Introduction: Among a variety of proteins included in a relatively wide GPCR family, serotonin 5-HT receptors (5-HT(6)Rs) are highly attractive as important biological targets with enormous clinical importance. Among this sub-class, 5-HT(6)R is the most recently discovered group. Available biological data clearly indicate that 5-HT(6)R 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 [1] 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-HT(6) 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-HT(6) 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-HT(6)R chemistry and pharmacology. Most of the described compounds are currently classified as multimodal agents with high affinity toward 5-HT(6)R.
Expert opinion: Recent progress in the understanding of the 5-HT(6) 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-HT(6)R. Many 'multitarget' drugs acting, for instance, against several isoforms of 5-HTR, including 5-HT(6)R 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-HT(6)R 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.