Synthesis and Pharmacological Evaluation of Enantiopure N-Substituted Ortho-c Oxide-Bridged 5-Phenylmorphans.
Synthesis and Pharmacological Evaluation of Enantiopure N-Substituted Ortho-c Oxide-Bridged 5-Phenylmorphans.
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DOI：
10.3390/molecules27248808
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发表时间：
2022-12-12
期刊：
影响因子：
--
通讯作者：
Rice KC
中科院分区：
文献类型：
--
作者：
Li F;Kopajtic TA;Katz JL;Luo D;Prisinzano TE;Imler GH;Deschamps JR;Jacobson AE;Rice KC
N-2-苯基环丙基甲基取代的邻-c 氧桥苯基吗啡烷、N-肉桂基部分的 E 和 Z 异构体以及 N-丙基对映体的对映纯立体异构体的设计基于将最有效的氧桥苯基吗啡烷（邻-c 异构体）与我们之前在 5-（3-羟基）苯基吗啡发现的最有效的 N-取代基相结合（即，N-2-苯基环丙基甲基部分、N-肉桂基和N-丙基取代基）。完成了八种对映体纯 N-2-苯基环丙基甲基邻氧桥苯基吗啡烷和 N-取代邻氧桥苯基吗啡烷的六种其他对映体（N-E 和 Z-肉桂基化合物以及 N-丙基化合物）的合成。该合成分别从常见中间体 (3R,6aS,11aS)-10-甲氧基-1,3,4,5,6,11a-六氢-2H-3,6a-甲酰基苯并呋喃并[2,3-c]阿佐辛 (+)-6 及其对映体 (3S, 6aR, 11aR)-(-)-6 开始。通过与(S)-(+)-和(R)-(-)-对甲基扁桃酸成盐得到±-6的对映体，并通过单晶X射线分析确定了(3S，6aR，11aR)-(-)-6的(R)-(-)-对甲基扁桃酸盐的绝对构型。对映体仲胺与N-(2-苯基环丙基)甲基衍生物、2-(E)-肉桂基溴和(Z)-3-苯基丙烯酸反应。这些产物产生了所有所需的邻-c氧化物桥联苯基吗啡烷的N-衍生物。测量了它们的阿片受体结合亲和力。在毛喉素诱导的 cAMP 积累测定中检查了 MOR 亲和力 < 50 nM 的化合物的功能活性。仅 N-苯乙基邻-c 氧化物桥联苯吗啡烷 ((-)-1) 的对映体，以及 (3S,6aR,11aR)-2-(((1S,2S)-2-苯基环丙基)甲基)-1,3,4,5,6,11a-六氢-2H-3,6a-甲基苯并呋喃[2,3-c]偶氮星-10-醇异构体((+)-17) 和 N-苯丙基衍生物 ((-)-25) 的阿片类药物结合亲和力 < 50 nM。在cAMP测定中，(-)-1和(-)-25都是部分激动剂，前者效力高但效力低，后者效力低且效力低。最有趣的是 N-2-苯基环丙基甲基 (3S,6aR,11aR)-2-(1S,2S)-对映体 ((+)-17)。该化合物具有良好的 MOR 结合亲和力 (Ki = 11.9 nM)，并且被发现具有类似纳曲酮的 MOR 拮抗剂效力 (IC50 = 6.92 nM)。
The design of enantiopure stereoisomers of N-2-phenylcyclopropylmethyl-substituted ortho-c oxide-bridged phenylmorphans, the E and Z isomers of an N-cinnamyl moiety, and N-propyl enantiomers were based on combining the most potent oxide-bridged phenylmorphan (the ortho-c isomer) with the most potent N-substituent that we previously found with a 5-(3-hydroxy)phenylmorphan (i.e., N-2-phenylcyclopropyl methyl moieties, N-cinnamyl, and N-propyl substituents). The synthesis of the eight enantiopure N-2-phenylcyclopropylmethyl ortho-c oxide-bridged phenylmorphans and six additional enantiomers of the N-substituted ortho-c oxide-bridged phenylmorphans (N-E and Z-cinnamyl compounds, and N-propyl compounds) was accomplished. The synthesis started from common intermediates (3R,6aS,11aS)-10-methoxy-1,3,4,5,6,11a-hexahydro-2H-3,6a-methano-benzofuro[2,3-c]azocine (+)-6 and its enantiomer, (3S, 6aR, 11aR)-(-)-6, respectively. The enantiomers of ±-6 were obtained through salt formation with (S)-(+)- and (R)-(-)-p-methylmandelic acid, and the absolute configuration of the (R)-(-)-p-methylmandelate salt of (3S, 6aR, 11aR)-(-)-6 was determined by single-crystal X-ray analysis. The enantiomeric secondary amines were reacted with N-(2-phenylcyclopropyl)methyl derivatives, 2-(E)-cinnamyl bromide, and (Z)-3-phenylacrylic acid. These products led to all of the desired N-derivatives of the ortho-c oxide-bridged phenylmorphans. Their opioid receptor binding affinity was measured. The compounds with MOR affinity < 50 nM were examined for their functional activity in the forskolin-induced cAMP accumulation assay. Only the enantiomer of the N-phenethyl ortho-c oxide-bridged phenylmorphan ((-)-1), and only the (3S,6aR,11aR)-2-(((1S,2S)-2-phenylcyclopropyl)methyl)-1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzofuro[2,3-c]azocin-10-ol isomer ((+)-17), and the N-phenylpropyl derivative ((-)-25) had opioid binding affinity < 50 nM. Both (-)-1 and (-)-25 were partial agonists in the cAMP assay, with the former showing high potency and low efficacy, and the latter with lower potency and less efficacy. Most interesting was the N-2-phenylcyclopropylmethyl (3S,6aR,11aR)-2-(1S,2S)-enantiomer ((+)-17). That compound had good MOR binding affinity (Ki = 11.9 nM) and was found to have naltrexone-like potency as a MOR antagonist (IC50 = 6.92 nM).
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影响因子：
7.3
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
通讯作者：
Rice KC
DOI：
10.3390/molecules25173870
发表时间：
2020-08-25
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Azevedo Neto J;Costanzini A;De Giorgio R;Lambert DG;Ruzza C;Calò G
通讯作者：
Calò G
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：
7.3
作者：
Cheng, Kejun;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