Potent MOR Agonists from 2'-Hydroxy-5,9-dimethyl-N-phenethyl Substituted-6,7-benzomorphans and from C8-Hydroxy, Methylene and Methyl Derivatives of N-Phenethylnormetazocine.
Potent MOR Agonists from 2'-Hydroxy-5,9-dimethyl-N-phenethyl Substituted-6,7-benzomorphans and from C8-Hydroxy, Methylene and Methyl Derivatives of N-Phenethylnormetazocine.
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有效的莫尔激动剂，来自2 '-羟基-5，9-二甲基-N-苯乙基取代的-6，7-苯并吗啉和来自N-苯乙基去甲唑辛的C8-羟基、亚甲基和甲基衍生物。
DOI：
10.3390/molecules28237709
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发表时间：
2023-11-22
期刊：
影响因子：
--
通讯作者：
Rice KC
中科院分区：
文献类型：
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作者：
Das M;Ward GW;Sulima A;Luo D;Prisinzano TE;Imler GH;Kerr AT;Jacobson AE;Rice KC
合成了 N-苯乙基部分芳环上带有对位 OH 或邻位 F 取代基的 (−)-5,9-二甲基-6,7-苯并吗啡烷（去甲佐辛）衍生物，并发现其在 MOR 下具有亚纳摩尔效力，并且两者在体外均完全有效。这些新化合物，(1R,5R,9R)-6,11-二甲基-3-(2-氟苯乙基)-1,2,3,4,5,6-六氢-2,6-亚甲基苯并[d]azocin-8-ol和(1R,5R,9R)-6,11-二甲基-3-(4-羟基苯乙基)-1,2,3,4,5,6-六氢-2,6-亚甲基苯并[d]azocin-8-ol比未取代的化合物N-苯乙基去甲佐辛更有效，分别比吗啡强约30或40倍。合成了 N-苯乙基部分芳环中邻位、间位或对位的各种取代基，其中 25 种化合物，通过毛喉素诱导的 cAMP 积累测定发现，它们对功效和功效具有不同的影响。 N-苯乙基部分也通过增加链长形成具有和不具有对硝基部分的N-苯丙基侧链以及通过N-肉桂基侧链进行修饰。此外，还合成了吲哚乙胺去甲佐辛来取代去甲佐辛中的N-苯乙胺侧链。苯丙胺、丙烯胺（肉桂基）和对硝基丙胺几乎没有或没有 MOR 效力。然而，去甲佐辛核上的吲哚乙胺具有中等效力 (MOR EC50 = 12 nM)，并且在 cAMP 测定中完全有效 (%Emax = 102%)。保留 N-苯乙基部分并在 (-)-N-苯乙基去甲佐辛中的 C8 上添加烷基和烯基部分，得到在 MOR 处具有亚纳摩尔效力的 C8-亚甲基衍生物和具有纳摩尔效力的 C8-甲基类似物。合成了五种C8取代的化合物。
(−)-5,9-Dimethyl-6,7-benzomorphan (normetazocine) derivatives with a para-OH or ortho-F substituent in the aromatic ring of the N-phenethyl moiety were synthesized and found to have subnanomolar potency at MOR, and both were fully efficacious in vitro. These new compounds, (1R,5R,9R)-6,11-dimethyl-3-(2-fluorophenethyl)-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol and (1R,5R,9R)-6,11-dimethyl-3-(4-hydroxyphenethyl)-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol, were more potent than the unsubstituted compound N-phenethylnormetazocine and about 30 or 40 times more potent than morphine, respectively. A variety of substituents in the ortho, meta, or para position in the aromatic ring of the N-phenethyl moiety were synthesized, 25 of these compounds, and found to have varying effects on potency and efficacy as determined by the forskolin-induced cAMP accumulation assay. The N-phenethyl moiety was also modified by increasing chain length to form a N-phenylpropyl side chain with and without a para-nitro moiety, and by an N-cinnamyl side chain. Also, an indole ethylamine normetazocine was synthesized to replace the N-phenethylamine side chain in normetazocine. The phenylpropylamine, propenylamine (cinnamyl) and the para-nitropropylamine had little or no MOR potency. The indole-ethylamine on the normetazocine nucleus, however, had moderate potency (MOR EC50 = 12 nM), and was fully efficacious (%Emax = 102%) in the cAMP assay. Retention of the N-phenethyl moiety and the addition of alkyl and alkenyl moieties on C8 in (−)-N-phenethylnormetazocine gave a C8-methylene derivative that had subnanomolar potency at MOR and a C8-methyl analog that had nanomolar potency. Five C8-substituted compounds were synthesized.
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影响因子：
2.4
作者：
BRINE, GA;BERRANG, B;CARROLL, FI
通讯作者：
CARROLL, FI
影响因子：
11
作者：
Hedrick SL;Luo D;Kaska S;Niloy KK;Jackson K;Sarma R;Horn J;Baynard C;Leggas M;Butelman ER;Kreek MJ;Prisinzano TE
通讯作者：
Prisinzano TE
影响因子：
2.7
作者：
VanAlstine, Melissa A.;Wentland, Mark P.;Bidlack, Jean M.
通讯作者：
Bidlack, Jean M.
影响因子：
7.3
作者：
MAY, EL;ACETO, MD;JACOBSON, AE
通讯作者：
JACOBSON, AE
具有阿片类激动剂/Sigma-1 受体拮抗剂的新型 N-去甲佐辛衍生物作为炎症性疼痛的潜在镇痛药。
DOI：
10.3390/molecules27165135
发表时间：
2022-08-12
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
通讯作者：
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