no effect on the duration of naloxone action. There is a correlation between tachyphylaxis observed on the inhibition of longitudinal muscle contraction and antagonist activity of narcotic agonists.
采用豚鼠回肠的离体纵行肌制备物（带有奥厄巴赫神经丛）来研究某些纳洛酮和纳曲酮衍生物以及环唑辛的构效关系和动力学。用于研究这些化合物拮抗作用的激动剂是6-叠氮吗啡（AM）。发现AM的激动活性约为吗啡的20倍。与环唑辛（其激动活性也约为吗啡的15倍）不同，纳洛酮没有可证实的激动活性，纳曲酮以及各种纳洛酮和纳曲酮衍生物只有微不足道的激动活性，其半数有效量/平衡解离常数（ED50/Ke）比值在2000至约120000之间。所有测试的化合物都是AM的竞争性可逆拮抗剂。6-亚甲基取代分别使纳洛酮和纳曲酮的拮抗活性提高了约50%和100%，并缩短了纳洛酮的作用持续时间。3-乙酸酯或3-烟酸酯取代降低了效力，且对纳洛酮的作用持续时间没有影响。在抑制纵行肌收缩时观察到的快速耐受性与麻醉性激动剂的拮抗活性之间存在相关性。
