Thalidomide-linker 5

5-Hydroxytryptamine (5-HT) receptors were originally subclassified into the subtypes M and D based on the findings that 5-HT contracted the guinea-pig ileum by two different mechanisms: (a) directly by an effect on receptors located on smooth muscles (via D receptors), and (b) indirectly by an effect on neuronal receptors (M receptors), the activation of which caused acetylcholine release. With the introduction of radioligand-binding studies and the development of more selective 5-HT agonists and antagonists, it rapidly became apparent that this subclassification is an oversimplification, and it is now accepted that at least three, possibly four main families of 5-HT receptors exist: 5-HT1, 5-HT2, 5-HT3 and possibly 5-HT4 receptors. Furthermore, 5-HT1 receptors are not a homogeneous class, but are subdivided further into four subtypes: 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D. Whether 5-HT2 and 5-HT3 receptors are also a heterogeneous class of receptors is still a matter of controversy. Besides the differences in specific agonists and antagonists, 5-HT-receptor subtypes seem to differ also in their signal-transduction mechanisms. 5-HT1 receptors (with the exception of 5-HT1C) are coupled to adenylate cyclase, predominantly in an inhibitory fashion, but 5-HT1-mediated activation of adenylate cyclase has been also described. 5-HT2 receptors (and 5-HT1C) are coupled to PI turnover, while 5-HT3 receptors appear to be coupled directly to fast ion channels. On the other hand, 5-HT4 receptors couple obviously in an excitatory fashion to adenylate cyclase.

If serotonin (5-hydroxytryptamin [5-HT]) is well known for its role in mood regulation, it also impacts numerous physiological functions at periphery. Serotonin is synthetized at the periphery into the gut by intestinal enterochromaffin cells and in the central nervous system (CNS) in the raphe nucleus from the essential amino acid tryptophan. Physiological effects of 5-HT are mediated by about 15 serotoninergic receptors grouped into seven broad families (5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, 5-HT7 receptor families). Except 5-HT3 receptor, a ligand-gated ion channels, all the others are G protein-coupled receptors. Serotonin's homeostasis involves serotoninergic autoreceptor such as 5-HT1A, 5-HT1B, 5-HT1D, the enzymatic degradation of serotonin by monoamine oxidase A (MAO-A), and a transporter (serotoninergic transporter [SERT]). In the CNS, the SERT is a key target for various antidepressant drugs such as Selective Serotonin Reuptake Inhibitors (SSRI), Serotonin Norepinephrin Reuptake Inhibitors (SNRI) and tricyclics family. However, antidepressant activity of SERT inhibitors is not directly mediated by the SERT inhibition, but a consequence of postsynaptic 5-HT receptor activation following the increase in 5-HT levels in the synaptic cleft. In pharmacology, SSRIs are defined as indirect agonist of postsynaptic receptor. Among all the 5-HT receptors, 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2B and 5-HT4 receptors activation would mediate antidepressant effects. In the meanwhile, 5-HT2A, 5-HT2C, 5-HT3, 5-HT6 and 5-HT7 receptors activation would induce opposite effects. The best serotoninergic antidepressant would directly activate 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2B and 5-HT4 and would block 5-HT2A, 5-HT2C, 5-HT3, 5-HT6 and 5-HT7 receptor. If the chemical synthesis of such a compound may be compromised, SERT inhibition associated with the blockade of some but not all 5-HT receptor could shorten onset of action and/or improve antidepressant efficacy on the overall symptomatology of depression.

Epigenetics has undergone an explosion in the past decade. DNA methylation, consisting of the addition of a methyl group at the fifth position of cytosine (5-methylcytosine, 5-mC) in a CpG dinucleotide, is a well-recognized epigenetic mark with important functions in cellular development and pathogenesis. Numerous studies have focused on the characterization of DNA methylation marks associated with disease development as they may serve as useful biomarkers for diagnosis, prognosis, and prediction of response to therapy. Recently, novel cytosine modifications with potential regulatory roles such as 5-hydroxymethylcytosine (5-hmC), 5-formylcytosine (5-foC), and 5-carboxylcytosine (5-caC) have been discovered. Study of the functions of 5-mC and its oxidation derivatives promotes the understanding of the mechanism underlying association of epigenetic modifications with disease biology. In this respect, much has been accomplished in the development of methods for the discovery, detection, and location analysis of 5-mC and its oxidation derivatives. In this review, we focus on the recent advances for the global detection and location study of 5-mC and its oxidation derivatives 5-hmC, 5-foC, and 5-caC.