Structure–Activity Relationship Study of CYM51010, an agonist for the µ–δ Opioid Receptor Heterodimer

Although opioid analgesics are indispensable in treating pain, these drugs are accompanied by life-threatening side effects. While clinically relevant opioid drugs target the µ opioid receptor (MOR), a heterodimer between the MOR and the δ opioid receptor (DOR) has emerged as another target to devel...

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Published in:	Chemical & pharmaceutical bulletin Vol. 72; no. 7; pp. 711 - 730
Main Authors:	Watanabe, Ayaka, Yamada, Shuma, Yoshida, Haruka, Inagaki, Miku, Atsumi, Nao, Matsushima, Aoba, Takahashi, Naoki, Ishibashi, Naoto, Ogino, Takumi, Someya, Ryoto, Taguchi, Ai, Kagaya, Ryo, Ashizawa, Karin, Mendori, Hinako, Karasawa, Yusuke, Ohshima, Kaori, Yokoyama, Akinobu, Nonaka, Miki, Miyano, Kanako, Karaki, Fumika, Hirayama, Shigeto, Itoh, Kennosuke, Uezono, Yasuhito, Fujii, Hideaki
Format:	Journal Article
Language:	English
Published:	Japan The Pharmaceutical Society of Japan 30-07-2024 Japan Science and Technology Agency
Subjects:	Agonists analgesic Analgesics Analgesics, Opioid - chemical synthesis Analgesics, Opioid - chemistry Analgesics, Opioid - pharmacology Animals CHO Cells Cricetulus Dose-Response Relationship, Drug Functional groups G protein-coupled receptor heterodimer Humans Molecular Structure Monomers Narcotics Opioid receptors Physiological effects Piperidine Receptors Receptors, Opioid, delta - agonists Receptors, Opioid, delta - metabolism Receptors, Opioid, mu - agonists Receptors, Opioid, mu - metabolism Side effects Structure-Activity Relationship Substitutes δ opioid receptor µ opioid receptor G protein-coupled receptor µ opioid receptor δ opioid receptor heterodimer analgesic
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Summary:	Although opioid analgesics are indispensable in treating pain, these drugs are accompanied by life-threatening side effects. While clinically relevant opioid drugs target the µ opioid receptor (MOR), a heterodimer between the MOR and the δ opioid receptor (DOR) has emerged as another target to develop safer analgesics. Although some heterodimer-preferring agonists have been reported so far, it is still difficult to activate the MOR/DOR heterodimer selectively in the presence of MOR or DOR monomers/homodimers. To gain insights to develop selective agonists for MOR/DOR, herein we prepared analogs of CYM51010, one of the reported heterodimer-preferring agonists, and collected structure–activity relationship information. We found that the ethoxycarbonyl group was needed for the activity for the heterodimer, although this group could be substituted with functional groups with similar sizes, such as an ethoxycarbonyl group. As for the acetylaminophenyl group, not a type of substituent, but rather a substituent located at a specific position (para-position) was essential for the activity. Changing the linker length between the acetylaminophenyl group and the piperidine moiety also had deleterious effects on the activity. On the other hand, the substitution of the acetylamino group with a trifluoroacetylamino group and the substitution of the phenethyl group with a benzyl group diminished the activities for the monomers/homodimers while keeping the activity for MOR/DOR, which enhanced the selectivity. Our findings herein will play an important role in developing selective agonists for MOR/DOR and for elucidating the physiological roles of this heterodimer in analgesic processes and in the establishment of side effects.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0009-2363 1347-5223 1347-5223
DOI:	10.1248/cpb.c24-00188