Dual dopamine D2/5-HT2A receptor antagonists have potent activity and are referred to atypical antipsychotics due to their lower propensity to elicit EPS and their moderate efficacy toward negative symptoms. However, an on-going challenge in developing atypical antipsychotics drugs is to maintain the favorable profiles and avoid of cardiovascular risk. In this paper, comparative pharmacophore analysis of dual dopamine D2/5-HT2A receptor antagonists, hERG K+ channel blockers, and alA adrenoceptor antagonists is carried out, and the results could give some insight into multi-target drug design.
Adrenergic alpha-1 Receptor Antagonists ; Dopamine D2 Receptor Antagonists ; Drug Delivery Systems ; Drug Design ; ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels ; antagonists & inhibitors ; chemistry ; Molecular Conformation ; Molecular Structure ; Receptor, Serotonin, 5-HT2A ; chemistry ; Receptors, Adrenergic, alpha-1 ; chemistry ; Receptors, Dopamine D2 ; chemistry ; Serotonin 5-HT2 Receptor Antagonists ; Structure-Activity Relationship

5-hydroxtryptamine (5-HT, serotonin) has been recognized not only as a neurotransmitter and vasoactive agent, but also as a growth factor. 5-HT mainly binds to 5-HT(2) receptors or 5-HT(1) receptors on cell surface to stimulate cell proliferation through Ras or MAPK pathway in many cell types. It has been reported that 5-HT stimulates megakaryocytopoiesis via 5-HT receptors. The possible mechanism of 5-HT on the proliferation and differentiation of megakaryocytes (MK) has been discussed in this review article. In early stage of megakaryocytopoiesis, 5-HT may bind to 5-HT(2B) receptor on megakaryocytes, and promotes their proliferation and differentiation. In the late stage, 5-HT may involve in the platelet release procedure by inducing nitric oxide (NO) synthesis via 5-HT(2A) receptors. 5-HT can also antagonize the apoptotic effect induced by thrombospondin-1 (TSP-1) which is a platelet alpha granule protein and has synergic effect with platelet-derived growth factor (PDGF) to enhance megakaryocytes proliferation. Therefore, 5-HT is likely to be an important substance in the feedback regulation of thrombopoiesis. In this review the 5-HT and its receptors, 5-HT as cell growth factor, pathway of 5-HT stimulating cell proliferation and influance of 5-HT on MK-progenitor cells were summarized.
Humans ; Megakaryocytes ; physiology ; Receptors, Serotonin ; metabolism ; Receptors, Serotonin, 5-HT2 ; metabolism ; Serotonin ; metabolism ; pharmacology ; Thrombopoiesis ; physiology ; Thrombopoietin ; physiology

OBJECTIVES: This study was designed to compare risperidone(as an atypical antipsychotic) with haloperidol(as a typical antipsychotic), so we examined the clinical effects and changes of plasma HVA, 5-HIAA & HVA/5-HIAA ratio after 8 week of risperidone or haloperidol trial. METHOD: Twenty-six male chronic schizophrenic patients were treated for 8 weeks with risperidone(N=14) and haloperidol(N=12). The duration of wash-out period was 14 days. The psychopathologic assessment was chechked by Positive and Negative Syndrome Scale(PANSS) and plasma HVA & 5-HIAA was measured by High Performance Liquid Chromatography(HPLC) with electrochemical detector. The checking points were just before drug trial and 1st, 2nd, 4th, and 8th week(total 5 times). RESULTS: 1) Risperidone trial group were more improved than haloperidol tiral group in PANSS scores(total, positive, negative and general psychopathy). 2) Changes of plasma HVA and 5-HIAA in the risperidone and haloperidol trial group were not statistically different. But because baseline 5-HIAA of risperidone trial group was higher than that of haloperidol trial group, the increase of haloperidol trial group would be more. 3) There was significant difference in changes of HVA/5-HIAA ratio between risperidone and haloperidol trial group. But the change of HVA compared with 5-HIAA in risperidone trial group was higher than that of haloperidol trial group. CONCLUSION: These results revealed that risperidone was more effective in clinical symptoms, and suggest that cause of these results may be due to blocking both of dopamine D2 receptors and serotonin 5-HT2 receptors of risperidone.
Haloperidol* ; Humans ; Hydroxyindoleacetic Acid* ; Male ; Plasma* ; Receptors, Dopamine D2 ; Receptors, Serotonin, 5-HT2 ; Risperidone* ; Tramadol

Risperidone is a relatively new antipsychotic agent. It is often referred to as 'atypical', because it has a mechanism of action that blocks post synaptic dopamine-2 and serotonin-2 receptors, it is associated with fewer extrapyramidal side effects, it is not yet associated with tardive dyskinesia, and it may have some efficacy on negative symptoms of schizophrenia. In despite of its 'atypical' nature, there are already more than 15 reports of risperidone-induced neuroleptic malignant syndrome. Only one case of risperidone-induced NMS was reported recently in Korea. We report one case of delayed risperidoneinduced neuroleptic malignant syndrome in young male patient and review the related articles.
Humans ; Korea ; Male ; Movement Disorders ; Neuroleptic Malignant Syndrome* ; Receptors, Serotonin, 5-HT2 ; Risperidone ; Schizophrenia

Nefazodone, a newer antidepressant is a phenylpiperazine derivative that inhibits the reuptake of both norepinephrine and serotonin, and antagonizes 5-HT2A and alpha1 adrenergic receptors. Compared with SSRIs nefazodone caused the fewer activating symptoms, adverse gastrointestinal effects(nausea, diarrhea, anorexia) and adverse effects of sexual function, but is associated with the more dizziness, dry mouth, constipation, visual disturbances and confusion. We report on 4 cases of visual disturbances and hallucinations in patients taking nefazodone. 1) Nefazodone, as a 5-HT2A antagonist, might induce visual disturbances. 2) mCPP, metabolite of nefazodone might contribute to the hallucination through action on 5-HT receptor. 3) Dopaminergic enhancing activity of nefazodone might cause hallucination. The case report raises the possibility that dose-related perceptual disturbances may exist with nefazodone. The fact emphasizes the need to pay close attention to all possible drug interactions, particularly in patients treated with multiple psychoactive agents, older patients, and patients with decreased hepatic function.
Constipation ; Diarrhea ; Dizziness ; Drug Interactions ; Hallucinations ; Humans ; Mouth ; Norepinephrine ; Psychotropic Drugs ; Receptors, Adrenergic ; Serotonin ; Serotonin 5-HT2 Receptor Antagonists

Serotonin has been implicated in the etiology and pathophysiology of mental illness such as depression, schizophrenia, anxiety disorder, eating disorder, obsessive compulsive disorder, and panic disorder. Many current used treatments of these disorders are thought to act through the modulation of the serotonergic tone. To improve on the efficacy of antipsychotics that are potent D2 receptor blockers, much interest has evolved around complimenting or replacing D2 dopaminergic antagonism by the action on serotonergic transmission. 5-HT2A receptor blockade, under the condition of weaker D2 receptor antagonism, may contribute to the ability of atypical antipsychotics to increase dopamine release in the medical prefrontal cortex while having a smaller effect on mesolimbic dopamine release. These effects may contribute to their advantage for cognition, negative symptoms and psychotic activity. The use of 5-HT1A receptor agonists may substitute for 5-HT2A antagonism and achieve many of the same benefits in combination with weak D2 receptors blockade. Antagonism of 5-HT2C receptors may also useful for improving cortical function. Thus, 5-HT has joined dopamine as a critical target for developing effective antipsychotics in schizophrenia. In the development of new first-line pharmacological treatment for major depressive disorder, 5-HT system will most likely remain important especially if agents can be developed with improved tolerability, faster onset of response or greater efficacy. The promising area for development of serotonergic antidepressants are agents that target the specific 5-HT receptor subtypes, and agents that affect 5-HT plus one or more of the noradrenaline, CRF, dopamine and glucocorticoids systems. Selective targeting of serotonin receptors such as 5-HT1, 5-HT2, or 5-HT7 may have considerable potential in the treatment of depressive disorders. Trophic agents that increased neuroplasticity or neurogenesis via the activation of cyclic AMP-CREB pathway may be beneficial as a target for novel antidepressants.
Antidepressive Agents ; Antipsychotic Agents ; Anxiety Disorders ; Cognition ; Depression* ; Depressive Disorder ; Depressive Disorder, Major ; Dopamine ; Feeding and Eating Disorders ; Glucocorticoids ; Neurogenesis ; Neuronal Plasticity ; Norepinephrine ; Obsessive-Compulsive Disorder ; Panic Disorder ; Prefrontal Cortex ; Receptor, Serotonin, 5-HT1A ; Receptor, Serotonin, 5-HT2A ; Receptor, Serotonin, 5-HT2C ; Receptors, Serotonin ; Schizophrenia* ; Serotonin ; Serotonin Agents*

AIMTo explore the modulation of 5-HT on GABA-activated current (I(GABA)) in the membrane of rat dorsal root ganglion (DRG) neurons and its mechanism.

METHODSRat DRG neurons were isolated mechanically and enzymatically, on which whole-cell patch clamp recording and repatch technique for intracellular dialysis were performed.

RESULTSIn the majority of neurons examined (92.0%, 69/75) GABA induced a concentration-dependent inward current. In neurons sensitive to GABA preapplication of 5-HT produced potentiation effect (82.6% , 57/69) on I(GABA). Preapplication of 5-HT at concentrations of 1 x 10(-6), 1 x 10(-5), 1 x 10(-4) and 1 x 10(-3) mol x L(-1) potentiated I(GABA) by (35 +/- 8)% (n=8), (47 +/- 11)% (n=10), (65 +/- 17)% (n=9) and (75 +/- 18)% (n=11), respectively. This effect was mimicked by alpha-methyl-5-HT (1 x 10(-6) mol x L(-1)), a specific 5-HT2 receptor agonist, and reversed by cyproheptadine, a selective 5-HT2 receptor antagonist. The potentiation of I(GABA) by 5-HT was irrespective to whether the I(5-HT) presents or not in a subset of neurons. The concentration-response curves for GABA before and after pretreatment with 5-HT manifested the same threshold value and similar EC50 (2.0 x 10(-5) and 1.9 x 10(-5) mol x L(-1), respectively) , while the maximal value of I(GABA) for the latter was 33.6% higher than that for the former. Intracellular dialysis with GDP-beta-S or H-7 abolished the potentiation of I(GABA) by 5-HT, while H-9 did not.

CONCLUSION5-HT can potentiate GABA-activated current via PKC-dependent phosphorylation of GABA(A) receptor following the activation of 5-HT2 receptor.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine ; pharmacology ; Animals ; Cyproheptadine ; pharmacology ; Female ; Ganglia, Spinal ; cytology ; physiology ; Male ; Membrane Potentials ; drug effects ; Neurons ; physiology ; Patch-Clamp Techniques ; Protein Kinase C ; antagonists & inhibitors ; Rats ; Rats, Sprague-Dawley ; Receptors, Serotonin, 5-HT2 ; Serotonin ; analogs & derivatives ; pharmacology ; Serotonin 5-HT2 Receptor Agonists ; Serotonin 5-HT2 Receptor Antagonists ; Signal Transduction ; gamma-Aminobutyric Acid ; pharmacology

AIMTo study the correlation between 5-HT-induced pain response and the contribution by individual 5-HTR subtypes including 5-HT1R, 5-HT2R and 5-HT3R at the level of peripheral primary afferent.

METHODSThe experiments were done on acutely isolated trigeminal ganglion (TG) neurons using whole-cell patch clamp technique and the nociceptive effect was observed on behavior experiments by intraplantar injection of test drugs.

RESULTSThe majority of cells examined responded to 5-HT in a manner of concentration dependence (10(-6) - 10(-3) mol/) (61.4%, 54/88) and with a fast activating and rapid desensitizing inward current (I(5-HT)), which was thought to be mediated by the activation of 5-HT3R, since it could be blocked by 5-HT3R antagonist ICS 205930 and mimicked by 5-HT3R agonist 2-methyl-5-HT. It was found that I(5-HT) was potentiated by 5-HT2R agonist alpha-methyl-5-HT markedly, while 5-HT1R agonist R-(+)-UH 301 did not. In behavioral experiment performed on conscious rats, intraplantar injection of 5-HT(10(-5), 10(-4) and 10(-3) mol/L) induced an increment of cumulative lifting time first 20 min in a manner of concentration dependence. By dissociating 5-HTR subtypes using their corresponding antagonists (ICS and CYP) the potency order of hindpaw lifting time was identified as follows: 5-HT > 5-HT + ICS > 5-HT + CYP.

CONCLUSIONThe results suggest that in 5-HT-induced nociceptive response at the primary sensory level 5-HT3R may play a role of initiation, but 5-HT2R mediates maintaining and modulatory effect in the processes of nociceptive information convey.

Animals ; Male ; Membrane Potentials ; Pain ; physiopathology ; Patch-Clamp Techniques ; Rats ; Rats, Sprague-Dawley ; Receptors, Serotonin, 5-HT1 ; metabolism ; Receptors, Serotonin, 5-HT2 ; metabolism ; Receptors, Serotonin, 5-HT3 ; metabolism ; Sensory Receptor Cells ; metabolism ; physiology

The superior colliculus is a laminated structure that consisted with superficial and deep layers in the roof of midbrain and the center of visual information and sensorimotor intergration. The deep layers of the mammalian superior colliculus are concerned with generation of eye movements. Serotonin is a neurotransmitter of the central nervous system and its binding sites can be classified into serotonin-1 receptor, serotonin-2 receptor and serotonin-3 receptor according to their pharmacological characteristics. The serotonin-2 receptors in the human brain presents in the motor cortex(area 4 of Brodmann) which role for the control of ocular motor activity and in the primary and secondary visual areas(areas 17 and 18 of Brodmann). Some of them presents in the limbic system role for the control of emotive activity, memory and other limbic functions. We performed this experiment to identify the anatomical distribution of the serotonergic nerve terminals in the superior colliculus of the rat by microscopicautography. It has been demonstrated that the serotonin-2 receptors of the superior colliculus are concerned with generation of saccade eye movements.
Adult* ; Animals ; Binding Sites ; Brain ; Central Nervous System ; Eye Movements ; Humans ; Limbic System ; Memory ; Mesencephalon ; Motor Activity ; Neurotransmitter Agents ; Rats* ; Receptors, Serotonin, 5-HT2 ; Saccades ; Serotonin ; Superior Colliculi

PURPOSE: The purpose of this study is to investigate in vitro the effects of serotonin on the rat detrusor. In particular, this study examines what drugs inhibit the serotonin-induced detrusor contractions. MATERIALS AND METHODS: Isometric tension changes of isolated rat bladder muscle strips were recorded in an organ bath using a force transducer. Acute effects of serotonin (0.0001-0.01mM) were assessed on resting tension. Electrical field stimulation (EFS), bethanechol (0.0001-0.01mM), ATP (1-3mM) or KCl(63.5-254mM)-induced contractions using application in organ bath were compared with serotonin-induced contractions. In order to examine the action mechanism of serotonin-induced stimulation, EFS, bethanechol, ATP or KCl-induced contraction under serotonin (0.001mM) was assessed and serotonin (0.001 to 0.1mM) was cumulatively added to the organ bath following pre-incubation with propranolol, ketanserine, tropisetron, propiverine, sodium nitroprusside or doxazocin. RESULTS: There are two phases to the serotonin-induced responsean initial transient contraction and a prolonged tonic phase. Serotonin produced a reversible and dose-dependent contraction of the detrusor strips. Responses to bethanechol significantly increased with a concentration of 0.001mM serotonin (p<0.05). There was no effect on the responses to ATP, KCl, or EFS under 0.001mM serotonin. The 5-HT2 receptor is mainly responsible for serotonin-induced contractions of the detrusor (p<0.05), while the 5-HT1 receptor is partially responsible. Doxazocin and propiverine each significantly suppressed the responses to serotonin, while sodium nitroprusside and tropisetron each had no effect (p<0.05). CONCLUSIONS: Because the 5-HT2 antagonist blocked the effect of serotonin-induced bladder contractions and the stimulation of the adrenoreceptors, the 5-HT2 antagonist seems to improve lower urinary tract symptoms.
Adenosine Triphosphate ; Animals ; Baths ; Bethanechol ; Ketanserin ; Lower Urinary Tract Symptoms ; Nitroprusside ; Propranolol ; Rats ; Receptors, Serotonin, 5-HT1 ; Serotonin ; Serotonin 5-HT2 Receptor Antagonists ; Transducers ; Urinary Bladder ; Urinary Bladder, Overactive*