Strategy for the development of small-molecule antidepressant targeting PAC1 receptor

Ichiro Takasaki*, Atsuko Hayata-Takano*, Yusuke Shintani, Takashi Kurihara, Hitoshi Hashimoto

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

Abstract

Major depressive disorder (MDD) is a psychiatric disorder that affects more than 300 million people worldwide and has a serious impact on society. Conventional antidepressants targeting monoamines in the brain based on the monoamine hypothesis are known to take a prolonged time to be effective or less effective in 30% of MDD patients. Hence, there is a need to develop antidepressants that are effective against treatment-resistant depression and have a new mechanism different from the monoamine hypothesis. An increasing number of research groups including us have been establishing that pituitary adenylate cyclase-activating polypeptide (PACAP) and one of its receptors, PAC1 receptor, are closely related to the etiology of stress-related diseases such as MDD. Therefore, it is strongly suggested that the PAC1 receptor is a promising target in the treatment of psychiatric disorders. We developed a novel, non-peptidic, small-molecule, high-affinity PAC1 receptor antagonists and conducted behavioral pharmacology experiments in mice to characterize a novel PAC1 receptor antagonist as a new option for MDD therapy. The results show that our novel PAC1 receptor antagonist has the potential to be a new antidepressant with a high safety profile. In this review, we would like to present the background of developing our novel PAC1 receptor antagonist and its effects on mouse models of acute stress.

Original languageEnglish
Pages (from-to)219-224
Number of pages6
JournalFolia Pharmacologica Japonica
Volume159
Issue number4
DOIs
StatePublished - 2024

ASJC Scopus subject areas

  • Pharmacology

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