title: 5-HT(6) receptor modulators: a patent update. Part 2. Diversity in heterocyclic scaffolds.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: ChemDiv, Inc., 6605 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Alexandre V
authors.initials: AV
authors.lastname: Ivachtchenko
authors.forename: Yan A
authors.initials: YA
authors.lastname: Ivanenkov
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Skorenko
mesh_terms: D000818:Animals; D002491:Central Nervous System Agents / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D010330:Patents as Topic; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D002491:Central Nervous System Agents; D006571:Heterocyclic Compounds; D008024:Ligands; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C097216:serotonin 6 receptor