Trace amine associated receptor 1 (TAAR1) modulators: a patent review (2010-present)

ABSTRACT

Introduction: The greater interest in TAAR1-mediated potential for the treatment of different pathologies, especially those related to CNS disorders, has given a considerable boost to the search for developing TAAR1-selective small molecules.

Areas covered: During the last decade, the medicinal chemistry efforts have allowed the yield of various chemotypes to be properly dressed toward TAAR1 receptor. The more relevant chemical features and structure–activity relationship studies on the TAAR1 ligands will be discussed in order to guide future drug discovery investigations.

Expert opinion: The discovery of TAAR receptors has allowed better investigation of the role played by TAs, not only as secondary neuromodulators, but also as neurotransmitters, even if it should still be completely clarified. This has drawn new ways for further insights around the TAAR1 involvement in numerous diseases. Despite this, the limited number of promising ligands targeting hTAAR1 orthologue makes the discovery of novel compounds still a challenging task. Relevant efforts have to be focused on safe ligands, devoid of any side-efficacy toward other highly related GPCR (monoaminergic systems). Moreover, species-specificity preferences experienced by numerous compounds so far investigated, based on rodent models and translated to the human environment, turn in a critical bottleneck in drug discovery.

KEYWORDS:

• Medicinal chemistry
• TAAR1 chemotypes
• TAAR1 agonists
• m/rTAAR1
• hTAAR1

Article highlights

• TAAR1 has been increasingly recognized as an innovative multi-druggable target in virtue of its wide range of potential therapeutic applications, especially those related to CNS disorders.

• Medicinal chemistry efforts have allowed the yield of various chemotypes to be properly dressed towards TAAR1 receptor.

• Chemotypes should include in their structures a basic moiety and an aromatic or heteroaromatic portion as required pharmacophoric features, linked through a spacer of variable nature and length, able to steer their structural flexibility and the related TAAR1 binding ability.

• The design of effective TAAR1 ligands is hampered by the selectivity issue over other TAARs, and also toward monoaminergic GPCRs.

• The species-specificity issue still represents a problem to be solved, since unreliable results are obtained by using rodent TAAR1 models as reference for human orthologue.

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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 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.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

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Funding

This paper was not funded.