The discovery and development of IP3 receptor modulators: an update

ABSTRACT

Introduction: Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular calcium (Ca²⁺) release channels located on the endoplasmic/sarcoplasmic reticulum. The availability of the structure of the ligand-binding domain of IP3Rs has enabled the design of compatible ligands, but the limiting step remains their actual effectiveness in a biological context.

Areas covered: This article summarizes the compelling literature on both agonists and antagonists targeting IP3Rs, emphasizing their strengths and limitations. The main challenges toward the discovery and development of IP3 receptor modulators are also described.

Expert opinion: Despite significant progress in recent years, the pharmacology of IP3R still has major drawbacks, especially concerning the availability of specific antag onists. Moreover, drugs specifically targeting the three different subtypes of IP3R are especially needed.

KEYWORDS:

• Adenophostin
• IP3
• IP3R
• ITPR
• xestospongin
• 2-APB
• drug design
• structure

Article highlights

• Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular calcium (Ca²⁺) release channels located on the endoplasmic reticulum, the major Ca²⁺ reservoir within the cell.

• Three different subtypes of IP3Rs are expressed in mammalian cells, namely IP3R1, IP3R2, and IP3R3.

• The intrinsic complexity of the recently solved structure of IP3R envisages the potential participation of the receptor to a dense network of processes.

• The structure of the ligand-binding domain of IP3Rs has facilitated the design of compatible ligands, but the limiting step remains their actual effectiveness in biological context.

• The availability of effective drugs targeting IP3Rs can be harnessed to better comprehend the biology of IP3R, exploring its involvement in various settings.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The Santulli’s Laboratory is supported in part by the National Institutes of Health (NIH): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK: R01-DK123259, R01-DK033823, R00-DK107895), National Heart, Lung, and Blood Institute (NHLBI: R01-HL146691, T32-HL144456), National Institute on Aging (NIA: R56-AG066431) to G.S. and by the American Heart Association (AHA-20POST35211151 to J.G.).