Probes for narcotic receptor mediated phenomena. 37. Synthesis and opioid binding affinity of the final pair of oxide-bridged phenylmorphans, the ortho- and para-b-isomers and their N-phenethyl analogues, and the synthesis of the N-phenethyl analogues of the ortho- and para-d-isomers.
Probes for narcotic receptor mediated phenomena. 37. Synthesis and opioid binding affinity of the final pair of oxide-bridged phenylmorphans, the ortho- and para-b-isomers and their N-phenethyl analogues, and the synthesis of the N-phenethyl analogues of the ortho- and para-d-isomers.
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DOI：
10.1021/jm800913d
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发表时间：
2008-12-25
影响因子：
7.3
通讯作者：
Rice KC
中科院分区：
文献类型：
--
作者：
Kurimura M;Liu H;Sulima A;Hashimoto A;Przybyl AK;Ohshima E;Kodato S;Deschamps JR;Dersch CM;Rothman RB;Lee YS;Jacobson AE;Rice KC
在氧化物桥联苯基吗啡烷的 12 种外消旋拓扑刚性 N-甲基类似物的异构体系列中，除了两种外消旋体（邻位和对位 b-氧化物桥联苯基吗啡烷 20 和 12）外，所有外消旋体仍有待合成。 b-异构体非常难以合成，因为必须形成高度紧张的 5,6-反式稠合环连接。我们成功的策略需要使用吸电子硝基对芳环上氟原子的对位（或邻位）进行功能化以激活该氟。在 [35S]GTPγS 测定中，外消旋 N-苯乙基类似物 24 和 16 是中等效力的 κ-受体拮抗剂。我们合成了邻位和对位氧化物桥联苯吗啡烷系列（51 和 52）中的 N-苯乙基取代的氧化物桥联苯吗啡烷系列（51 和 52），之前未使用当代受体结合测定对其进行评估，以了解它们是否也比其 N-甲基亲属 46 和 47 具有更高的阿片受体亲和力。
In the isomeric series of 12 racemic topologically rigid N-methyl analogues of oxide-bridged phenylmorphans, all but two of the racemates, the ortho- and para-b-oxide-bridged phenylmorphansa 20 and 12, have remained to be synthesized. The b-isomers were very difficult to synthesize because of the highly strained 5,6-trans-fused ring junction that had to be formed. Our successful strategy required functionalization of the position para (or ortho) to a fluorine atom on the aromatic ring using an electron-withdrawing nitro group to activate that fluorine. The racemic N-phenethyl analogues 24 and 16 were moderately potent κ-receptor antagonists in the [35S]GTPγS assay. We synthesized the N-phenethyl-substituted oxide-bridged phenylmorphans in the ortho- and para-d oxide-bridged phenylmorphana series (51 and 52) which had not been previously evaluated using contemporary receptor binding assays to see whether they also have higher affinity for opioid receptors than their N-methyl relatives 46 and 47.
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影响因子：
3.6
作者：
BURKE, TR;JACOBSON, AE;RICE, KC
通讯作者：
RICE, KC
影响因子：
7.3
作者：
Hiebel, Anne-Cecile;Lee, Yong Sok;Rice, Kenner C.
通讯作者：
Rice, Kenner C.
影响因子：
2.1
作者：
Tadic, D;Linders, JTM;Rice, KC
通讯作者：
Rice, KC
影响因子：
7.3
作者：
BURKE, TR;JACOBSON, AE;SILVERTON, JV
通讯作者：
SILVERTON, JV
影响因子：
3.6
作者：
Hashimoto, A;Przybyl, AK;Rice, KC
通讯作者：
Rice, KC