Receptor Affinity Profile Research Articles

Effect of intermittent subchronic MK-801 administration on dopamine synthesis capacity and responsiveness in the prefrontal cortex.

The therapeutic potential of N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists, particularly ketamine, in mood disorders, is linked to their modulation of dopamine dynamics in the medial prefrontal cortex (mPFC). However, conflicting effects of distinct NMDAR antagonists, like ketamine and phencyclidine, on mPFC dopamine levels stem from variances in their receptor affinity profiles. This study investigates the impact of intermittent subchronic administration of an NMDAR antagonist on dopamine synthesis capacity and responsiveness within the mPFC, focusing on Dizocilpine (MK-801), a highly selective NMDAR antagonist. In vivo microdialysis and high-performance liquid chromatography assessed extracellular dopamine levels in the mPFC following subchronic MK-801 treatment. Locomotor activity was measured using a computed video tracking system. Intermittent subchronic MK-801 administration, followed by a 24-h withdrawal, preserved both dopamine synthesis capacity and responsiveness to MK-801 challenge in the mPFC. However, altered locomotor activity was observed, deviating from previous findings indicating impaired dopamine synthesis and responsiveness in the mPFC with twice-daily subchronic NMDAR antagonist treatment. These findings offer crucial biochemical insights into the diverse impacts of NMDAR antagonists on dopamine dynamics and the distinct therapeutic mechanisms associated with ketamine in depression treatment. However, further investigation is imperative to pinpoint potential inconsistencies stemming from variances in drug type, dosage, or administration frequency.

Effects of Replacing a Central Glycine Residue in GLP-1 on Receptor Affinity and Signaling Profile.

Agonists of the glucagon-like peptide-1 receptor (GLP-1R) are used to treat diabetes and obesity. Cryo-EM structures indicate that GLP-1 is completely α-helical when bound to the GLP-1R. The mature form of this hormone, GLP-1(7-36), contains a glycine residue near the center (Gly22). Since glycine has the second-lowest α-helix propensity among the proteinogenic α-amino acid residues, and Gly22 does not appear to make direct contact with the receptor, we were motivated to explore the impact on agonist activity of altering the α-helix propensity at this position. We examined GLP-1 analogues in which Gly22 was replaced with L-Ala, D-Ala, or β-amino acid residues with varying helix propensities. The results suggest that the receptor is reasonably tolerant of variations in helix propensity, and that the functional receptor-agonist complex may comprise a conformational spectrum rather than a single fixed structure.

A new class of 5-HT1A receptor antagonists with procognitive and antidepressant properties.

Aims: 5-HT1A receptor antagonists constitute a potential group of drugs in the treatment of CNS diseases. The aim of this study was to search for new procognitive and antidepressant drugs among amide derivatives of aminoalkanoic acids with 5-HT1A receptor antagonistic properties. Materials & methods: Thirty-three amides were designed and evaluated in silico for their drug-likeness. The synthesized compounds were tested in vitro for their 5-HT1A receptor affinity and functional profile. Moreover, their selectivity over 5-HT7, 5-HT2Aand D2 receptors and ability to inhibit phosphodiesterases were evaluated. Results:A selected 5-HT1A receptor antagonist 20 (Ki=35nM, Kb=4.9nM) showed procognitive and antidepressant activity in vivo. Conclusion: Novel 5-HT1A receptor antagonists were discovered and shown as potential psychotropic drugs.

Lurasidone for Adolescents With Complex Mental Disorders: A Case Series

Objectives: Lurasidone is a new second generation (atypical) antipsychotic agent with unique receptor affinity and side-effect profiles, but limited literature is available on its use in adolescent populations. Contrasting with research treatment trials which typically recruit patients by stringent selection criteria, this case series examined the effects and tolerability of using lurasidone in adolescents within real-life clinical settings in treating complex cases who had not responded to other therapy options. Methods: We conducted a retrospective case-note audit of 6 adolescents aged 14 to 17 years old attending community child and adolescent mental health services (CAMHS) who were prescribed lurasidone. Results: Lurasidone had been prescribed for a range of “hard-to-manage” conditions with complex comorbidities, in adolescents in relation to specific use of lurasidone on the basis of clinical and pharmacological indications after exhausting more conventional treatment options. Case-note review suggested response to lurasidone was clinically positive in 3 cases, equivocal/marginal in 2 cases, and ineffective in 1 case. There were no cases of poor tolerance or adverse effects. Notably, positive responses for depressive and irritable mood symptoms were specifically recorded by prescribing clinicians, indicative of benefits on symptom improvement. No lurasidone attributed weight gain, galactorrhoea, metabolic abnormalities, sexual dysfunction or intolerance were reported. Pro-cognitive effects were not detected; but our findings were constrained by the non-systematic and incomplete information ascertainment, typical in retrospective case-note review. Conclusion: This case series provides preliminary data supporting lurasidone’s potential use in adolescents of complex clinical needs (but without a clinical diagnosis of bipolar disorder) within real-life clinical settings. Lurasidone appears to show a weight-sparing effect, in addition to improving mood symptoms in some cases. Lurasidone deserves further study for its use in the adolescent population (outside the remit of FDA) given its potential more favorable risk-benefit profile in young people. The favorable tolerability appear to be borne out by the pharmacodynamic predictions in our complex patients who would be excluded in formal clinical trial studies.

Rehospitalization Risk of Receptor-Affinity Profile in Antipsychotic Drug Treatment: A Propensity Score Matching Analysis Using a Japanese Employment-Based Health Insurance Database.

PurposeThe aim of this study was to examine whether there is a difference in the risk of rehospitalization when antipsychotics are classified into two groups treated using drugs with a higher or lower affinity to H1 or α1 receptors than to D2 receptors (histamine H1 receptors, adrenaline α1 receptors [HA] high- and HA low-affinity drug group, respectively) based on affinity to receptors related to sedation using a nationwide insurance claims database in Japan.Patients and MethodsWe identified eligible patients by the following two criteria: (i) hospitalization due to schizophrenia (International Classification of Disease [ICD]-10 code: F20 or F25) in psychiatric wards between January 1st, 2005 and August 31st, 2017, and (ii) administration of HA high- or HA low-affinity drugs in the next month after discharge from the earliest hospitalization due to schizophrenia (index month). The primary endpoint was rehospitalization due to schizophrenia. The secondary endpoints were (i) involuntary rehospitalization, (ii) concomitant use of anxiolytics/hypnotics, mood stabilizers, and antiparkinsonian drugs, (iii) all-cause death, and (iv) medication discontinuation. Propensity score (PS) matching analysis was applied, and the hazard ratio (HR) of the event rate in the HA high-affinity drug group relative to the HA low-affinity drug group was calculated using Cox’s proportional hazards model.ResultsTwo thousand nine hundred and forty patients were identified as eligible patients. Among PS-matched patients (819 in each group), the HR in the HA high-affinity drug group compared with the HA low-affinity drug group was 1.018 (0.822–1.260, P = 0.870). Other outcomes did not differ significantly between the two groups.ConclusionNo significant difference was observed in the rehospitalization risk due to schizophrenia associated with HA high-affinity antipsychotic drugs. Although this study was a retrospective PS-matched cohort study, the possibility of masking of the rehospitalization risk cannot be excluded because more than 80% of the patients were administered an anxiolytic/hypnotic at the time of admission.

Effect of amisulpride, olanzapine, quetiapine, and aripiprazole single administration on c-Fos expression in vasopressinergic and oxytocinergic neurons of the rat hypothalamic supraoptic nucleus.

The goal of this study was to reveal the impact of four types of atypical antipsychotics including amisulpride (AMI), olanzapine (OLA), quetiapine (QUE), and aripiprazole (ARI), with different receptor-affinity profile and dissociation constant, on the activity of hypothalamic supraoptic nucleus (SON) vasopressinergic and oxytocinergic neurons. Male Sprague Dawley rats received a single injection of vehicle (VEH) (0.1 ml/100g), AMI (20 mg/kg), OLA (5 mg/kg), QUE (15 mg/kg/) or ARI (10 mg/kg). Ninety min after treatment, the animals were fixed by transcardial perfusion, the brains removed, and cryocut into serial coronal sections of 35 µm thickness. The sections were processed for c-Fos staining using an avidin-biotin-peroxidase complex and visualized by nickel intensified diaminobenzidine to reach black end product. Afterwards, the sections were exposed to vasopressin (AVP) and oxytocin (OXY) antibodies and the reaction product visualized by biotin-labeled fluorescent Alexa Fluor 568 dye. The data were evaluated from c-Fos and AVP or OXY merged sections. The present study shows that all four antipsychotics applied induced c-Fos expression in the SON. With respect to the stimulation efficacy of the individual antipsychotics, estimated based on the quantity of c-Fos-labeled AVP and OXY neurons, could be a preferential action assigned to QUE over moderate effect of ARI and lower effect to OLA and reduced effect of AMI (VEH < AMI < OLA < ARI < QUE). The present data for the first time provide an insight into the quantitative pattern of brain activity within the clusters of SON AVP and OXY cells in response to different atypical antipsychotics single treatment.

An evaluation of lumateperone tosylate for the treatment of schizophrenia

ABSTRACTIntroduction: Schizophrenia, a devastating disorder with onset in adolescence or young adulthood, afflicts 1% of the population leading to severe social, educational, and occupational impairments. Lumateperone is a first-in-class investigational drug under development for the treatment of multiple neuropsychiatric and neurodegenerative disorders including schizophrenia. Its unique receptor affinity profile together with synergistic modulation of serotonergic, glutamatergic, and dopaminergic pathways imparts efficacy over a broad-spectrum of symptoms associated with schizophrenia.Areas covered: This narrative drug evaluation includes a review of lumateperone tosylate (lumateperone, ITI-007, ITI-722, Intra-Cellular Therapies, Inc.) for patients with schizophrenia. This review describes the receptor affinity profile, pharmacodynamics, pharmacokinetics, distribution, metabolism, and clinical trials that address how lumateperone could potentially emerge as an important therapeutic option for schizophrenia patients.Expert opinion: The unique pharmacological properties of lumateperone may provide the key to dramatically ameliorate the symptoms of schizophrenia as indicated by some clinical trials. Future clinical trials may be enhanced by the administration of more comprehensive long-term behavioral measures and utilization of molecular imaging to confirm the target engagement of the many possible sites of action. The results of ongoing and future studies will provide the evidence to determine if lumateperone will revolutionize the therapy of schizophrenia.

Management of asenapine treatment in clinical practice: Recommendations from a panel of experts

IntroductionThe choice of an antipsychotic should be based on bipolar disorder (BD) symptoms and the particular needs of each patient, as well as the adverse events potentially associated with treatment. Asenapine is an atypical antipsychotic indicated for the management of type-I BD, with distinct pharmacokinetic and receptor affinity profiles. Material and methodsRecommendations document developed by a panel of experts with extensive experience in the use of asenapine in psychiatric care, including emergency department, hospital, and outpatient care. Recommendations were discussed in a single meeting and were based on both the clinical experience of the panel of experts and the empirical evidence provided in the scientific literature. ResultsThe present document describes the patient profile that best suits the pharmacodynamic characteristics of asenapine, as well as the advantages and limitations of the pharmacokinetics associated with the sublingual route. The document also addresses the main safety issues of asenapine and suggests interventions aimed at mitigating the most frequent adverse reactions associated with asenapine treatment. Finally, the article provides advice on dosing and overall management of asenapine treatment, including the combination with other treatments and the switch from other antipsychotics to asenapine. ConclusionsIn this recommendations document, we provide clinicians with guidance on the use of asenapine in real-life practice, including the identification of patients who best suit the characteristics of this antipsychotic.

Morphiceptin analogs as potential analgesic and anti-diarrheal agents

Morphiceptin (Tyr-Pro-Phe-Pro-NH&lt;sub&gt;2&lt;/sub&gt;) – an opioid peptide, originating from enzymatic degradation of milk protein, β-casein, is a selective ligand μ-opioid receptors. These receptors play a an important role in reduction of pain sensitivity and in the regulation of the functions of many systems, including the gastrointestinal tract. Due to the rapid degradation by proteolytic enzymes and low bioavailability, morphiceptin can not be used as a medicine. The aim of the project was the synthesis and evaluation of the pharmacological profile of novel morphiceptin analogs, in search of compounds with a strong analgesic and anti-diarrheal activity, which acted only peripherally and are active after oral administration. We synthesized five series of morphiceptin analogs. The most interesting turned out compounds modified with the use of β-amino acids. Modification of morphiceptin at positions 2 or 3 by introduction of β&lt;sup&gt;2&lt;/sup&gt;- or β&lt;sup&gt;3&lt;/sup&gt;-amino acids and additionally in position 1 by replacing Tyr by Dmt (2’,6’-dimethyltyrosine), resulted in obtaining enzymatically stable analogs with mixed opioid receptor affinity profiles. An analog of the sequence Dmt-D-Ala-(R)-β&lt;sup&gt;2&lt;/sup&gt;-1-Nal-Pro-NH&lt;sub&gt;2&lt;/sub) [Nal= 3-(1-naphthyl)-alanine] was selected for &lt;i&gt;in vivo&lt;/i&gt; experiments in mice. This peptide showed a strong antinociceptive effect (peripheral analgesic) and antidiarrheal activity (comparable to loperamide) after intraperitoneal as well as oral administration. The PAMPA test, showed that this compound did not cross the artificial membrane imitating the blood-brain barrier and therefore its action should be only peripheral. The new analog may become an interesting lead compound in the development of peripherally restricted drugs for the treatment of gastrointestinal disorders.

Meta-analysis: Risk of dry mouth with second generation antidepressants

ObjectiveThe goal of this meta-analysis was to quantify the risk of dry mouth associated with commonly prescribed antidepressant agents and examine the potential implications of medication class, dose, and pharmacodynamics and dose on risk of treatment-induced dry mouth. Data sources and study selectionA PubMed search was conducted to identify double-blind, randomized, placebo-controlled trials examining the efficacy and tolerability of second generation antidepressant medications for adults with depressive disorders, anxiety disorders, and OCD. Data extractionA random-effects meta-analysis was used to quantify the pooled risk ratio of treatment-emergent dry mouth with second generation antidepressants compared to placebo. Stratified subgroup analysis and meta-regression was utilized to further examine the effects antidepressant agent, class, dosage, indication, and receptor affinity profile on the measured risk of dry mouth. Results99 trials involving 20,868 adults. SNRIs (Relative Risk (RR)=2.24, 95% Confidence Interval (CI): 1.95–2.58, z=11.2, p<0.001) were associated with a significantly greater risk of dry mouth (test for subgroup differences χ2=7.6, df=1; p=0.006) compared to placebo than SSRIs (RR=1.65, 95% CI: 1.39–1.95, z=5.8, p<0.001). There was a significant difference found in the risk of dry mouth between diagnostic indications within the SNRI class (test for subgroup differences χ2=9.63, df=1; p=0.002). Anxiety diagnoses (RR=2.78, 95% CI: 2.29–3.38, z=10.32, p<0.001) were associated with a greater risk of dry mouth compared to depression (RR=1.80, 95% CI: 1.48–2.18, z=5.85, p<0.001). Decreased affinity for Alpha-1 (PE=0.18, 95% CI: 0.07–0.28, z=3.26, p=0.001) and Alpha-2 (PE=0.49, 95% CI: 0.22–0.75, z=3.64, p<0.001) receptors and SERT (PE=0.07, 95% CI: 0.01–0.14, z=2.10, p<0.05) was significantly associated with increased risk of dry mouth. ConclusionsThe current meta-analysis suggests that SSRIs, SNRIs, and atypical antidepressants are all associated with varying degrees of increased risk of dry mouth. SNRIs were associated with a significantly greater risk of dry mouth compared to SSRIs.

Meta-analysis: Risk of hyperhidrosis with second-generation antidepressants.

Our goal was to quantify the risk of hyperhidrosis associated with commonly used antidepressant agents and examine the impact of medication class, pharmacodynamics, and dose on risk of hyperhidrosis. We conducted a PubMed search to identify all double-blind, randomized, placebo-controlled trials examining the efficacy of second-generation antidepressant medications in the treatment of adults with a depressive disorder, anxiety disorders, or obsessive-compulsive disorder. We used a random-effects meta-analysis to examine the pooled risk ratio of hyperhidrosis reported as a side effect in adults treated with second-generation antidepressants compared to placebo. We used stratified subgroup analysis and metaregression to examine the effects of medication type, class, dosage, indication, and receptor affinity profile on the measured risk of hyperhidrosis. We identified 76 trials involving 28,544 subjects. There was no significant difference in the risk of hyperhidrosis between serotonin-norepinephrine reuptake inhibitors (SNRI) [risk ratio (RR)=3.17, 95% CI: 2.63-3.82] and selective serotonin reuptake inhibitors (SSRI) (RR=2.93, 95% CI: 2.46-3.47) medications compared to placebo. All antidepressant medications were associated with a significantly increased risk of hyperhidrosis except fluvoxamine (RR=0.56, 95% CI: 0.12-2.53), bupropion (RR=1.23, 95% CI: 0.57-2.67), and vortioxetine (RR=1.35, 95% CI: 0.79-2.33). The dose of SSRI/SNRI medications was not significantly associated with the risk of hyperhidrosis. Increased risk of hyperhidrosis was associated with increased affinity of SSRI/SNRI medications to the dopamine transporter. Risk of hyperhidrosis was significantly increased with most antidepressant medications but was associated with dopamine transporter affinity.

Synthesis and activity of opioid peptidomimetics with β2- and β3-amino acids

Morphiceptin (Tyr-Pro-Phe-Pro-NH2) is a selective ligand of the mu opioid receptor, an important target in pain regulation. In this study, morphiceptin was modified at positions 2 or 3 by introduction of β2- or β3-amino acids and additionally in position 1 by replacing Tyr by Dmt (2′,6′-dimethyltyrosine), which resulted in obtaining enzymatically stable analogs with mixed opioid receptor affinity profiles. An analog of the sequence Dmt-d-Ala-(R)-β2-1-Nal-Pro-NH2 [Nal=3-(1-naphthyl)-alanine] showed very high activity at the mu and delta receptors in the calcium mobilization functional test but did not cross the artificial membrane imitating the blood-brain barrier. In the in vivo test this analog induced strong antinociceptive effect in the writhing test in mice after intraperitioneal but also oral administration and inhibited diarrhea similarly to loperamide. Therefore, it may become an interesting lead compound in the development of peripherally restricted drugs for the treatment of gastrointestinal disorders.

F17464 a new antipsychotic with preferential D3 antagonist, 5-HT1A partial agonist properties. Neurochemical studies

F17464 is a new dopamine receptor antagonist that recently demonstrated antipsychotic activity in a proof of concept study in schizophrenic patients under acute exacerbation. The compound has a unique profile with high affinity for hD3 receptors (Ki = 0.17 nM) and lower affinity for hD2L (Ki = 12.1 nM) and hD2S (Ki = 6.5 nM). F17464 exhibits also high affinity for h5-HT1A receptors (Ki = 0.16 nM). F17464 is a hD3 antagonist (pKB = 9.13), hD2S very week partial agonist (pKB = 7.87, emax 8% of DA stimulated in ERK assay) and a 5-HT1A partial agonist (pEC50 = 7.99). F17464 exhibits consistent affinities for rat striatal D2 (Ki = 4.8 nM) and for rat hippocampal 5-HT1A receptors (Ki = 1.14 nM). Neurochemical studies show that F17464 ip (1 h post-dose) produces a significant dose–dependent increase in the levels of DOPAC and HVA in the frontal cortex, caudate-putamen and limbic forebrain and an increase in 3-MT levels in the latter two regions with no changes in total DA content. The effect is significant at the doses of 0.63–2.5 mg/kg ip (PK/PD data will be provided). This pattern of DA metabolite changes is similar to that described for several antipsychotic drugs in rodents and it is indicative of a cortical effect of F17464. F17464 has a very low cataleptogenic activity in rats and mice and does not induce serotoninergic signs typical of 5-HT1A. F17464 is therefore a novel a D3 preferential antipsychotic with a unique mechanism of action and receptor affinity profile and a consistent effect in neurochemistry studies in rodents.Disclosure of interestThe authors have not supplied their declaration of competing interest.

H1-histamine receptor affinity predicts weight gain with antidepressants

Weight gain and metabolic abnormalities are extensively found in patients taking psychotropic medications. Although mainly antipsychotics have been implicated, also antidepressants carry the potential to induce weight gain, with tricyclics and mirtazapine being associated with the greatest weight gain. It has been suggested that this could be due to the different ability of antidepressants to block adrenergic, cholinergic, and histaminergic postsynaptic receptors. To date, however, the link between antidepressant-induced weight gain and their receptor affinity profile has not been established. We reanalysed data from a previous meta-analysis to evaluate whether weight change is associated with specific receptor affinity of antidepressants.We retrieved data from the only meta-analysis that assessed weight change with antidepressants. We searched in the Psychoactive Drug Screening Program (PDSP) Ki database data on the affinities of antidepressants to receptors hypothetically linked with weight change: H1-histamine, 5HT2c, M3-muscarinic, and α1A-adrenergic receptors. The association between weight change and receptor affinities was estimated using meta-regression.We found a significant association between the affinity of antidepressants to H1-receptor and weight gain (p value: <0.001). An association between weight gain and receptor affinity was also observed in the models for 5HT2c, M3, and α1A receptors. However, the association disappeared when H1-receptor was included in the models.This reanalysis of data demonstrates that anti-histaminergic activity is the strongest predictor of weight gain with antidepressants. These results further stress a reclassification of antidepressants according to their pharmacodynamic properties, and suggest avoiding prescribing antidepressants with an anti-histaminergic profile to patients at risk for cardio-metabolic disturbances.

Effects of aripiprazole and haloperidol on neural activation during the n-back in healthy individuals: A functional MRI study

ObjectiveAntipsychotic drugs target neurotransmitter systems that play key roles in working memory. Therefore, they may be expected to modulate this cognitive function via their actions at receptors for these neurotransmitters. However, the precise effects of antipsychotic drugs on working memory function remain unclear. Most studies have been carried out in clinical populations, making it difficult to disentangle pharmacological effects from pathology-related brain activation. In this study, we aim to investigate the effects of two antipsychotic compounds on brain activation during working memory in healthy individuals. This would allow elucidation of the effects of current antipsychotic treatments on brain function, independently of either previous antipsychotic use or disease-related pathology. MethodsWe carried out a fully counterbalanced, randomised within-subject, double-blinded and placebo-controlled, cross-over study of the effects of two antipsychotic drugs on working memory function in 17 healthy individuals, using the n-back task. Participants completed the functional MRI task on three separate occasions (in randomised order): following placebo, haloperidol, and aripiprazole. For each condition, working memory ability was investigated, and maps of neural activation were entered into a random effects general linear regression model to investigate main working memory function and linear load. Voxel-wise and region of interest analyses were conducted to attain regions of altered brain activation for each intervention. ResultsAripiprazole did not lead to any changes in neural activation compared with placebo. However, reaction time to a correct response was significantly increased following aripiprazole compared to both placebo (p=0.046) and haloperidol (p=0.02). In contrast, compared to placebo, haloperidol dampened activation in parietal (BA 7/40; left: FWE-corr. p=0.005; FWE-corr. right: p=0.007) and frontal (including prefrontal; BA 9/44/46; left: FWE-corr. p=0.009; right: FWE-corr. p=0.014) cortices and the left putamen (FWE-corr. p=0.004). Compared with aripiprazole, haloperidol dampened activation in parietal cortex (BA7/40; left: FWE-corr. p=0.034; right: FWE-corr. p=0.045) and the left putamen (FWE-corr.p=0.015). Haloperidol had no effect on working memory performance compared with placebo. ConclusionCognitive functions are known to be impaired in schizophrenia and as such are an important target of treatments. Elucidating the mechanisms by which antipsychotic medications alter brain activation underlying cognition is essential to advance pharmacological treatment of this disorder. Studies in healthy individuals can help elucidate some of these mechanisms, whilst limiting the confounding effect of the underlying disease-related pathology. Our study provides evidence for immediate and differential effects of single-dose haloperidol and aripiprazole on brain activation during working memory in healthy individuals. We propose that these differences likely reflect their different receptor affinity profiles, although the precise mechanisms underlying these differences remain unclear.

D1-like receptors distinguishing thieno-azecine regioisomers

Design of novel azecine derivatives with modulated dopaminergic receptor selectivity and affinity profiles.

Off-label use of atypical antipsychotic agents for treatment of insomnia

Despite limited supporting evidence, off-label uses of atypical or second generation antipsychotics (particularly olanzapine, quetiapine, and risperidone) are not uncommon. The off-label use of these agents for the treatment of insomnia is the focus of this review. While atypical antipsychotics are associated with a lower risk of tardive dyskinesia, extrapyramidal side effects, and more favorable effects on cognitive deficits and negative symptomatology in schizophrenic patients compared to typical or first generation antipsychotic agents, they are not without risks. Metabolic adverse effects are particularly problematic with atypical antipsychotics, even at doses lower than those used to treat FDA-approved indications. The receptor affinity profiles of most atypical antipsychotic agents promote sedation. The level of H1-histamine receptor blockade is believed to be most associated with somnolence and sedation. Several studies evaluating the safety and efficacy of the atypical antipsychotics quetiapine, olanzapine, and risperidone for the treatment of insomnia were identified and are summarized in this article.

Novel S1P1 Receptor Agonists − Part 3: From Thiophenes to Pyridines

In preceding communications we summarized our medicinal chemistry efforts leading to the identification of potent, selective, and orally active S1P1 agonists such as the thiophene derivative 1. As a continuation of these efforts, we replaced the thiophene in 1 by a 2-, 3-, or 4-pyridine and obtained less lipophilic, potent, and selective S1P1 agonists (e.g., 2) efficiently reducing blood lymphocyte count in the rat. Structural features influencing the compounds' receptor affinity profile and pharmacokinetics are discussed. In addition, the ability to penetrate brain tissue has been studied for several compounds. As a typical example for these pyridine based S1P1 agonists, compound 53 showed EC50 values of 0.6 and 352 nM for the S1P1 and S1P3 receptor, respectively, displayed favorable PK properties, and penetrated well into brain tissue. In the rat, compound 53 maximally reduced the blood lymphocyte count for at least 24 h after oral dosing of 3 mg/kg.

Novel S1P1 Receptor Agonists - Part 2: From Bicyclo[3.1.0]hexane-Fused Thiophenes to Isobutyl Substituted Thiophenes

Previously, we reported on the discovery of a novel series of bicyclo[3.1.0]hexane fused thiophene derivatives that serve as potent and selective S1P1 receptor agonists. Here, we discuss our efforts to simplify the bicyclohexane fused thiophene head. In a first step the bicyclohexane moiety could be replaced by a simpler, less rigid cyclohexane ring without compromising the S1P receptor affinity profile of these novel compounds. In a second step, the thiophene head was simplified even further by replacing the cyclohexane ring with an isobutyl group attached either to position 4 or position 5 of the thiophene. These structurally much simpler headgroups again furnished potent and selective S1P1 agonists (e.g., 87), which efficiently and dose dependently reduced the number of circulating lymphocytes upon oral administration to male Wistar rats. For several compounds discussed in this report lymphatic transport is an important route of absorption that may offer opportunities for a tissue targeted approach with minimal plasma exposure.

Peptide receptor imaging in neuroendocrine tumors: comparison between diagnostic scintigraphy and post-therapy whole-body scan

Several different somatostatin analogs labeled with gamma or positron-emitting radionuclides exist for diagnostic imaging of neuroendocrine tumors (NETs). Differences between standard diagnostic scintigraphy (SDS) and post-therapy whole-body scan (PTWBS) at peptide receptor radionuclide therapy in lesion detection are known; such differences have been correlated with the varying degree of receptor subtype expression and the varying receptor affinity profile of the different ligands. The aim of this study is to investigate differences between SDS and PTWBS obtained using the same radiopharmaceutical. We retrospectively reviewed clinical records of 53 patients with a diagnosis of NET, who underwent both SDS and PTWBS using (111)In-Pentetreotide. We compared the number of lesions for each body region detected by SDS and PTWBS. In 14/53 patients (26.4%) discrepancies between SDS and PTWBS were found. PTWBS detected 68 additional lesions with respect to SDS that were distributed as follows: head and neck, 6; mediastinum, 1; liver, 10; abdomen/pelvis, 1; bone, 44; other localizations, 6. The number of lesions detected by SDS was significantly different from that revealed by PTWBS (Wilcoxon matched pairs test, P = 0.0313). The regions that contributed significantly to reach this difference were head and neck (McNemar test, P = 0.0412), liver (McNemar test, P = 0.0044), bone (McNemar test, P < 0.0001) and other localizations (McNemar test, P = 0.0412). PTWBS shows more lesions than SDS with a significant discrepancy. We suppose that administration of higher radiopharmaceutical activity, use of larger peptide amount and the different time interval between radiopharmaceutical administration and scan execution can determine a higher sensitivity of PTWBS.