Lurasidone — novel atypical neuroleptic with antidepressant activity

Lurasidon to nowy lek przeciwpsychotyczny II generacji (SGA) o dodatkowej aktywności przeciwdepresyjnej, zatwierdzony przez Food and Drug Administration do leczenia schizofrenii i objawów depresyjnych w przebiegu choroby afektywnej dwubiegunowej (ChAD). Podobnie jak inne, atypowe neuroleptyki, lurasidon posiada wysokie powinowactwo do receptorów D2 i 5-HT2A, jak również do 5-HT7 oraz umiarkowane wobec receptorów 5-HT1A i alfa2C. Stosując zwierzęce modele zaburzeń pamięci i uczenia wykazano, że lurasidon poprawia funkcje poznawcze zaburzone podaniem MK-801 czy fencyklidyny oraz przejawia aktywność przeciwdepresyjną w krótko- i długoterminowych modelach depresji u gryzoni. Skuteczność i profil bezpieczeństwa lurasidonu w aktywnej i przewlekłej fazie schizofrenii oraz epizodów depresyjnych w przebiegu ChAD były szacowane w kilkunastu randomizowanych, wykonanych metodą podwójnie ślepej próby badaniach klinicznych, z wykorzystaniem różnych dawek. Lurasidon w porównaniu z kontrolą (placebo) powodował istotną poprawę w zakresie redukcji objawów pozytywnych i negatywnych schizofrenii oraz osiowych objawów depresji w przebiegu ChAD. Lurasidon jest dobrze tolerowany; do najczęściej obserwowanych działań niepożądanych należą: nudności, senność i akatyzje (5–15%). W porównaniu z innymi SGA, lurasidon wywiera słabszy wpływ na parametry metaboliczne, powodując nieznaczny przyrost masy ciała u pacjentów, klinicznie nieistotne zmiany w stężeniu glukozy, lipidów czy długości odcinka QT. Wygodne dawkowanie (raz dziennie z posiłkiem) oraz poszerzony profil aktywności czynią z lurasidonu konkurencyjnego kandydata w farmakoterapii chorób psychicznych.Lurasidone is a novel second generation antipsychotic (SGA) with antidepressant-like activity, approved by FDA for the treatment of schizophrenia and depressive symptoms in the bipolar disorder type 1 (BP I). Similar to other atypical antipsychotics, lurasidon has a potent affinity for D2, 5-HT2A and 5-HT7 receptors, and moderate for 5-HT1A and alfa2C ones. Using animal models of learning and memory it has been shown that lurasidone displays ability to improve memory dysfunctions caused by MK-801 or fencyclidine and evokes potential antidepressant activity in short- and long-term rodent models of depression. The efficacy and tolerability of lurasidone for treatment of acute and chronic schizophrenia as well as major depressive episodes occurring in BP I have been evaluated in few double-blind randomized, fixed-dose clinical trials. Lurasidone, compared to placebo, showed a significantly greater improvement in reduction of positive and negative symptoms of schizophrenia and core symptoms of depression in BP I. Lurasidone is well tolerated; nausea, somnolence and akathisia are the most common adverse effects (with 5–15% of frequency). In comparison to other SGA, lurasidone seems to have no significant influence on metabolic parameters like glucose and lipids level or QT lenght, producing only slight weight gain in patients. Comfortable dosing (once daily with meal) and wider activity profile make lurasidone a competitive candidate for pharmacotherapy of psychiatric disorders

Idalopirdine : a small molecule antagonist of 5-HT_6 with therapeutic potential against obesity

5HT(6) receptor antagonists offer the potential for safe and effective drugs against obesity, because they can reduce weight without causing serious side effects in the cardiovascular system. Also, their anorexic effect is associated with reduced food intake via an enhancement of satiety. In the present study we investigated the anorexic effect of idalopirdine (LuAE58054) in a model of obesity induced by high-fat diet. To induce obesity in rats, the animals were treated with feed with a fat content of 40 %. Body weight was controlled and the amount of food and water consumed was determined. The influence of the test compound on the lipid profile and glucose level was measured, as well as locomotor activity in home cages on the 20th day of the treatment. LuAE58054, at 5 mg kg(−1)/day i.p., was significantly anorectic in this model of obesity. Animals treated with LuAE58054 weighed 8 and 9.2 % less than the control obese animals on the 12th and 21st days, respectively. It significantly reduced food intake and the amount of peritoneal fat in animals, and reduced the level of triglycerides in plasma. LuAE58054 did not have a statistically significant effect on the spontaneous activity of diet-induced obese rats. The present study clearly demonstrates the effectiveness of LuAE58054 in reducing body weight. This compound is in phase III of clinical trials for the treatment of cognitive deficits associated with Alzheimer’s disease and schizophrenia. It is a 5HT(6) receptor antagonist and is, therefore, free of those unacceptable side effects that preclude chronic use of anti-obesity drugs with other mechanisms of action. The search for an effective and safe anti-obesity drug is essential for an increasingly obese population; therefore, the anorectic action of LuAE58054 is important and there is a need for more research in this direction

Study on a three-step rapid assembly of zolpidem and its fluorinated analogues employing microwave-assisted chemistry

We developed an efficient microwave-assisted three-step synthesis of zolpidem and its fluorinated analogues 1–3. The procedure relays on the utilization of easily accessible and inexpensive starting materials. Our protocol shows superior performance in terms of yield and purity of products, compared to conventional heating systems. Notably, the total time needed for reaction accomplishment is significantly lower comparing to oil bath heating systems. Finally, we have performed a detailed study on the preparation of zolpidem tartrate salt I, and we assessed its particle-sizes using a polarizing microscope. Our goal was to select the appropriate method that generates the acceptable particle-size, since the solid-size directly influences solubility in biological fluids and further bioavailability. We believe that the disclosed procedure will help to produce a lab-scale quantity of zolpidem and its fluorinated derivatives 1–3, as well as zolpidem tartrate salt I, with suitable fine-particle size for further biological experimentation

Antipsychotic, antidepressant, and cognitive-impairment properties of antipsychotics : rat profile and implications for behavioral and psychological symptoms of dementia

Many dementia patients exhibit behavioral and psychological symptoms (BPSD), including psychosis and depression. Although antipsychotics are frequently prescribed off-label, they can have marked side effects. In addition, comparative preclinical studies of their effects are surprisingly scarce, and strategies for discovery of novel pharmacotherapeutics are lacking. We therefore compared eight antipsychotics in rat behavioral tests of psychosis, antidepressant-like activity, and cognitive impairment as a basis for preclinical evaluation of new drug candidates. The methods used in this study include inhibition of MK-801-induced hyperactivity, forced swim test (FST), passive avoidance (PA), spontaneous locomotor activity, and catalepsy. The drugs exhibited antipsychotic-like activity in the MK-801 test but with diverse profiles in the other models. Risperidone impaired PA performance, but with some dose separation versus its actions in the MK-801 test. In contrast, clozapine, olanzapine, lurasidone, and asenapine showed little or no dose separation in these tests. Aripiprazole did not impair PA performance but was poorly active in the MK-801 test. Diverse effects were also observed in the FST: chlorpromazine was inactive and most other drugs reduced immobility over narrow dose ranges, whereas clozapine reduced immobility over a wider dose range, overlapping with antipsychotic activity. Although the propensity of second-generation antipsychotics to produce catalepsy was lower, they all elicited pronounced sedation. Consistent with clinical data, most currently available second-generation antipsychotics induced cognitive and motor side effects with little separation from therapeutic-like doses. This study provides a uniform in vivo comparative basis on which to evaluate future early-stage drug candidates intended for potential pharmacotherapy of BPSD

The use of machine learning-based sequential virtual screening in the search of new ligands of 5-HT6 receptor

5-HT6 receptor takes part in learning and memory processes. For this reason, the use of ligands of this receptor in the treatment of neurodegenerative diseases such as Alzheimer's disease, depression or autism is being investigated. The development of machine learning (ML) and access to large compound databases allow for the increasing use of these methods in search of new drugs. The use of ML in pre-clinical tests allows for a reduction in time and costs of drug discovery. In this study, we used a sequential virtual screening approach in search of new structures with potential high affinity for the 5-HT6 receptor. Data from the ChEMBL database containing ligand binding affinities, measured as an inhibition constant (Ki), was used as the training dataset. Each step of the screening was based on machine learning models, the task of which was to classify compounds as potentially active and inactive. The first step included a ligand-based drug discovery (LBDD) approach, in which, using Klekota-Roth fingerprints and descriptors describing the chemical structure of the ligands, a classification model was developed to select a preliminary group of candidates from the Otava chemical compound database. In the second step, a structure-based drug discovery (SBDD) approach was used. For this purpose, compounds were docked to the homology model of the 5-HT6 receptor, developed using the AlphaFold algorithm and optimized by Induced-Fit Docking tool and molecular dynamics. Docking poses were scored by a trained Extra Trees classifier. Interactions of a reference ligand with 14 binding site residues were used as features for the trained model. The use of machine learning as a scoring function allowed to improve the virtual screening parameters compared to the Glide GScore scoring function. Based on the obtained model, it was also confirmed that the location of a ligand near the Ser5.43 and Phe5.38 residues is important for binding the compound to the receptor. The procedure has allowed to select 20 candidates with new chemical structures compared to known ligands. In addition, the obtained compounds had a relatively low basic pKa compared to known ligands and thus may be suspected to have a low affinity for hERG channels and good brain penetration

ADN-1184, a monoaminergic ligand with 5-HT_{6/7} receptor antagonist action, exhibits activity in animal models of anxiety

Behavioral and psychological symptoms of dementia (BPSD) include apathy, sleep problems, irritability, wandering, elation, agitation/aggression, and mood disorders such as depression and/or anxiety. Elderly patients are usually treated with second-generation antipsychotics; however, they present not enough efficacy against all symptoms observed. Hence, there still is an unmet need for novel pharmacotherapeutic agents targeted BPSD. A novel arylsulfonamide derivative ADN-1184 has been developed that possesses a preclinical profile of activity corresponding to criteria required for treatment of both psychosis and depressive symptoms of BPSD without exacerbating cognitive impairment or inducing motor disturbances. To broaden its pharmacological efficacy toward anxiety symptoms, its anxiolytic properties have been examined in common animal preclinical models in rats and mice. ADN-1184 significantly increased the number of entries into open arms measured in the elevated plus-maze test; however, it simultaneously increased parameters of exploratory activity. In the Vogel conflict drinking test, ADN-1184 dose-dependently and significantly increased the number of shocks accepted and the number of licks. Moreover, in mice, it also had specific anxiolytic-like activity in the four-plate test, and only negligible one at a specific mid-range dose measured in the spontaneous marble burying test. The obtained findings reveal that ADN-1184 displays anxiolytic-like activity in animal models of anxiety which employed punished stimuli. In its unusual combination of some anxiolytic action with already proven antipsychotic and antidepressant properties, and lack of any disruptive impact on learning and memory processes and motor coordination, ADN-1184 displays a profile that would be desired for a novel therapeutic for BPSD

Study of a mechanism responsible for potential antidepressant activity of EMD 386088, a 5-HT_6 partial agonist in rats

It was shown that 5-HT(6) receptor agonists can exert pharmacological activity due to various modifications in monoamines’ level and metabolism activity in rats’ brain structures. This finding was correlated with antidepressant- or anxiolytic-like properties of these compounds. The study was designed to establish a possible mechanism of the antidepressant-like activity of the partial 5-HT(6) receptor agonist EMD386088 (5-chloro-2-methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole hydrochloride) in rats. The concentrations of monoamines (dopamine (DA), noradrenaline (NA), and serotonin (5-HT)) and the rate of their metabolism were measured ex vivo in the brain structures (hippocampus, nucleus accumbens, striatum) using high-performance liquid chromatography (HPLC). The rats were killed after the forced swim test (FST); the collected tissue samples were used to ex vivo experiments. The potency of EMD386088 to blockade dopamine transporter (DAT) was tested in a functional in vitro study. FST was used to assess the involvement of D(1)- and D(2)-like receptor subfamilies in antidepressant-like properties of EMD386088. Neurochemical data from ex vivo experiments showed that antiimmobility activity of EMD386088 may be connected with the activation of dopaminergic system, while neither noradrenergic nor serotonergic ones are involved in its effect. EMD386088 also possesses a significant affinity for DAT which may be a mechanism in the abovementioned effect. Behavioral data seem to confirm the importance of dopaminergic system activation in antidepressant-like activity of EMD386088, since this effect, observed in the FST, was abolished by the preferential D(1)- and D(2)-like receptor subfamily antagonists SCH23390 and sulpiride, respectively. Dopaminergic system is involved in antidepressant-like activity of EMD386088

Evaluation of antiplatelet activity of novel guanidine derivatives in the aspects of their adrenergic receptor activity

Designed acetamide derivatives based on guanidine and various heteroaryl carboxylic acids, were preliminary in vitro study of their adrenergic receptor affinity and anti-plateled effects. The obtained results have showed that exchange of 2,6-dichloro-phenyl substituent of guanidine into heteroaryl moieties, caused the decrease of receptor affinity, especially for α1-adrenoceptors. The observed receptor profile of activity for α2BAR was not changed compared to α1-ARs. Moreover, the observed effects on platelet aggregation induced by sub-threshold concentration of collagen and adrenaline strongly suggested that antiaggregant effect of N- (diaminomethylene)-2-(pyridin-3-yl)acetamide and N-(diaminomethylene)-2-(pyridin-4-yl)acetamide depends on their α2B-ARs antagonistic activity