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Structure-Activity Relationship Study of CYM51010, an agonist for the µ-δ Opioid Receptor Heterodimer.
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.
Afiliación
  • Watanabe A; Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University.
  • Yamada S; Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University.
  • Yoshida H; Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University.
  • Inagaki M; Department of Pain Control Research, The Jikei University School of Medicine.
  • Atsumi N; Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University.
  • Matsushima A; Department of Pain Control Research, The Jikei University School of Medicine.
  • Takahashi N; Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University.
  • Ishibashi N; Department of Pain Control Research, The Jikei University School of Medicine.
  • Ogino T; Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University.
  • Someya R; Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University.
  • Taguchi A; Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University.
  • Kagaya R; Department of Pain Control Research, The Jikei University School of Medicine.
  • Ashizawa K; Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University.
  • Mendori H; Department of Pain Control Research, The Jikei University School of Medicine.
  • Karasawa Y; Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University.
  • Ohshima K; Department of Pain Control Research, The Jikei University School of Medicine.
  • Yokoyama A; Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University.
  • Nonaka M; Department of Pain Control Research, The Jikei University School of Medicine.
  • Miyano K; Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University.
  • Karaki F; Department of Pain Control Research, The Jikei University School of Medicine.
  • Hirayama S; Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University.
  • Itoh K; Department of Pain Control Research, The Jikei University School of Medicine.
  • Uezono Y; Department of Pain Control Research, The Jikei University School of Medicine.
  • Fujii H; Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science.
Chem Pharm Bull (Tokyo) ; 72(7): 711-730, 2024.
Article en En | MEDLINE | ID: mdl-39085079
ABSTRACT
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores Opioides delta / Receptores Opioides mu Límite: Animals / Humans Idioma: En Revista: Chem Pharm Bull (Tokyo) Año: 2024 Tipo del documento: Article Pais de publicación: Japón
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores Opioides delta / Receptores Opioides mu Límite: Animals / Humans Idioma: En Revista: Chem Pharm Bull (Tokyo) Año: 2024 Tipo del documento: Article Pais de publicación: Japón