GABA_A receptor subtype modulators in medicinal chemistry: an updated patent review (2014-present)

ABSTRACT

Introduction: Ligands at the benzodiazepine binding site of the GABA_A receptor (GABA_AR) act by modulating the effect of GABA (γ-aminobutyric acid). The benzodiazepine drugs are conventionally categorized as positive allosteric modulators enhancing the chloride ion current GABA-induced. In literature there are also reported ligands that act as negative allosteric modulators, reducing chloride ion current, and silent allosteric modulators not influencing the chloride ion flux.

Areas covered: This review covers patents published from 2014 to present on ligands for the benzodiazepine binding site of the GABA_ARs. Patents filed from different companies and research groups report many compounds that may be used in the treatment/prevention of a large variety of diseases.

Expert opinion: Since the discovery of the first benzodiazepine about 60 years have passed and about 50 years since the identification of their target, GABA_A receptor. Even if benzodiazepines are the most popular anxiolytic drugs, the research in this field is still very active. From patents/application analysis arises that most of them claim methods for alleviating specific symptoms in different neurodegenerative diseases and their related memory deficits. Noteworthy is the presence of the α4- and α5-GABA_A receptor subtype ligands as new pharmacological tools for airway hyperresponsiveness, inflammation diseases, and asthma.

KEYWORDS:

• Benzodiazepine binding site
• GABA_a receptor subtype
• allosteric modulators
• neurodegenerative disease
• neuropathic pain
• airway hyperresponsiveness

Article Highlights

• This review focuses on allosteric modulators of GABA_A receptor subtype (α_n-GABA_AR) disclosed in patents/applications reported in the literature from 2014 to present.

• In the last five years, the cryo-electron microscopy permitted the 3D high-resolution structure of the GABA_A receptor in complex with different ligands, establishing binding modes and structural effects of these ligands and mechanism of their action.

• In this review are pointed out the GABA_AR subtype ligands currently in clinical trials (NCT number is reported).

• Most of the analyzed patents claim the new therapeutic applications of known positive allosteric modulators (PAMs) and negative allosteric modulators (NAMs) and their deuterated analogues, to alleviate symptoms in neurodegenerative diseases and epilepsy disorders as well as to modulate the inflammatory response, pain, itch, and beta cells activity in humans.

The classification of ligands is made on the basis of the number of (hetero)cycles in the chemical structure: monocycle, bicycles, and tricycles and tetracycles compounds and the applicants are reported in alphabetical order.

This box summarizes key points contained in the article.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grant or patents received or pending, or royalties.

Reviewer Disclosures

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

Additional information

Funding

This paper was funded by a grant from the Italian Ministry of University and Research (MIUR).