The first structure-activity relationship study of oxytocin as a positive allosteric modulator for the µ opioid receptor.

Receptors, Opioid Allosteric Regulation Oxytocin Receptors, Opioid, mu / metabolism Structure-Activity Relationship Analgesics
Analgesics Cyclic peptide Oxytocin Positive allosteric modulator μ Opioid receptor

Journal

Peptides
ISSN: 1873-5169
Titre abrégé: Peptides
Pays: United States
ID NLM: 8008690

Informations de publication

Date de publication:
01 2023
Historique:
received: 04 08 2022
revised: 02 11 2022
accepted: 03 11 2022
pubmed: 9 11 2022
medline: 17 1 2023
entrez: 8 11 2022
Statut: ppublish

Résumé

Positive allosteric modulators (PAMs) of G protein-coupled receptors (GPCRs) have drawn attention as novel drug candidates. PAMs can enhance the activities of endogenous agonists which are not only secreted at appropriate times and in parts of the body, but also are immediately metabolized. Therefore, they are expected to show fewer side effects than exogeneous orthosteric ligands. Recently, we have reported that oxytocin (OT) functioned as a PAM of the μ opioid receptor (MOR) which was one of the most potent targets for analgesics. OT is thus thought to be a useful compound for the development of novel analgesics. In this study, several OT analogs were synthesized and evaluated with an intact cell-based assay to investigate the crucial structures of OT for exerting the PAM activity. The assay results indicated that the cyclic structure formed by an intramolecular disulfide bond and the three C-terminal residues containing a small Gly residue of OT were essential for their function as a MOR-PAM. Intriguingly, two analogs having an amide or an ethylene tether instead of the intramolecular disulfide bridge did not have any PAM effects. The results suggested that the disulfide linkage of OT would be a key structure for exerting the PAM activity at the MOR.

Identifiants

DOI: 10.1016/j.peptides.2022.170901 PMID: 36347314
pubmed: 36347314
pii: S0196-9781(22)00167-X
doi: 10.1016/j.peptides.2022.170901
pii:
doi:

Substances chimiques

Receptors, Opioid 0
Oxytocin 50-56-6
Receptors, Opioid, mu 0
Analgesics 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

170901

Informations de copyright

Copyright © 2022 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Conflicts of interest There is no conflict of interest.

Auteurs

Takaaki Mizuguchi (T)

Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan; Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.

Kanako Miyano (K)

Department of Pain Control Research, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan.

Risa Yamauchi (R)

Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.

Yuki Yoshida (Y)

Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641, Yamazaki, Noda, Chiba 278-8510, Japan.

Hideki Takahashi (H)

Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.

Ami Yamazaki (A)

Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.

Haruka Ono (H)

Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.

Miku Inagaki (M)

Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.

Miki Nonaka (M)

Department of Pain Control Research, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan.

Yasuhito Uezono (Y)

Department of Pain Control Research, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan. Electronic address: yuezono@jikei.ac.jp.

Hideaki Fujii (H)

Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan; Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan. Electronic address: fujiih@pharm.kitasato-u.ac.jp.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs peptidiques › Récepteur aux neuropeptides › Récepteurs aux opioïdes › The first structure-activity relationship...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Régulation allostérique › The first structure-activity relationship...
questionsmedicales.fr › Acides aminés, peptides et protéines › Peptides › Hormones peptidiques › Hormones hypophysaires › Hormones post-hypophysaires › Ocytocine › The first structure-activity relationship...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs peptidiques › Récepteur aux neuropeptides › Récepteurs aux opioïdes › Récepteur mu › The first structure-activity relationship...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Relation structure-activité › The first structure-activity relationship...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Agents du système nerveux central › Analgésiques › The first structure-activity relationship...