Pharmacokinetics and pharmacodynamics of MT-1207, a novel multitarget blocker of α1 receptor, 5-HT2A receptor, and calcium channel, in healthy subjects.

BACKGROUND: MT-1207 is a novel multitarget blocker of α1 receptor, 5-HT2A receptor, and calcium channel that is currently under development for the treatment of hypertension. In this study, we evaluated the tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of MT-1207 in healthy Chinese subjects. RESEARCH DESIGN AND METHODS: We examined the effects of a single-ascending dose (SAD) of MT-1207 (5-40 mg) and MT-1207 (40 mg) administered in combination with food in 56 healthy subjects. RESULTS: No serious adverse events or discontinuations due to adverse events (related to MT-1207) occurred in either study. MT-1207 was rapidly absorbed (median Tmax: 0.5-1.25 h). The mean t1/2 of MT-1207 was approximately 4-7 hours. Systemic exposure (Cmax and AUC) to MT-1207 increased in proportion to dose. Food had little effect on the pharmacokinetics of MT-1207, such as t1/2 and AUC. For 4h-24 h after administration, the blood pressure reduction in the MT-1207 group was higher than that in the placebo group, showing the antihypertensive effect. Blood pressure reduction after MT-1207 administration showed some dose-dependent trend in the 5-20 mg groups. CONCLUSIONS: MT-1207 was well tolerated in all subjects. PD measurements demonstrated the antihypertensive effects of MT-1207.

Suppression of cocaine relapse-like behaviors upon pimavanserin and lorcaserin co-administration.

Cocaine use disorder (CUD) is a major public health challenge for which there are no pharmacotherapeutics approved by the United States Food and Drug Administration (FDA). The propensity to relapse in CUD involves several vulnerability factors including sensitivity to cues associated with cocaine-taking. Serotonin (5-hydroxytryptamine, 5-HT) neurotransmission, particularly through the 5-HT2A receptor (5-HT2AR) and 5-HT2C receptor (5-HT2CR), is mechanistically linked to cocaine-seeking in preclinical models. In the present experiments, we employed self-administration assays in male rats to investigate whether acute and/or repeated administration of the FDA-approved selective 5-HT2AR antagonist/inverse agonist pimavanserin, selective 5-HT2CR agonist lorcaserin or their combination would alter cocaine intake and/or cocaine-seeking behavior. We found that acute administration of lorcaserin, but not pimavanserin, attenuated cocaine intake while pimavanserin plus lorcaserin did not impact cocaine self-administration. In contrast, 10-days of repeated administration of pimavanserin, lorcaserin, or pimavanserin plus lorcaserin during forced abstinence from cocaine self-administration, blunted cocaine-seeking, similar to the acute administration of each ligand. Taken together, these data reveal the efficacy of repeated treatment with pimavanserin plus lorcaserin to attenuate factors important to relapse-like behaviors in rodent models of CUD. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.

The highly selective 5-HT2A antagonist EMD-281,014 reduces dyskinesia and psychosis in the l-DOPA-treated parkinsonian marmoset.

Blockade of serotonin 2A (5-HT2A) receptors is regarded as an anti-dyskinetic and anti-psychotic strategy in Parkinson's disease (PD). However, the 5-HT2A antagonists tested so far exhibited affinity for other receptors, which might have played a role in their action. EMD-281,014 is the most selective 5-HT2A antagonist available, with approximately 2,000-fold selectivity over serotonin 2C (5-HT2C) receptors. EMD-281,014 was previously tested in the clinic and has high translational potential. In the present study, we assessed the effect of EMD-281,014 on dyskinesia and psychosis in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmoset. We first determined the pharmacokinetic profile of EMD-281,014 in the marmoset, after which doses leading to clinically-relevant plasma levels (0.01, 0.03 and 0.1 mg/kg) or vehicle were administered to MPTP-lesioned marmosets, in combination with L-3,4-dihydroxyphenylalanine (l-DOPA). The effects of EMD-281,014 on dyskinesia, psychosis-like behaviours (PLBs) and parkinsonism were then evaluated. When added to l-DOPA, EMD-281,014 (0.03 and 0.1 mg/kg) reduced peak dose dyskinesia, by 41.8% and 54.5% (P < 0.05 and P < 0.001), when compared to l-DOPA/vehicle. EMD-281,014 (0.03 and 0.1 mg/kg) also significantly reduced the severity of peak dose PLBs, by 42.5% and 45.9% (P < 0.05 and P < 0.001), when compared to vehicle. The anti-dyskinetic and anti-psychotic effects of EMD-281,014 were achieved without interfering with l-DOPA anti-parkinsonian action. Our results suggest that highly-selective 5-HT2A receptor blockade with EMD-281,014 is an effective way to alleviate both dyskinesia and psychosis in PD, without adversely affecting parkinsonian disability.

Pharmacological Characterization of H05, a Novel Serotonin and Noradrenaline Reuptake Inhibitor with Moderate 5-HT2A Antagonist Activity for the Treatment of Depression.

Multitarget antidepressants selectively inhibiting monoaminergic transporters and 5-hydroxytryptamine (5-HT) 2A receptor have demonstrated higher efficacy and fewer side effects than selective serotonin reuptake inhibitors. In the present study, we synthesized a series of novel 3-(benzo[d][1,3]dioxol-4-yloxy)-3-arylpropyl amine derivatives, among which compound H05 was identified as a lead, exhibiting potent inhibitory effects on both serotonin (Ki = 4.81 nM) and norepinephrine (NE) (Ki = 6.72 nM) transporters and moderate 5-HT2A antagonist activity (IC50 = 60.37 nM). H05 was able to dose-dependently reduce the immobility duration in mouse forced swimming test and tail suspension test, with the minimal effective doses lower than those of duloxetine, and showed no stimulatory effect on locomotor activity. The administration of H05 (5, 10, and 20 mg/kg, by mouth) significantly shortened the immobility time of adrenocorticotropin-treated rats that serve as a model of treatment-resistant depression, whereas imipramine (30 mg/kg, by mouth) and duloxetine (30 mg/kg, by mouth) showed no obvious effects. Chronic treatment with H05 reversed the depressive-like behaviors in a rat model of chronic unpredictable mild stress and a mouse model of corticosterone-induced depression. Microdialysis analysis revealed that the administration of H05 at either 10 or 20 mg/kg increased the release of 5-HT and NE from the frontal cortex. The pharmacokinetic (PK) and brain penetration analyses suggest that H05 has favorable PK properties with good blood-brain penetration ability. Therefore, it can be concluded that H05, a novel serotonin and NE reuptake inhibitor with 5-HT2A antagonist activity, possesses efficacious activity in the preclinical models of depression and treatment-resistant depression, and it may warrant further evaluation for clinical development.

The pharmacodynamic effects of combined administration of flibanserin and alcohol.

WHAT IS KNOWN AND OBJECTIVE: Flibanserin is a serotonin 5-HT1A agonist and 5-HT2A antagonist approved for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Because of the increased risk of hypotension- and syncope-related adverse events (AEs) observed with coadministration of flibanserin and alcohol, alcohol use is contraindicated. To provide a more comprehensive understanding of the interaction between flibanserin and alcohol, the results of a dedicated phase 1 alcohol-interaction study and a pooled analysis of phase 3 studies of premenopausal women with HSDD are presented. METHODS: In the phase 1 study, healthy participants (males [n=23] and females [n=2]) were randomly assigned to one of five sequence groups, which determined the order in which they were to receive flibanserin 100 mg or placebo, with or without ethanol 0.4 g/kg or 0.8 g/kg. Change from baseline in seated blood pressure, orthostatic vital signs, AEs and visual analogue scale sedation outcomes were examined. Blood samples were collected at baseline and for up to 4 hours after dosing to determine flibanserin area under the plasma concentration-time curve from 0 to 4 hours (AUC0-4 ). Pooled data from five phase 3 studies of patients receiving flibanserin 100 mg once daily (n=1543), or placebo (n=1905), were analysed. RESULTS: In the phase 1 study, the incidence of hypotension and syncope increased when flibanserin was coadministered with ethanol. Sedation increased 20% and 27% from baseline with flibanserin plus ethanol 0.4 g/kg and 0.8 g/kg, respectively, at 4 hours post-dose. In the pooled analysis of phase 3 studies, 58.2% and 63.6% of participants receiving flibanserin or placebo, respectively, reported baseline alcohol use. In patients receiving flibanserin, fatigue and dizziness occurred more frequently in patients with vs. without alcohol use. WHAT IS NEW AND CONCLUSION: Results from this study suggest that increased incidence of hypotension- and syncope-related events may result from a pharmacodynamic interaction between flibanserin and alcohol, although the clinical significance of these interactions in real-world populations remains unclear.

Pharmacokinetic drug evaluation of extended release lorcaserin for the treatment of obesity.

INTRODUCTION: Lorcaserin is a serotonin 2C receptor antagonist that was FDA approved in 2012. Lorcaserin is recently available as an extended-release (ER) formulation for the treatment of obesity as an adjunct to lifestyle modification. Areas covered: The pharmacokinetics, pharmacodynamics, efficacy, and safety of lorcaserin ER will be reviewed. Expert opinion: Lorcaserin ER 20mg daily provides drug exposure bioequivalent to lorcaserin immediate release (IR) 10mg twice daily. Lorcaserin IR is associated with 3.3 and 3.0% placebo-subtracted weight loss in patients without and with diabetes, respectively. A1C was reduced by 0.9% in patients with diabetes. Common side effects include headache, dry mouth, constipation, dizziness, fatigue, and nausea. Lorcaserin provides potential advantages over other antiobesity medications in regards to tolerability and simplicity of medication initiation, but may not be as effective as other options. Lorcaserin ER offers improved ease of administration and anticipated adherence compared to the IR formulation. The place in therapy for lorcaserin ER and other antiobesity medications will be further clarified by results of pending clinical trials addressing cardiovascular outcomes as well as the role pharmacogenomics and comorbid disease states may play in choosing patient-specific therapy.

Pharmacokinetics and Pharmacodynamics of Lurasidone Hydrochloride, a Second-Generation Antipsychotic: A Systematic Review of the Published Literature.

Lurasidone hydrochloride, a benzisothiazol derivative, is a second-generation (atypical) antipsychotic agent that has received regulatory approval for the treatment of schizophrenia in the US, Canada, the EU, Switzerland, and Australia, and also for bipolar depression in the US and Canada. In addition to its principal antagonist activity at dopamine D2 and serotonin 5-HT2A receptors, lurasidone has distinctive 5-HT7 antagonistic activity, and displays partial agonism at 5-HT1A receptors, as well as modest antagonism at noradrenergic α2A and α2C receptors. Lurasidone is devoid of antihistaminic and anticholinergic activities. It is administered once daily within the range of 40-160 mg/day for schizophrenia and 20-120 mg/day for bipolar depression, and its pharmacokinetic profile requires administration with food. In adult healthy subjects and patients, a 40 mg dose results in peak plasma concentrations in 1-3 h, a mean elimination half-life of 18 h (mostly eliminated in the feces), and apparent volume of distribution of 6173 L; it is approximately 99 % bound to serum plasma proteins. Lurasidone's pharmacokinetics are approximately dose proportional in healthy adults and clinical populations within the approved dosing range, and this was also found in a clinical study of children and adolescents. Lurasidone is principally metabolized by cytochrome P450 (CYP) 3A4 with minor metabolites and should not be coadministered with strong CYP3A4 inducers or inhibitors. Lurasidone does not significantly inhibit or induce CYP450 hepatic enzymes.

Preparation and in vivo evaluation of a gel-based nasal delivery system for risperidone.

The aim of this study was to prepare a nasal gel of risperidone and to investigate the pharmacokinetics and relative bioavailability of the drug in rats. Compared with oral dosing, the risperidone nasal gel exhibited very fast absorption and high bioavailability. Maximal plasma concentration (cmax) and the time to reach cmax (tmax) were 15.2 µg mL-1 and 5 min for the nasal gel, 3.6 µg mL-1 and 30 min for the oral drug suspension, respectively. Pharmacokinetic parameters such as tmax', cmax and AUC of oral and nasal routes were significantly different (p < 0.01). Relative bioavailability of the drug nasal preparation to the oral suspension was up to 1600.0 %. Further, the in vitro effect of the risperidone nasal gel on nasal mucociliary movement was also investigated using a toad palate model. The risperidone nasal formulation showed mild ciliotoxicity, but the adverse effect was temporary and reversible.

Serotonin 2A receptor agonist binding in the human brain with [(11)C]Cimbi-36: Test-retest reproducibility and head-to-head comparison with the antagonist [(18)F]altanserin.

INTRODUCTION: [(11)C]Cimbi-36 is a recently developed serotonin 2A (5-HT2A) receptor agonist positron emission tomography (PET) radioligand that has been successfully applied for human neuroimaging. Here, we investigate the test-retest variability of cerebral [(11)C]Cimbi-36 PET and compare [(11)C]Cimbi-36 and the 5-HT2A receptor antagonist [(18)F]altanserin. METHODS: Sixteen healthy volunteers (mean age 23.9 ± 6.4years, 6 males) were scanned twice with a high resolution research tomography PET scanner. All subjects were scanned after a bolus of [(11)C]Cimbi-36; eight were scanned twice to determine test-retest variability in [(11)C]Cimbi-36 binding measures, and another eight were scanned after a bolus plus constant infusion with [(18)F]altanserin. Regional differences in the brain distribution of [(11)C]Cimbi-36 and [(18)F]altanserin were assessed with a correlation of regional binding measures and with voxel-based analysis. RESULTS: Test-retest variability of [(11)C]Cimbi-36 non-displaceable binding potential (BPND) was consistently <5% in high-binding regions and lower for reference tissue models as compared to a 2-tissue compartment model. We found a highly significant correlation between regional BPNDs measured with [(11)C]Cimbi-36 and [(18)F]altanserin (mean Pearson's r: 0.95 ± 0.04) suggesting similar cortical binding of the radioligands. Relatively higher binding with [(11)C]Cimbi-36 as compared to [(18)F]altanserin was found in the choroid plexus and hippocampus in the human brain. CONCLUSIONS: Excellent test-retest reproducibility highlights the potential of [(11)C]Cimbi-36 for PET imaging of 5-HT2A receptor agonist binding in vivo. Our data suggest that Cimbi-36 and altanserin both bind to 5-HT2A receptors, but in regions with high 5-HT2C receptor density, choroid plexus and hippocampus, the [(11)C]Cimbi-36 binding likely represents binding to both 5-HT2A and 5-HT2C receptors.

Synthesis and imaging validation of [¹8F]MDL100907 enabled by Ni-mediated fluorination.

Several voids exist in reliable positron emission tomography (PET) radioligands for quantification of the serotonin (5HT) receptor system. Even in cases where 5HT radiotracers exist, challenges remain that have limited the utility of 5HT imaging in clinical research. Herein we address an unmet need in 5HT2a imaging using innovative chemistry. We report a scalable and robust synthesis of [(18)F]MDL100907, which was enabled by a Ni-mediated oxidative fluorination using [(18)F]fluoride. This first demonstration of a Ni-mediated fluorination used for PET imaging required development of a new reaction strategy that ultimately provided high specific activity [(18)F]MDL100907. Using the new synthetic strategy and optimized procedure, [(18)F]MDL100907 was evaluated against [(11)C]MDL100907 for reliability to quantify 5HT2a in the nonhuman primate brain and was found to be superior based on a single scan analysis using the same nonhuman primate. The use of this new 5HT2a radiotracer will afford clinical neuroscience research the ability to distinguish 5HT2a receptor abnormalities binding between healthy subjects and patients even when group differences are small.

Design of novel multiple-acting ligands towards SERT and 5-HT2C receptors.

This Letter describes our attempts to elaborate dually acting compounds possessing serotonin re-uptake transporter inhibitor and serotonin 5-HT2C receptor antagonist properties. A novel series of 1,3-diphenylureas and N-phenylbenzamides have thus been prepared and evaluated. Based on its in vitro and in vivo activities, as well as pharmacokinetic profile, compound 16a was identified as a lead compound. The synthesis and structure-activity relationship of this series of compounds is presented herein.

Comparison of the anti-dopamine D2 and anti-serotonin 5-HT(2A) activities of chlorpromazine, bromperidol, haloperidol and second-generation antipsychotics parent compounds and metabolites thereof.

Second-generation antipsychotics, which have become the standard drug therapies for schizophrenia, are known to have a serotonin 5-HT(2A) receptor blocking effect in addition to a dopamine D2 receptor blocking effect. However, although chlorpromazine (CPZ) has a 5-HT(2A) receptor blocking effect and has the profile of a second-generation antipsychotic in vitro, it loses this pharmacological profile in vivo. In order to elucidate the differences between the in vivo and in vitro pharmacological characteristics of CPZ, we used a radioreceptor assay to measure the anti-D2 activity and the anti-5-HT(2A) activity of CPZ and five major metabolites of CPZ, and compared the results to the anti-D2 activity and anti-5-HT(2A) activity of risperidone, zotepine, perospirone, the major metabolites of each of these drugs, and olanzapine, bromperidol, and haloperidol. The subjects were 182 patients who had received diagnoses of schizophrenia based on the DSM-IV criteria. The results revealed that CPZ exhibited little anti-5-HT(2A) activity, regardless of the anti-D2 activity level, and that none of the metabolites possessed anti-5-HT(2A) activity. However, both the parent compounds and the metabolites of each of the second-generation antipsychotics possessed both anti-D2 activity and anti-5-HT(2A) activity. This clarified that, unlike second-generation antipsychotics, the reason CPZ loses its second-generation antipsychotic profiles in vivo is because it does not have any metabolites that possess anti-5-HT(2A) activity.

5-HT 2A receptor activation of the external urethral sphincter and 5-HT 2C receptor inhibition of micturition: a study based on pharmacokinetics in the anaesthetized female rat.

Central and peripheral 5-hydroxytryptamine (5-HT) receptors play a critical role in the regulation of micturition. Bolus doses of 5-HT(2A/2C) receptor agonists have been shown to activate the external urethral sphincter (EUS) and to inhibit micturition. This study was designed to determine the contribution of these two 5-HT receptor subtypes to activation of the EUS and inhibition of micturition utilising pharmacokinetic knowledge to better control drug exposure. Recordings of urethral and bladder pressure, EUS-Electromyogram (EMG), the micturition reflex induced by bladder filling, blood pressure and heart rate were made in anaesthetized female rats. The effects of intravenous (i.v.) infusions of the 5-HT(2) receptor agonist (2S)-1-(6-chloro-5-fluoroindol-1-yl)propan-2-amine fumarate (Ro 60-0175) in the absence or presence of the selective 5-HT(2C) receptor antagonist 6-chloro-5-methyl-N-[6-(2-methylpyridin-3-yl)oxypyridin-3-yl]-2,3-dihydroindole-1-carboxamide dihydrochloride (SB 242084) or 5-HT(2A) receptor antagonist (R)-(2,3-dimethoxyphenyl)-[1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]methanol (MDL-100,907) were studied on these variables. Continuous infusion of increasing concentrations of Ro 60-0175 only evoked EUS-EMG activity at the highest concentration, which was blocked by co-infusion of MDL-100,907 but not SB 242084. Urethral pressure was unaffected by any drug infusion. Ro 60-0175 at the lowest concentration inhibited the micturition reflex but as the concentration increased this was reversed to facilitation. SB 242084 blocked the inhibition while MDL-100,907 blocked the excitation. Activation of 5-HT(2A) not 5-HT(2C) receptors evoked EUS-EMG activity. In conclusion, 5-HT(2A) receptor activation facilitated the micturition reflex and evoked EUS-EMG while 5-HT(2C) receptor activation only inhibited the micturition reflex.

Identification of fused bicyclic heterocycles as potent and selective 5-HT(2A) receptor antagonists for the treatment of insomnia.

A series of fused bicyclic heterocycles was identified as potent and selective 5-HT(2A) receptor antagonists. Optimization of the series resulted in compounds that had improved PK properties, favorable CNS partitioning, good pharmacokinetic properties, and significant improvements on deep sleep (delta power) and sleep consolidation.

Sustained recreational use of ecstasy is associated with altered pre and postsynaptic markers of serotonin transmission in neocortical areas: a PET study with [¹¹C]DASB and [¹¹C]MDL 100907.

3,4-Methylenedioxymethamphetamine (MDMA), the main psychoactive component of the recreational drug ecstasy, is a potent serotonin (5-HT) releaser. In animals, MDMA induces 5-HT depletion and toxicity in 5-HT neurons. The aim of this study was to investigate both presynaptic (5-HT transporter, SERT) and postsynaptic (5-HT(2A) receptor) markers of 5-HT transmission in recently abstinent chronic MDMA users compared with matched healthy controls. We hypothesized that MDMA use is associated with lower SERT density and concomitant upregulation of 5-HT(2A) receptors. Positron emission tomography studies using the SERT ligand [¹¹C]DASB and the 5-HT(2A) receptor ligand [¹¹C]MDL 100907 were evaluated in 13 current and recently detoxified MDMA users and 13 matched healthy controls. MDMA users reported a mean duration of ecstasy use of 8 years, regular exposure, and at least 2 weeks of abstinence before the scans. SERT and 5-HT(2A) receptor availability (binding potential, BP(ND)) were analyzed with a two-tissue compartment model with arterial input function. Current recreational MDMA use was significantly associated with lower SERT BP(ND) and higher 5-HT(2A) receptor BP(ND) in cortical, but not subcortical regions. Decreased SERT BP(ND) was regionally associated with upregulated 5-HT(2A) receptor BP(ND). In light of the animal literature, the most parsimonious interpretation is that repeated exposure to MDMA in humans, even in moderate amounts, leads to damage in 5-HT neuron terminals innervating the cortex. Alterations in mood, cognition, and impulse control associated with these changes might contribute to sustain MDMA use. The reversibility of these changes upon abstinence remains to be firmly established.

The relationship between clinical pharmacokinetics of aripiprazole and CYP2D6 genetic polymorphism: effects of CYP enzyme inhibition by coadministration of paroxetine or fluvoxamine.

PURPOSE: To investigate the effects of coadministration of paroxetine or fluvoxamine on the pharmacokinetics of aripiprazole in healthy adult Japanese with different CYP2D6 genotypes. METHODS: Fourteen CYP2D6 extensive metabolizer (EM) and 14 CYP2D6 intermediate metabolizer (IM) subjects were coadministered a single oral dose of aripiprazole 3 mg after steady-state plasma concentrations of the SSRIs paroxetine (20 mg/day) or fluvoxamine (100 mg/day) were reached by repeated oral doses for 6-7 days. The pharmacokinetics of aripiprazole with and without coadministration of SSRIs were compared according to CYP2D6 genotypes. RESULTS: Coadministration of paroxetine, a potent CYP2D6 inhibitor, decreased systemic clearance (CL/F) of aripiprazole by 58 and 23% in CYP2D6 EMs and IMs, respectively, demonstrating that the percentage inhibition of CYP2D6 activity by coadministration of paroxetine was apparently greater in CYP2D6 EMs than in IMs. Coadministration of fluvoxamine, a less potent CYP3A4 inhibitor, decreased the CL/F of aripiprazole by 39% in CYP2D6 EMs and 40% in IMs, indicating the same inhibitory effect on CYP enzymes, regardless of the CYP2D6 genotype. Percent contribution of CYP2D6 to total CL/F (CYP2D6 plus CYP3A4) of aripiprazole estimated as a reduced percentage of CL/F by CYP enzyme inhibition was 62% for CYP2D6 EMs and 24% for IMs in paroxetine coadministration, and 40% for CYP2D6 EMs and 18% for IMs in fluvoxamine coadministration. CONCLUSIONS: There were marked differences in the degree of influence of paroxetine coadministration on the pharmacokinetics of aripiprazole between CYP2D6 EMs and IMs, but no apparent differences were found between two CYP2D6 genotypes in fluvoxamine coadministration. Aripiprazole can be used safely in combination with SSRIs that have a CYP enzyme-inhibitory action.

C-122, a novel antagonist of serotonin receptor 5-HT2B, prevents monocrotaline-induced pulmonary arterial hypertension in rats.

Pulmonary arterial hypertension (PAH) is a chronic disease characterized by sustained elevation of pulmonary arterial pressure that leads to right ventricle failure and death. Pulmonary resistance arterioles in PAH undergo progressive narrowing and/or occlusion. Currently approved therapies for PAH are directed primarily at relief of symptoms by interfering with vasoconstrictive signals, but do not halt the microvascular cytoproliferative process. In this study we show that C-122 (2-amino-N-(2-{4-[3-(2-trifluoromethyl-phenothiazin-10-yl)-propyl]-piperazin-1-yl}-ethyl)-acetamide trihydrochloride, a novel antagonist of serotonin receptor 5-HT(2B) (Ki=5.2 nM, IC(50)=6.9 nM), when administered to rats for three weeks in daily oral 10mg/kg doses, prevents not only monocrotaline (MCT)-induced elevations in pressure in the pulmonary arterial circuit (19 ± 0.9 mmHg vs. 28 ± 2 mmHg in MCT-vehicle group, P<0.05) and hypertrophy of the right ventricle (right ventricular wt./body wt. ratio 0.52 ± 0.02 vs. 0.64 ± 0.04 in MCT-vehicle group, P<0.05), but also muscularization of pulmonary arterioles (23% vs. 56% fully muscularized in MCT-vehicle group, P<0.05), and perivascular fibrosis in the lung. C-122 is orally absorbed in the rat, and partitions strongly into multiple tissues, including heart and lung. C-122 has significant off-target antagonist activity for histamine H-1 and several dopamine receptors, but shows no evidence of crossing the blood-brain barrier after a single 10mg/kg oral dose in rats. We conclude that C-122 can prevent microvascular remodeling and associated elevated pressures in the rat MCT model for PAH, and offers promise as a new therapeutic entity to suppress vascular smooth muscle cell proliferation in PAH patients.

Design and synthesis of novel arylpiperazine derivatives containing the imidazole core targeting 5-HT(2A) receptor and 5-HT transporter.

Serotonin antagonist reuptake inhibitor (SARI) drugs that block both 5-HT(2) receptors and the serotonin transporters have been developed. The human 5-HT(2A/2C) receptor has been implicated in several neurological conditions, and potent selective 5-HT(2A/2C) ligands may have therapeutic potential for treatment of CNS diseases such as depression. An imidazole moiety usually provides good pharmacokinetic properties as a drug substance, and thus considerable efforts have been devoted to develop imidazole derivatives into drug candidates. The imidazole series of compounds was evaluated against 5-HT(2A/2C) and serotonin reuptake inhibition. A few of the compounds in the series showed promising IC(50) values and antidepressant-like effect in in vivo forced swimming test (FST). On the basis of these results, further lead optimization studies resulted in identifying promising compounds potentially for therapeutic use.

Liquid chromatography tandem mass spectrometry method for the quantification of sarpogrelate, a selective 5-HT(2A) receptor antagonist, in plasma: application to a pre-clinical pharmacokinetic study.

A simple LC-MS/MS method was developed and validated for the estimation of sarpogrelate in 50 µL of rat plasma. The analyte and internal standard (IS) were extracted from rat plasma by acetonitrile precipitation and they were separated on a reversed-phase C8 column with gradient program. The MS acquisition was performed with multiple reaction monitoring mode using m/z 430.2 to m/z 135.0 for analyte and m/z 448.2 to m/z 285.3 for IS. The calibration curves were linear over the range of 1-1000 ng/mL with the correlation coefficient greater than 0.999. With dilution integrity up to 20-fold, the upper limit of quantification was extendable up to 15,000 ng/mL. The method was successfully applied to the analysis of rat plasma samples after single dose oral administration of sarpogrelate at 5 mg/kg to rats for the determination of its pharmacokinetics. Following oral administration the maximum mean concentration in plasma (C(max), 11514 ng/mL) was achieved at 0.25 h (T(max)) and the area under curve (AUC0-24) was 11051 ± 3315 ng h/mL. The half-life (t(¹/2)) and clearance (Cl) were 2.9 ± 1.1 h and 490 ± 171 mL/h/kg, respectively. We believe that development of a method in rodent plasma would facilitate the ease of adaptability of sarpogrelate in human plasma.