Dopamine D3 receptor ligands: a patent review (2014–2020)

ABSTRACT

Introduction

Compelling evidence identified D3 dopamine receptor (D3R) as a suitable target for therapeutic intervention on CNS-associated disorders, cancer, and other conditions. Several efforts have been made toward developing potent and selective ligands for modulating signaling pathways operated by these GPCRs. The rational design of D3R ligands endowed with a pharmacologically relevant profile has traditionally not encountered much support from computational methods due to a very limited knowledge of the receptor structure and of its conformational dynamics. Recent progress in structural biology will change this state of affairs in the next decade.

Areas covered

This review provides an overview of the recent (2014–2020) patent literature on novel classes of D3R ligands developed within the framework of CNS-related diseases, cancer, and additional conditions. When possible, an in-depth description of both in vitro and in vivo generated data is presented. New therapeutic applications of known molecules with activity at D3R are discussed.

Expert opinion

Building on current knowledge, future D3R-focused drug discovery campaigns will be propelled by a combination of unprecedented availability of structural information with advanced computational and analytical methods. The design of D3R ligands with the sought activity, efficacy, and selectivity profile will become increasingly more streamlined.

KEYWORDS:

• Dopamine
• D3 dopamine receptor
• D3R ligands
• GPCR
• amine-containing scaffold
• CNS-related disorders

Article highlights

• D3R is a validated target for the treatment of several CNS-related diseases and cancer. More recently, this target has been investigated for relieving menopausal symptoms.

• The rational design of D3R-selective ligands still represents a demanding task due to the high degree of sequence identity with its close analogue D2R and several other aminergic receptor subtypes.

• The increasing availability of X-ray crystal structures of GPCRs is leading to a deeper understanding of the structural basis of both selectivity and efficacy at D3R.

• In recent years, different amine-containing scaffolds have been explored to develop novel D3R compounds with clinical ambitions, exploiting unique interactions at the D3R binding pocket.

• Novel therapeutic applications of molecules with known D3R activity have been disclosed either as single drugs or in combination therapies.

• The combination of unprecedented availability of structural information with insights generated by advanced computational methods will inform future synthetic campaigns targeting D3R.

This box summarizes key points contained in the article.

Declaration of interests

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 matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants 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

No funding to declare.