Docking of highly selective peptide ligands of 5HT2A/C receptors with antipsychotic activity

Search for new ligands selective to various 5HT2 receptor subtypes is an important scientific and practical problem for experimental psychopharmacology and clinical medicine. Most of existing antagonists of the 5HT2A- and 5HT2C- subtypes have necessary anti-anxiety and antipsychotic properties, but they are partially selective to 5HT2B receptors. The activation of the latter ones leads to cardiotoxic side effects, so it significantly limits clinical use of these drugs. For the search of new highly selective ligands of 5HT2A/C receptors an in silico screening algorithm was proposed using PScore.Max and Affinity.maxPScore indices, taking into account the affinity of low molecular weight compounds to each of 5HT2 receptor subtype. Cyclic physiologically active substances of peptide nature have been proposed as new promising drugs with antipsychotic activity. Based on the CXXC library, a number of cyclopeptides with a high selectivity of the structure to the target binding sites were selected for further in vitro studies by extending the peptide chain.It was also found that a promising direction for increasing the selectivity of peptide ligands to 5HT2A/C receptors is the introduction of non-proteinogenic amino acids during the formation of a starting docking library. Their choice will be stipulated by the nature of interactions between the reference ligands and amino acid residues of the binding site.

Serotonin and Its Metabolism Enhances Megakaryopoiesis and Proplatelet Formation

Serotonin (5-HT) has been recently identified as a novel growth factor. We previously demonstrated that 5-HT enhances murine megakaryopoiesis via 5-HT2 receptors and has promotor effect on hematopoiesis(Yang M et al, Stem Cells, 2007). However, the molecular mechanism remains under explored. In the terminal stage of mammalian megakaryocyte development, platelets are released from proplatelet protruding from megakaryocytes via cytoskeleton reorganization. 5-HT is shown to modulate cell migration and remolding by activating cytoskeleton reorganization, but the effects of 5-HT on proplatelet formation have not been investigated. Our results showed that 5-HT significantly promoted human CFU-MK formation and reduced apoptosis on human megakaryocytes through phosphorylation of Akt. These effects were attenuated by addition of ketanserin, a 5HT2 receptor inhibitor. 5-HT also stimulated proplatelet formation through activating the p-Erk1/2 expression and F-actin reorganization. Melatonin, the metabolism of 5-HT, promoted the recovery of platelets and the formation of bone marrow colony forming units in irradiated mice. Our findings suggested that 5-HT and melatonin plays an important role in human megakaryopoiesis. Interaction of 5-HT and 5-HTR2B induced downstream activation of PI3-k/Akt signal pathway leading to human MK cell proliferation. In addition, activation of 5-HTR2B also induced Erk1/2 phosphorylation, which then promoted cytoskeleton reorganization and subsequent proplatelet formation. We also proved that melatonin exerts a protective effect on MK and platelets in the irradiation mice model. Disclosures: No relevant conflicts of interest to declare.

Sedative antidepressants and insomnia

OBJECTIVE: The present review addresses the relationship between sleep and depression and how serotonergic transmission is implicated in both conditions. METHOD: Literature searches were performed in the PubMed and MedLine databases up to March 2010. The terms searched were "insomnia", "depression", "sedative antidepressants" and "serotonin". In order to pinpoint the sedative antidepressants most used to treat insomnia, 34 ISI articles, mainly reviews and placebo-controlled clinical trials, were selected from 317 articles found in our primary search. RESULTS: Sleep problems may appear months before the diagnosis of clinical depression and persist after the resolution of depression. Treatment of insomnia symptoms may improve this comorbid disease. Some antidepressant drugs can also result in insomnia or daytime sleepiness. Serotonin (5-HT) demonstrates a complex pattern with respect to sleep and wakefulness that is related to the array of 5-HT receptor subtypes involved in different physiological functions. It is now believed that 5HT2 receptor stimulation is subjacent to insomnia and changes in sleep organization related to the use of some antidepressants. CONCLUSION: Some drugs commonly prescribed for the treatment of depression may worsen insomnia and impair full recovery from depression. 5-HT2 receptor antagonists are promising drugs for treatment strategies since they can improve comorbid insomnia and depression.

Dynamics of platelet mobilisation into lungs in response to 5-hydroxytryptamine (serotonin) in mice

SummaryIn experimental animals, the lung rapidly removes intravenously injected 5-hydroxytryptamine (5HT), but the mechanism underlying this pulmonary 5HT removal (P-5HT-R) and the responsible cells remains unclear. 5HT reportedly induces rapid pulmonary platelet accumulation (P-PLT-A). Here, we examined the relationship between P-5HT-R and P-PLT-A in mice by comparing the platelet count in the blood with the endogenous 5HT in the tissues (a marker for platelets because the 5HT is largely contained within platelets). 5HT levels in murine blood and tissues were also examined after intravenous injection of 5HT. The data revealed that: (i) 5HT injection (at ≥ 0.04 μmol/kg) induced a transient P-PLT-A (occurring within 6 seconds), (ii) platelets rapidly took up injected 5HT, (iii) the P-5HT-R was saturated following injection of 5HT at 1 μmol/kg, (iv) ketanserin (5HT2-receptor antagonist) strongly inhibited P-PLT-A, (v) under fluoxetine (5HT-uptake inhibitor), 5HT levels at 6 seconds after 5HT injection were markedly higher in blood, but significantly lower in lung (versus fluoxetine-untreated mice), (vi) P-5HT-R was barely detectable in mutant mice with platelets lacking dense bodies, and was much reduced in platelet-depleted mice, (vii) 5HT injected intravenously at 10 μmol/kg had a half-life in the lung of < 20 seconds, and (viii) unlike 5HT, injected histamine was largely excreted by the kidney. These results demonstrate that platelets rapidly translocate into the lung upon stimulation of 5HT2 receptors, take up 5HT (and possibly swiftly metabolise it), and then return to the circulation. Hence, pulmonary platelet accumulation plays an important role in pulmonary 5HT removal in mice.

A meta-analysis of clinical trials comparing the serotonin (5HT)-2 receptor antagonists trazodone and nefazodone with selective serotonin reuptake inhibitors for the treatment of major depressive disorder

ObjectiveTo compare response rates among patients with major depressive disorder (MDD) treated with either a serotonin-2 (5HT2-) receptor antagonist or a selective serotonin reuptake inhibitor (SSRI).MethodsMedline and PubMed were searched for double-blind, randomized clinical trials comparing either trazodone or nefazodone with an SSRI for the treatment of MDD. Data from 9 reports involving a total 988 patients were identified and combined using a random-effects model.ResultsPatients randomized to treatment with a 5HT2 antagonist were as likely to experience clinical response as patients randomized to treatment with an SSRI (RR = 1.002, 95% CI: 0.85–1.17, P = 0.978). Pooled response rates for trazodone/nefazodone and the SSRis were 61.1% and 61.7%, respectively. There was also no difference in overall discontinuation rates (P = 0.334), discontinuation due to adverse events (P = 0.676), or discontinuation due to inefficacy (P = 0.289) between the two groups.ConclusionsThese results suggest that the 5HT2-receptor antagonists trazodone and nefazodone and the SSRis do not differ with respect to their overall efficacy and tolerability in the treatment of MDD. Although the sample size was relatively large and conveyed sufficient statistical power to test for differences in the overall sample, depression is a heterogeneous condition and differences may exist between treatments in particular subgroups of patients.

Disturbance of serotonin 5HT2 receptors in remitted patients suffering from hereditary depressive disorder

SummaryAim: The characteristics of 5HT2 receptor binding were investigated in major depression in vivo using positron emission tomography and the radioligand F-l 8-altanserin. Methods: Twelve patients from families with high loading of depression living in a geographically restricted region were examined and compared with normal control subjects. At the time of the PET measurement all patients were remitted; in some of them remission was sustained by antidepressive medication. Binding potential was assessed by Logan’s graphical analysis method. Results: The binding of F-l 8-altanserin was about 38% lower in patients than in healthy controls (p <0.00D. A multiple regression analysis revealed that this difference was mainly induced by depression rather than by medication. Conclusions: The data suggest that 5HT2 receptors are altered in depression. We present evidence for a reduction of the receptor density, which might be usable as trait marker of subjects susceptible for depressive illness.