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Cherepanov SM, Yokoyama S, Mizuno A, et al. Structure-specific effects of lipidated oxytocin analogs on intracellular calcium levels, parental behavior, and oxytocin concentrations in the plasma and cerebrospinal fluid in mice. Pharmacol Res Perspect. 2017;5(1):e00290doi: 10.1002/prp2.290.
Cherepanov, S. M., Yokoyama, S., Mizuno, A., Ichinose, W., Lopatina, O., Shabalova, A. A., Salmina, A. B., Yamamoto, Y., Okamoto, H., Shuto, S., & Higashida, H. (2017). Structure-specific effects of lipidated oxytocin analogs on intracellular calcium levels, parental behavior, and oxytocin concentrations in the plasma and cerebrospinal fluid in mice. Pharmacology research & perspectives, 5(1), e00290. https://doi.org/10.1002/prp2.290
Cherepanov, Stanislav M, et al. "Structure-specific effects of lipidated oxytocin analogs on intracellular calcium levels, parental behavior, and oxytocin concentrations in the plasma and cerebrospinal fluid in mice." Pharmacology research & perspectives vol. 5,1 (2017): e00290. doi: https://doi.org/10.1002/prp2.290
Cherepanov SM, Yokoyama S, Mizuno A, Ichinose W, Lopatina O, Shabalova AA, Salmina AB, Yamamoto Y, Okamoto H, Shuto S, Higashida H. Structure-specific effects of lipidated oxytocin analogs on intracellular calcium levels, parental behavior, and oxytocin concentrations in the plasma and cerebrospinal fluid in mice. Pharmacol Res Perspect. 2017 Jan 17;5(1):e00290. doi: 10.1002/prp2.290. eCollection 2017 Feb. PMID: 28596839; PMCID: PMC5461640.
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Pharmacol Res Perspect. 2017 Jan 17;5(1):e00290. doi: 10.1002/prp2.290. eCollection 2017 Feb.

Structure-specific effects of lipidated oxytocin analogs on intracellular calcium levels, parental behavior, and oxytocin concentrations in the plasma and cerebrospinal fluid in mice.

Pharmacology research & perspectives

Stanislav M Cherepanov, Shigeru Yokoyama, Akira Mizuno, Wataru Ichinose, Olga Lopatina, Anna A Shabalova, Alla B Salmina, Yasuhiko Yamamoto, Hiroshi Okamoto, Satoshi Shuto, Haruhiro Higashida

Affiliations

  1. Department of Basic Research on Social Recognition Research Center for Child Mental Development Kanazawa University Kanazawa 920-8640 Japan.
  2. Faculty of Pharmaceutical Sciences Hokkaido University Kita-12, Nishi-6, Kita-ku Sapporo 060-0812 Japan.
  3. Research Institute of Molecular Medicine & Pathobiochemistry Krasnoyarsk State Medical University named after Prof. V.F. Voino-Yasenetsky Krasnoyarsk 660022 Russia.
  4. Department of Biochemistry and Molecular Vascular BiologyGraduate School of Medical Sciences Kanazawa University Kanazawa 920-8640 Japan.
  5. Department of Advanced Biological Sciences for Regeneration (Kotobiken Medical Laboratories) Tohoku University Graduate School of Medicine Sendai 980-8575 Japan.
  6. Center for Research and Education on Drug Discovery Hokkaido University Kita-12, Nishi-6, Kita-ku Sapporo060-0812 Japan.

PMID: 28596839 PMCID: PMC5461640 DOI: 10.1002/prp2.290

Abstract

Oxytocin (OT) is a neuroendocrine nonapeptide that plays an important role in social memory and behavior. Nasal administration of OT has been shown to improve trust in healthy humans and social interaction in autistic subjects in some clinical trials. As a central nervous system (CNS) drug, however, OT has two unfavorable characteristics: OT is short-acting and shows poor permeability across the blood-brain barrier, because it exists in charged form in the plasma and has short half-life. To overcome these drawbacks, an analog with long-lasting effects is required. We previously synthesized the analog, lipo-oxytocin-1 (LOT-1), in which two palmitoyl groups are conjugated to the cysteine and tyrosine residues. In this study, we synthesized and evaluated the analogs lipo-oxytocin-2 (LOT-2) and lipo-oxytocin-3 (LOT-3), which feature the conjugation of one palmitoyl group at the cysteine and tyrosine residues, respectively. In human embryonic kidney-293 cells overexpressing human OT receptors, these three LOTs demonstrated comparably weak effects on the elevation of intracellular free calcium concentrations after OT receptor activation, compared to the effects of OT. The three LOTs and OT exhibited different time-dependent effects on recovery from impaired pup retrieval behavior in sires of CD38-knockout mice. Sires treated with LOT-1 showed the strongest effect, whereas others had no or little effects at 24 h after injection. These results indicated that LOTs have structure-specific agonistic effects, and suggest that lipidation of OT might have therapeutic benefits for social impairment.

Keywords: Autism; CD38; lipidation; oxytocin; oxytocin analog; parental behavior

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