Structure-Activity Relationships and Therapeutic Potential of Purinergic P2X7 Receptor Antagonists


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Abstract

The purinergic P2X7 receptor (P2X7R), an ATP-gated non-selective cation channel, has emerged as a gatekeeper of inflammation that controls the release of proinflammatory cytokines. As a key player in initiating the inflammatory signaling cascade, the P2X7 receptor is currently under intense scrutiny as a target for the treatment of different pathologies, including chronic inflammatory disorders (rheumatoid arthritis and osteoarthritis), chronic neuropathic pain, mood disorders (depression and anxiety), neurodegenerative diseases, ischemia, cancer (leukemia), and many others. For these reasons, pharmaceutical companies have invested in discovering compounds able to modulate the P2X7R and filed many patent applications. This review article presents an account of P2X7R structure, function, and tissue distribution, emphasizing its role in inflammation. Next, we illustrate the different chemical classes of non-competitive P2X7R antagonists reported by highlighting their properties and qualities as clinical candidates for treating inflammatory disorders and neurodegenerative diseases. We also discuss the efforts to develop effective Positron Emission Tomography (PET) radioligands to progress the understanding of the pathomechanisms of neurodegenerative disorders, to provide evidence of drug-target engagement, and to assist clinical dose selection for novel drug therapies.

About the authors

Imane Ghafir El Idrissi

Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari Aldo Moro

Email: info@benthamscience.net

Sabina Podlewska

Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences

Email: info@benthamscience.net

Carmen Abate

Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari Aldo Moro

Email: info@benthamscience.net

Andrzej Bojarski

Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences

Email: info@benthamscience.net

Enza Lacivita

Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari Aldo Moro

Author for correspondence.
Email: info@benthamscience.net

Marcello Leopoldo

Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari Aldo Moro

Email: info@benthamscience.net

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