ANTIPODAL ALPHA-N-(METHYL THROUGH DECYL)-N-NORMETAZOCINES (5,9-ALPHA-DIMETHYL-2'-HYDROXY-6,7-BENZOMORPHANS) - IN-VITRO AND IN-VIVO PROPERTIES
ANTIPODAL ALPHA-N-(METHYL THROUGH DECYL)-N-NORMETAZOCINES (5,9-ALPHA-DIMETHYL-2'-HYDROXY-6,7-BENZOMORPHANS) - IN-VITRO AND IN-VIVO PROPERTIES
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DOI：
10.1021/jm00046a026
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发表时间：
1994-09-30
影响因子：
7.3
通讯作者：
JACOBSON, AE
中科院分区：
文献类型：
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作者：
MAY, EL;ACETO, MD;JACOBSON, AE
合成了5，9-二甲基-2‘-羟基-6，7-苯并吗啉对映体(-)-和(+)-N-(甲基至癸基)去甲咪唑类化合物，并测定了它们的体内外活性。越来越多的N-烷基对映体被制备出来，直到它们与或受体的相互作用减弱，它们的不溶性成为它们在体内和/或体外评价的障碍。在甩尾、苯醌和热板试验中，(-)-甲基、-戊基、-己基和-庚基同系物基本上与吗啡一样有效，甚至比吗啡更有效；在甩尾和吗啡试验中，(-)-丙基同系物具有纳洛啡和纳洛酮之间的麻醉拮抗活性，在恒河猴单剂量抑制试验中也显示出拮抗特性。抗伤害性强的(-)-庚基同系物不能在猴子身上替代吗啡，但在持续输注的大鼠的初级身体依赖研究中确实显示出类似吗啡的特性。所有五个有效的化合物都显示出对大鼠和猴子制剂中的u阿片受体和kappa阿片受体(
The enantiomeric (-)- and (+)-N-(methyl through decyl) normetazocines (5,9 alpha-dimethyl-2'hydroxy-6,7-benzomorphans) were synthesized and their in vitro and in vivo activities determined. Increasingly bulky enantiomeric N-alkyl homologs were prepared until their interaction with the or receptor decreased and their insolubility became a hindrance to their evaluation in vivo and/or in vitro. The(-)-methyl, -pentyl, -hexyl, and -heptyl homologs were essentially as potent as, or more potent than, morphine in the tail-flick, phenylquinone, and hot-plate assays for antinociceptive activity; the (-)-propyl homolog had narcotic antagonist activity between that of nalorphine and naloxone in the tail-flick vs morphine assay, and it also displayed antagonist properties in the single-dose suppression assay in the rhesus monkey. The antinociceptively potent (-)-heptyl homolog did not substitute for morphine in monkeys but did show morphine-like properties in a primary physical-dependence study in continuously infused rats. All five potent compounds showed high affinity for the mu opioid receptor from both rat and monkey preparations and the kappa opioid receptor (