Jacobson A E, Rice K C, Burke T R, Lupinacci L, Mattson M V, Aceto M D, Harris L S
J Pharm Sci. 1987 Mar;76(3):248-52. doi: 10.1002/jps.2600760315.
2,5-Dimethyl-2'-hydroxy-9 alpha-(3-methylbutyl)-6,7-benzomorphan, the 9 beta-analogue, and 9 alpha-N-substituted (N-ethyl, propyl, butyl, pentyl, hexyl, phenylethyl, allyl, and cyclopropylmethyl) compounds were synthesized and evaluated biochemically and pharmacologically. The 9 beta N-methyl compound was found to be as potent as morphine in the mouse hot plate assay and had one-seventh the affinity of morphine for the opioid receptor. The N-alkyl and N-phenethyl 9 alpha-substituted compounds were either inactive or relatively ineffective as antinociceptive agents. None of the examined compounds substituted for morphine in single-dose suppression studies in the rhesus monkey. The N-cyclopropylmethyl compound in the 9 alpha series had half the narcotic antagonist potency of nalorphine and one-eighth of its affinity for the opioid receptor. The 9 alpha-(3-methylbutyl) moiety, unlike bulky substituents in the 9 beta position of 6,7-benzomorphans, generally lowers affinity for the mu opioid receptor and diminishes their in vivo activity as agonists or antagonists.
合成了2,5-二甲基-2'-羟基-9α-(3-甲基丁基)-6,7-苯并吗啡烷、其9β类似物以及9α-N-取代（N-乙基、丙基、丁基、戊基、己基、苯乙基、烯丙基和环丙基甲基）的化合物，并对其进行了生化和药理学评估。发现9β-N-甲基化合物在小鼠热板试验中的效力与吗啡相当，对阿片受体的亲和力为吗啡的七分之一。N-烷基和N-苯乙基9α-取代化合物作为抗伤害感受剂无活性或相对无效。在恒河猴的单剂量抑制研究中，所检测的化合物均不能替代吗啡。9α系列中的N-环丙基甲基化合物的麻醉拮抗效力为烯丙吗啡的一半，对阿片受体的亲和力为其八分之一。与6,7-苯并吗啡烷9β位的庞大取代基不同，9α-(3-甲基丁基)部分通常会降低对μ阿片受体的亲和力，并减弱其作为激动剂或拮抗剂的体内活性。
