7β-Methyl substituent is a structural locus associated with activity cliff for nepenthone analogues

Sun, Huijiao; Wang, Yuhua; Yuan, Congmin; Kong, Linghui; Xu, Xuejun; Wang, Yujun; Wu, Haihao; Lin, Cheng; Qian, Yuanyuan; Huang, Huoming; Xiao, Li; Liu, Xiao; He, Qiang; Fang, Shengyang; Xue, Ding; Yang, Xiao; Chen, Hao; Zheng, Yuxin; Zheng, Lan; Yu, Linqian; Xie, Qiong; Fu, Wei; Li, Wei; Liu, Jing-Gen; Qiu, Zhuibai; Shao, Liming

doi:10.1016/j.bmc.2018.07.020

Cited by 10 publications

(29 citation statements)

References 25 publications

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“…In addition to the pioneering work of Bentley and Harvey, , Husbands and Traynor’s recent work − revealed a variation in the opioid-like properties of these compounds. As part of our ongoing efforts, we utilized substituted styrenes and phenyl vinyl ketones as dienophiles to react with thebaine, and subsequently, the yielded adducts underwent transformations to obtain 7α-phenyl-6,14-endoetheno-tetrahydrothebaine and nepenthone derivatives, respectively. − Despite high diversity in the structure–activity relationship (SAR) profiles, there seemed to be a dominant κ component in these compounds, including the representative compounds SLL-020ACP and SLL-039 , which provided a structural basis for identifying potential κOR agonists with an improved safety profile.…”

Section: Introductionmentioning

confidence: 99%

Discovery of an M-Substituted N-Cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaine as a Selective, Potent, and Orally Active κ-Opioid Receptor Agonist with an Improved Central Nervous System Safety Profile

Wei

Liu

et al. 2021

J. Med. Chem.

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The search for selective kappa opioid receptor (κOR) agonists with an improved safety profile is an area of interest in opioid research. In this work, a series of m-substituted analogs were designed, synthesized, and assayed, resulting in the identification of compound 6c (SLL-1206) as a κOR agonist with single-digit nanomolar activities. The subtype selectivity of compound 6c appeared to be a consequence of an enormous decrease in the affinity for μOR and δOR, rather than a significant increase in the affinity for κOR, which was not the case for SLL-039, another selective and potent κOR agonist identified in our previous work. Besides reduced central nervous system effects, SLL-1206 exhibited substantially improved physicochemical and pharmacokinetic properties compared with SLL-039, with increases of over 20-fold in aqueous solubility and approximately 40-fold in oral bioavailability in rats.

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Section: Introductionmentioning

confidence: 99%

Discovery of an M-Substituted N-Cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaine as a Selective, Potent, and Orally Active κ-Opioid Receptor Agonist with an Improved Central Nervous System Safety Profile

Wei

Liu

et al. 2021

J. Med. Chem.

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“…A series of N -cyclopropylmethyl-7α-arylacetamidylphenyl-6,14-endoethano-tetrahydronorthebaine analogues were synthesized in a similar way as described in our previous work, , which was depicted in Scheme . With the aniline 3 as the key intermediate, the final products 4b – q were prepared with a variety of acids under appropriate conditions.…”

Section: Results and Discussionmentioning

confidence: 99%

“…The synthesis of northebaine hydrochloride and compounds 1 – 3 was according to the procedure described in our previous work. , …”

Section: Methodsmentioning

confidence: 99%

“…The synthesis of northebaine hydrochloride and compounds 1−3 was according to the procedure described in our previous work. 27,28 General Procedure for the Synthesis of Acetates 4b−n. To a solution of corresponding acid (0.24 mmol) in dichloromethane (10 mL) were added DIPEA (62 mg, 0.48 mmol) and HATU (137 mg, 0.36 mmol).…”

Section: Methodsmentioning

confidence: 99%

“…As part of our ongoing efforts − to develop κOR modulators from morphinan-based scaffold, SLL-039 (Figure ), an N -cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaine analogue, was identified as a highly selective and potent κOR agonist . Additionally, SLL-039 did not produce significant sedative effects compared with U50,488H at relevant doses for analgesia in rodent models.…”

Section: Introductionmentioning

confidence: 99%

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Exploration of the SAR Connection between Morphinan- and Arylacetamide-Based κ Opioid Receptor (κOR) Agonists Using the Strategy of Bridging

Liu

Jiang

Kong

et al. 2021

ACS Chem. Neurosci.

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κ opioid receptor (κOR) is a subtype of opioid receptors, and there are two major κOR agonists currently available, morphinans and arylacetamides, which are structurally distinct from each other. Numerous efforts had been made to correlate these series of compounds in order to establish a consensus binding pattern for κOR agonists. Unfortunately, no morphinan-based agent with an arylacetamidyl substituent has been identified as a κOR agonist with a pharmacological profile similar to arylacetamides. Since the recently described morphinan-based compound SLL-039 was identified as a selective and potent κOR agonist that contains a unique benzamidyl substituent in structure similar to arylacetamides, numerous arylacetamidyl substituents were introduced to this scaffold to examine whether the structure−activity relationships (SARs) of arylacetamides in conferring κOR agonistic activities could be reproduced by these analogues. Thus, a series of Ncyclopropylmethyl-7α-arylacetamidylphenyl-6,14-endoethanotetrahydronorthebaine analogues were designed, synthesized, and assayed for biological activities. Among these compounds, compound 4j with a 3′,4′-dimethylphenylacetamidyl substituent showed a single digit low nanomolar affinity to the κOR and relatively high subtype selectivity in binding assays, but this profile was not reproduced in functional assays. In contrast, compound 4i displayed moderately selective κOR agonistic activities in functional assays, which was inconsistent with its nonselective nature in binding assays. Overall, introduction of an arylacetamidyl substituent to the morphinan-based scaffold was associated with pharmacological diversity in both binding and functional activities on opioid receptors in vitro. The resultant SARs were inconsistent with that of classical arylacetamides as κOR agonists, despite bearing a similar arylacetamidyl substituent in the structure. Therefore, the arylacetamidyl substituent of the morphinan-based scaffold was found to be disconnected from that of arylacetamides in conferring κOR activities.

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Cross‐Coupling‐Cyclocondensation Reaction Sequence to Access a Library of Ring‐C Bridged Pyrimidino‐tetrahydrothebaines and Pyrimidinotetrahydrooripavines

et al. 2021

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Ring‐C bridged 1‐(pyrimidinyl)tetrahydrothebaines were convenience synthesized by a consecutive three‐component alkynylation–cyclocondensation sequence starting from 1‐ethynyl‐7α,8α‐(2,5‐dioxo‐N‐phenylpyrrolidino)‐[3,4‐h]‐6,14‐endo‐etheno‐tetrahydrothebaine, aroyl chlorides, and amidinium hydrochlorides. Several derivatizations and transformations of selected 1‐pyrimidinyl substituted tetrahydrothebaines were carried out. The analgesic activity of new type of hybrid compounds in the tail‐flick test in rats was evaluated. The data revealed that the antinociceptive potency was stroungly depended on the nature of the substituent in the C‐6 position of the pyrimidine nucleus. Docking study was undertaken to gain insight into the possible binding mode with the μ‐opioid receptor.

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7β-Methyl substituent is a structural locus associated with activity cliff for nepenthone analogues

Cited by 10 publications

References 25 publications

Discovery of an M-Substituted N-Cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaine as a Selective, Potent, and Orally Active κ-Opioid Receptor Agonist with an Improved Central Nervous System Safety Profile

Discovery of an M-Substituted N-Cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaine as a Selective, Potent, and Orally Active κ-Opioid Receptor Agonist with an Improved Central Nervous System Safety Profile

Exploration of the SAR Connection between Morphinan- and Arylacetamide-Based κ Opioid Receptor (κOR) Agonists Using the Strategy of Bridging

Cross‐Coupling‐Cyclocondensation Reaction Sequence to Access a Library of Ring‐C Bridged Pyrimidino‐tetrahydrothebaines and Pyrimidinotetrahydrooripavines

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