Intranasal administration of a stapled relaxin-3 mimetic has anxiolytic- and antidepressant-like activity in rats

Br J Pharmacol. 2019 Oct;176(20):3899-3923. doi: 10.1111/bph.14774. Epub 2019 Sep 11.

Abstract

Background and purpose: Depression and anxiety are common causes of disability, and innovative tools and potential pharmacological targets are actively sought for prevention and treatment. Therapeutic strategies targeting the relaxin-3 peptide or its primary endogenous receptor, RXFP3, for the treatment of major depression and anxiety disorders have been limited by a lack of compounds with drug-like properties. We proposed that a hydrocarbon-stapled mimetic of relaxin-3, when administered intranasally, might be uniquely applicable to the treatment of these disorders.

Experimental approach: We designed a series of hydrocarbon-stapled relaxin-3 mimetics and identified the most potent compound using in vitro receptor binding and activation assays. Further, we assessed the effect of intranasal delivery of relaxin-3 and the lead stapled mimetic in rat models of anxiety and depression.

Key results: We developed an i,i+7 stapled relaxin-3 mimetic that manifested a stabilized α-helical structure, proteolytic resistance, and confirmed agonist activity in receptor binding and activation in vitro assays. The stapled peptide agonist enhanced food intake after intracerebral infusion in rats, confirming in vivo activity. We showed that intranasal delivery of the lead i,i+7 stapled peptide or relaxin-3 had orexigenic effects in rats, indicating a potential clinically translatable route of delivery. Further, intranasal administration of the lead i,i+7 stapled peptide exerted anxiolytic and antidepressant-like activity in anxiety- and depression-related behaviour paradigms.

Conclusions and implications: Our preclinical findings demonstrate that targeting the relaxin-3/RXFP3 receptor system via intranasal delivery of an i,i+7 stapled relaxin-3 mimetic may represent an effective treatment approach for depression, anxiety, and related neuropsychiatric disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intranasal
  • Animals
  • Anti-Anxiety Agents / administration & dosage
  • Anti-Anxiety Agents / chemistry
  • Anti-Anxiety Agents / pharmacology*
  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / chemistry
  • Antidepressive Agents / pharmacology*
  • Anxiety / drug therapy*
  • Cells, Cultured
  • Depression / drug therapy*
  • Dose-Response Relationship, Drug
  • Female
  • HEK293 Cells
  • Humans
  • Male
  • Models, Molecular
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, G-Protein-Coupled / administration & dosage
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / metabolism*

Substances

  • Anti-Anxiety Agents
  • Antidepressive Agents
  • RXFP3 protein, human
  • Receptors, G-Protein-Coupled