Discovery of a Potent Highly Biased MOR Partial Agonist among Diastereomeric C9-Hydroxyalkyl-5-phenylmorphans.
Discovery of a Potent Highly Biased MOR Partial Agonist among Diastereomeric C9-Hydroxyalkyl-5-phenylmorphans.
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DOI：
10.3390/molecules28124795
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发表时间：
2023-06-15
期刊：
影响因子：
4.6
通讯作者：
Rice, Kenner C.
中科院分区：
文献类型：
--
作者：
Lutz, Joshua A.;Sulima, Agnieszka;Gutman, Eugene S.;Bow, Eric W.;Luo, Dan;Kaska, Sophia;Prisinzano, Thomas E.;Paronis, Carol A.;Bergman, Jack;Imler, Gregory H.;Kerr, Andrew T.;Jacobson, Arthur E.;Rice, Kenner C.
关键词：
diastereomersC9-hydroxyalkyl 5-phenylmorphansm-hydroxy-N-phenethyl-5-phenylmorphansN-phenethyl-2-azabicyclo[331]nonan-5-yl)phenolsmu-opioid receptor (MOR)delta-opioid receptor (DOR)kappa-opioid receptor (KOR) ligandspartial MOR agonistrespiratory depressionantinociceptive activityforskolin-induced cAMP accumulation assayG-protein biasbeta-arrestin2
合成了所有可能的非对映异构体C9-羟甲基-、羟乙基-和羟丙基-取代的5-苯基吗啉，以探索C9取代基周围的三维空间，从而寻找有效的莫尔部分激动剂。这些化合物被设计为减少用其C9-烯基取代的相关物观察到的亲脂性。发现获得的12种非对映异构体中的许多在毛喉素诱导的cAMP蓄积测定中具有纳摩尔或亚纳摩尔效力。几乎所有这些有效化合物都是完全有效的，其中三种选择用于体内评估的化合物（15、21和36）都对G蛋白有极强的偏见;这三种化合物都没有招募β-抑制蛋白2。12种非对映异构体中只有一种，21（3-（（1 S，5 R，9 R）-9-（2-羟乙基）-2-苯乙基-2-氮杂双环[3.3.1]壬-5-基）苯酚）是莫尔部分激动剂，在cAMP测定中具有良好但不完全的功效（Emax = 85%）和亚纳摩尔效力（EC 50 = 0.91 nM）。它没有任何KOR激动剂活性。这种化合物与吗啡不同，因为它在体内的镇痛作用有限。21的活性可能与三种众所周知的理论中的一种或多种有关，这些理论试图预测所需镇痛与临床使用的阿片类药物相关的不良阿片样副作用的分离。根据这些理论，21是有效的莫尔部分激动剂，它是高度G蛋白偏向的并且不吸引β-抑制蛋白2，并且发现它具有莫尔和DOR激动剂活性。合成的所有其他非对映体要么比21的效力低得多，要么对于我们的目的来说功效太少或太多。还注意到，具有1 R，5S，9 R立体化学的C9-甲氧基甲基化合物（41）比可比较的C9-羟甲基化合物11更有效（41的EC 50 = 0.65 nM，11的EC 50 = 2.05 nM）。41和11都是完全有效的。
All possible diastereomeric C9-hydroxymethyl-, hydroxyethyl-, and hydroxypropyl-substituted 5-phenylmorphans were synthesized to explore the three-dimensional space around the C9 substituent in our search for potent MOR partial agonists. These compounds were designed to lessen the lipophilicity observed with their C9-alkenyl substituted relatives. Many of the 12 diastereomers that were obtained were found to have nanomolar or subnanomolar potency in the forskolin-induced cAMP accumulation assay. Almost all these potent compounds were fully efficacious, and three of those chosen for in vivo evaluation, 15, 21, and 36, were all extremely G-protein biased; none of the three compounds recruited beta-arrestin2. Only one of the 12 diastereomers, 21 (3-((1S,5R,9R)-9-(2-hydroxyethyl)-2-phenethyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol), was a MOR partial agonist with good, but not full, efficacy (Emax = 85%) and subnanomolar potency (EC50 = 0.91 nM) in the cAMP assay. It did not have any KOR agonist activity. This compound was unlike morphine in that it had a limited ventilatory effect in vivo. The activity of 21 could be related to one or more of three well-known theories that attempt to predict a dissociation of the desired analgesia from the undesirable opioid-like side-effects associated with clinically used opioids. In accordance with the theories, 21 was a potent MOR partial agonist, it was highly G-protein biased and did not attract beta-arrestin2, and it was found to have both MOR and DOR agonist activity. All the other diastereomers that were synthesized were either much less potent than 21 or had either too little or too much efficacy for our purposes. It was also noted that a C9-methoxymethyl compound with 1R,5S,9R stereochemistry (41) was more potent than the comparable C9-hydroxymethyl compound 11 (EC50 = 0.65 nM for 41 vs. 2.05 nM for 11). Both 41 and 11 were fully efficacious.
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