A Journey through Diastereomeric Space: The Design, Synthesis, In Vitro and In Vivo Pharmacological Activity, and Molecular Modeling of Novel Potent Diastereomeric MOR Agonists and Antagonists.
A Journey through Diastereomeric Space: The Design, Synthesis, In Vitro and In Vivo Pharmacological Activity, and Molecular Modeling of Novel Potent Diastereomeric MOR Agonists and Antagonists.
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DOI：
10.3390/molecules27196455
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发表时间：
2022-09-30
期刊：
影响因子：
--
通讯作者：
Rice KC
中科院分区：
文献类型：
--
作者：
Chambers DR;Sulima A;Luo D;Prisinzano TE;Goldberg A;Xie B;Shi L;Paronis CA;Bergman J;Nassehi N;Selley DE;Imler GH;Jacobson AE;Rice KC
设计了四组非对映异构体C9-烯基5-苯基吗啉，不同的C9-烯基链的长度，研究这些空间上不同的配体对阿片受体的影响。通过毛喉素诱导的cAMP积累试验获得功能活性，并在[35 S]GTPgS试验和呼吸抑制试验中检查了几种化合物。在四组中的每一组中，观察到的相似性和差异取决于它们的C9-烯基链的长度，最重要的是，它们的立体化学。发现三种莫尔拮抗剂与纳洛酮一样或更有效，并且与纳洛酮不同，没有一种具有莫尔、KOR或DOR激动剂活性。获得了几种有效的莫尔完全激动剂，并且特别感兴趣的是，发现部分激动剂表现出比吗啡引起的呼吸抑制更少的呼吸抑制。立体化学和C9-烯基链的长度的影响也探讨了使用分子建模。发现莫尔拮抗剂与无活性（4DKL）莫尔晶体结构相互作用，发现激动剂与活性（6DDF）莫尔晶体结构相互作用。它们在小鼠莫尔的结合模式的比较用于深入了解它们的立体化学诱导的药理学差异的结构基础。
Four sets of diastereomeric C9-alkenyl 5-phenylmorphans, varying in the length of the C9-alkenyl chain, were designed to examine the effect of these spatially distinct ligands on opioid receptors. Functional activity was obtained by forskolin-induced cAMP accumulation assays and several compounds were examined in the [35S]GTPgS assay and in an assay for respiratory depression. In each of the four sets, similarities and differences were observed dependent on the length of their C9-alkenyl chain and, most importantly, their stereochemistry. Three MOR antagonists were found to be as or more potent than naltrexone and, unlike naltrexone, none had MOR, KOR, or DOR agonist activity. Several potent MOR full agonists were obtained, and, of particular interest partial agonists were found that exhibited less respiratory depression than that caused by morphine. The effect of stereochemistry and the length of the C9-alkenyl chain was also explored using molecular modeling. The MOR antagonists were found to interact with the inactive (4DKL) MOR crystal structures and agonists were found to interact with the active (6DDF) MOR crystal structures. The comparison of their binding modes at the mouse MOR was used to gain insight into the structural basis for their stereochemically induced pharmacological differences.
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影响因子：
64.8
作者：
Koehl A;Hu H;Maeda S;Zhang Y;Qu Q;Paggi JM;Latorraca NR;Hilger D;Dawson R;Matile H;Schertler GFX;Granier S;Weis WI;Dror RO;Manglik A;Skiniotis G;Kobilka BK
通讯作者：
Kobilka BK
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：
64.5
作者：
Schmid CL;Kennedy NM;Ross NC;Lovell KM;Yue Z;Morgenweck J;Cameron MD;Bannister TD;Bohn LM
通讯作者：
Bohn LM
影响因子：
7.3
作者：
Hiebel, Anne-Cecile;Lee, Yong Sok;Rice, Kenner C.
通讯作者：
Rice, Kenner C.
DOI：
10.1124/jpet.114.213694
发表时间：
2014-06-01
影响因子：
3.5
作者：
Linz, Klaus;Christoph, Thomas;Frosch, Stefanie
通讯作者：
Frosch, Stefanie