5-HT₆ receptor modulators: a patent update. Part 2. Diversity in heterocyclic scaffolds

Abstract

Introduction: Among a variety of proteins included in a relatively wide GPCR family, serotonin 5-HT receptors (5-HT₆Rs) are highly attractive as important biological targets with enormous clinical importance. Among this sub-class, 5-HT₆R is the most recently discovered group. Available biological data clearly indicate that 5-HT₆R antagonists can be used as effective regulators in a variety of contexts, including memory formation, age-related cognitive impairments and memory deficits associated with conditions such as schizophrenia, Parkinson's disease (PD) and Alzheimer's disease (AD). Therefore, this receptor has already attracted a considerable attention within the scientific community, due to its versatile therapeutic potential.

Areas covered: The current paper is an update to the comprehensive review article published previously in Expert Opinion on Therapeutic Patents Ivashchenko AV, Ivanenkov YA, Tkachenko SE. 5-Hydroxytryptamine subtype 6 receptor modulators: a patent survey. Expert Opin. Ther. Pat, 2010, 20, 1171-1196. Here, the authors mainly focus on small-molecule compounds – 5-HT₆ antagonists – which have been described in recent patent literature, since the end of 2009. To obtain a clear understanding of the situation and dynamic development within the field of 5-HT₆ ligands, having an obvious pharmaceutical potential in terms of related patents, the authors provide a comprehensive search through several key patent collections. They describe the reported heterocyclic compounds with no sulfonyl moiety in sufficient detail to provide a valuable insight in the 5-HT₆R chemistry and pharmacology. Most of the described compounds are currently classified as multimodal agents with high affinity toward 5-HT₆R.

Expert opinion: Recent progress in the understanding of the 5-HT₆ receptor function and structure includes a suggested constitutive activity for the receptor, development of a number of multimodal small-molecule ligands and re-classification of many selective antagonists as pseudo-selective agents. Several heterocylic structures with or without any basic center provide sufficient supramolecular interactions and show high agonistic/antagonistic activity against 5-HT₆R. Many ‘multitarget' drugs acting, for instance, against several isoforms of 5-HTR, including 5-HT₆R subtype, as well as against dopamine and/or histamine receptors were shown to have beneficial therapeutic effects. At the same time, these ‘unselective' compounds may also increase the side-effect potential. The ensemble of antagonistic activity against 5-HT₆R and inhibition potency against BuChE can be regarded as the most promising basis for the development of effective drugs with a sufficient therapeutic window for the treatment of several neurodegenerative diseases, including AD and PD.

Keywords::

• 5-HT₆R
• Alzheimer's disease
• antagonists
• depression
• Huntington's disease
• ligands
• obesity
• schizophrenia
• serotonin receptors

Acknowledgment

The authors would like to extend their sincere gratitude to Dr. Sergey E Tkachenko, Dr. Ilya M Okun and Madina G Kadieva for invaluable help during the manuscript preparation.

Notes

This box summarizes key points contained in the article.