5-HT6 receptors

The serotonin 6 (5-HT6) receptor is one of the most recently studied serotonin receptors, and an important candidate gene for the study of MDD because it is abundant in the limbic system and some antidepressants have a high affinity for it (Monsma, Shen, Ward etal, 1993). 

Lee, S. H., Lee, K. J., Lee, H. J. etal. (2005). Association between the 5-HT6 receptor C267T polymorphism and response to antidepressants treatment in major depressive disorder. Psychiatry Clin. Neurosci., 59, 140-5. 

Masellis M, Basils VS, Meltzer HY, Lieberman JA, Sevy S, Goldman DA et al. Lack of association between the T to C 267 serotonin 5-HT6 receptor gene (HTR6) polymorphism and prediction of response to clozapine in schizophrenia. Schizophr Res 2001 47(1) 49—58. 

The 5-HT4, 5-hts and 5-HT7 receptors are coupled to the stimulation of adenylyl cyclase. 5-HT4, 5-htg and 5-HT7 receptors preferentially couple to the stimulation of adenylyl cyclase, increasing cAMP formation, via the Gs family of G proteins (see Chs 19 and 21). These receptors, however, share only >35% overall sequence homology. For this reason, they are classified as distinct receptor groups or classes and not subtypes of a family. The grouping of these receptors together is considered to be somewhat arbitrary and may be modified in the future. A lower-case appellation is used for the 5-ht6 receptor because a physiological role for these receptors in intact tissue has not been found [28]. 

D. R. Bicyclic piperazinylbenzenesulfona-mides are potent and selective 5-HT6 receptor antagonists. Bioorg. Med. Chem. Lett. 2002, 22, 1357-1360. 

Figure 6.7. Distribution of 5-HT6 and 5-HT7 receptors. Unlike the widely distributed 5-HTj and 5-HT2 receptors, the 5-HT6 receptors are primarily located in the hippocampus and the 5-HT7 receptors restricted to the thalamus. 

Olanzapine, like clozapine, has a broad spectrum of action on dopamine, 5-HT, adrenergic, histaminei and muscarinic receptors (see Table 11.6). While the precise significance is presently unclear, it is of interest that whereas clozapine binds with a high affinity to 5-HT6 and 5-HT7 receptors, olanzapine only shows a high affinity for 5-HT6 receptors. 

Figure 2 shows an alignment of 104 of the known 5-HT receptors from vertebrates, for clarity, sequences for which the databases contain incomplete or incorrect sequences (see above) have been omitted. In TM1, the index residue N1.50 is completely conserved among all 104 receptors position 1.53 is a valine in all but the 5-HT6 receptors, in which it is a leucine. In helix 2, residue D2.50 is completely conserved among all 104 receptors, as are S2.45 and V2.57. In TM3, the DRY motif is conserved in all but one of the receptors, the exception being one of the two 5-HT7-like receptors from the pufferfish... 

Olsen MA, Nawoschik SP, Schurman BR, et al. Identification of a human 5-HT6 receptor variant produced by alternative splicing. Brain Res Mol Brain Res 1999 64 255-263. 

Ruat M, Traiffort E, Arrang JM, et al. A novel rat serotonin (5-HT6) receptor molecular cloning, localization and stimulation of cAMP accumulation. Biochem Biophys Res Commun 1993 193 268-276. 

Boess FG, Monsma FJ Jr, Sleight AJ, Launay JM. Identification of residues in transmembrane regions III and VI that contribute to the ligand binding site of the serotonin 5-HT6 receptor. J Neurochem 1998 71 2169-2177. 

Pullagurla MR, Westkaemper RB, Glennon RA. Possible differences in modes of agonist and antagonist binding at human 5-HT6 receptors. Biooig Med Chem Lett 2004 14 4569-4573. 

Tsai SJ, et al. Association analysis of the 5-HT6 receptor polymorphism C267T in Alzheimer s disease. Neurosci Lett 1999 276(2) 138—139. 

We had shown (vide supra) that a 4 -amino group was tolerated by the benzenesulfonyltryptamines. It was also tolerated by gramine 82 (i.e., 83 Kt = 6.9 nM). The basic amine of 82 could now be removed (note that at least one basic amine must be present in order to prepare a water-soluble salt). Skatole 84 (Kf= 12 nM), a 4 -monoamineigic analog of 83, retained 5-HT6 receptor affinity (92). This was quite an interesting turn of events the binding of skatole 84 indicated that the tryptamine amine is not required for binding Does the... 

Fig. 7. Schematic representation of the interaction of simple tiyptamines, such as serotonin, and Nj-substituted tryptamines, such as benzenesulfonyltryptamines where X = S02, with receptor features as identified using automated docking studies and a graphics model of the human 5-HT6 receptors. Although both types of ligand might utilize the aspartate moiety of TM3, they seem to be oriented in different sterically accessible pockets. (Adapted from ref. 96.)...

There is no guarantee that structurally similar agents will bind at 5-HT6 receptors in a similar manner (85). The tryptamines are a case in point. Upon casual inspection, because they share such gross structural commonalities as an indole nucleus separated from a basic terminal amine by a two-carbon-atom fragment, it might be expected that various tryptamines bind in a similar fashion at 5-HT6 receptors. This turns out not to be the case. Sufficient examples... 

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