Pitolisant protects mice chronically treated with corticosterone from some behavioral but not metabolic changes in corticosterone-induced depression model

Purpose: Histamine H3 receptor ligands may have antidepressant and anxiolytic effects. They can also compensate for metabolic disorders, which affect glucose or triglyceride levels. In previous studies, we have shown that pitolisant, a histamine H3 receptor antagonist/inverse agonist and σ1 receptor agonist, prevented the development of certain metabolic and depressive-like disorders in mice that have been treated chronically with olanzapine. Methods: As a continuation of our previous experiments, this study aimed to investigate the antidepressant- and anxiolytic-like activity of pitolisant in mice using the corticosterone-induced depression model. The forced swim and the elevated plus maze tests were used as behavioral endpoints. We also studied the effect pitolisant had on the level of acetoacetic acid in the urine as well as the glucose tolerance and body weight of the mice that had been administered corticosterone. Results: Pitolisant (10 mg/kg b.w.) did not prevent depressive-like behavior in mice during the chronic corticosterone administration but did counteract anxiety-like behavior, whilst fluoxetine (10 mg/kg) was shown to protect the mice from both of these behaviors. None of the treatments that were used in the study showed an effect on the locomotor activity of the mice. Pitolisant did not prevent an increase in acetoacetic acid levels in the urine, nor did it improve glucose tolerance in the tested mice. Conclusion: Although literature data indicates that there is significant potential for finding an antidepressant and anti-diabetic drug among the histamine H3 and σ1 receptor ligands, in our study, pitolisant was shown to only slightly compensate for corticosterone-induced abnormalities. However, further research will be required to study pitolisant's anxiolytic-like activity

HBK-17, a 5-HT1A Receptor Ligand With Anxiolytic-Like Activity, Preferentially Activates ß-Arrestin Signaling

Numerous studies have proven that both stimulation and blockade of 5-HT1A and the blockade of 5-HT7 receptors might cause the anxiolytic-like effects. Biased agonists selectively activate specific signaling pathways. Therefore, they might offer novel treatment strategies. In this study, we investigated the anxiolytic-like activity, as well as the possible mechanism of action of 1-[(2,5-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-17). In our previous experiments, HBK-17 showed high affinity for 5-HT1A and 5-HT7 receptors and antidepressant-like properties. We performed the four plate test and the elevated plus maze test to determine anxiolytic-like activity. Toward a better understanding of the pharmacological properties of HBK-17 we used various functional assays to determine its intrinsic activity at 5-HT1A, 5-HT2A, 5-HT7, and D2 receptors and UHPLC-MS/MS method to evaluate its pharmacokinetic profile. We observed the anxiolytic-like activity of HBK-17 in both behavioral tests and the effect was reversed by the pretreatment with WAY-100635, which proves that 5-HT1A receptor activation was essential for the anxiolytic-like effect. Moreover, the compound moderately antagonized D2, weakly 5-HT7 and very weakly 5-HT2A receptors. We demonstrated that HBK-17 preferentially activated ß-arrestin signaling after binding to the 5-HT1A receptor. HBK-17 was rapidly absorbed after intraperitoneal administration and had a half-life of about 150 min. HBK-17 slightly penetrated the peripheral compartment and showed bioavailability of approximately 45%. The unique pharmacological profile of HBK-17 encourages further experiments to understand its mechanism of action fully

Synthesis and Evaluation of the Antidepressant-like Properties of HBK-10, a Novel 2-Methoxyphenylpiperazine Derivative Targeting the 5-HT1A and D2 Receptors

The increasing number of patients reporting depressive symptoms requires the design of new antidepressants with higher efficacy and limited side effects. As our previous research showed, 2-methoxyphenylpiperazine derivatives are promising candidates to fulfill these criteria. In this study, we aimed to synthesize a novel 2-methoxyphenylpiperazine derivative, HBK-10, and investigate its in vitro and in vivo pharmacological profile. After assessing the affinity for serotonergic and dopaminergic receptors, and serotonin transporter, we determined intrinsic activity of the compound at the 5-HT1A and D2 receptors. Next, we performed behavioral experiments (forced swim test, tail suspension test) to evaluate the antidepressant-like activity of HBK-10 in naïve and corticosterone-treated mice. We also assessed the safety profile of the compound. We showed that HBK-10 bound strongly to 5-HT1A and D2 receptors and presented antagonistic properties at these receptors in the functional assays. HBK-10 displayed the antidepressant-like effect not only in naïve animals, but also in the corticosterone-induced mouse depression model, i.e., chronic administration of HBK-10 reversed corticosterone-induced changes in behavior. Moreover, the compound’s sedative effect was observed at around 26-fold higher doses than the antidepressant-like ones. Our study showed that HBK-10 displayed a favorable pharmacological profile and may represent an attractive putative treatment candidate for depression

Antidepressant- and anxiolytic-like effects of serotonin 5-HT1A receptor ligands

Patomechanizm wielu chorób ośrodkowego układu nerwowego jest związany z układem serotoninowym. Znaczącą rolę odgrywa receptor serotoninowy 5-HT1A, zlokalizowany w wielu strukturach mózgowych. W celu optymalizacji terapii oraz zmniejszenia lub wyeliminowania ewentualnych działań niepożądanych poszukuje się obecnie selektywnych funkcjonalnie agonistów, którzy pobudzając określony podtyp danego receptora aktywują w komórce wybrany szlak sygnalizacyjny, nie pobudzając bądź blokując inną odpowiedź. Celem pracy była ocena potencjalnej aktywności przeciwdepresyjnej, przeciwlękowej oraz wpływu na funkcje poznawcze nieselektywnych i stronniczych pre- lub postsynaptycznych agonistów receptora serotoninowego 5-HT1A tj. befiradolu, F15599, F13714 oraz związku 1.Wszystkie eksperymenty przeprowadzono na myszach. Potencjalną aktywność przeciwdepresyjną oceniono w dwóch modelach depresji: wywołanej podaniem kortykosteronu lub nieprzewidywalnym chronicznym łagodnym stresem, wykorzystując test wymuszonego pływania. Potencjalną aktywność anksjolityczną zbadano w teście czterech płytek u myszy, natomiast wpływ na funkcje poznawcze w teście rozpoznawania nowego obiektu. Dodatkowo dokonano oceny aktywności presynaptycznej badanych związków względem receptora 5-HT1A poprzez ich wpływ na temperaturę ciała myszy.F15599 i befiradol w obu modelach depresji wykazały potencjalne działanie przeciwdepresyjne po jednorazowym podaniu. W modelu nieprzewidywalnego chronicznego łagodnego stresu taką aktywność wykazał też F13714, natomiast związek 1 nie wywoływał efektu w żadnym modelu depresji. Wszystkie badane związki z wyjątkiem F13714 wykazały potencjalne działanie przeciwlękowe. Jedynie F15599 w żadnej dawce nie wpływał na funkcje poznawcze, z kolei związek 1 tylko w niskich dawkach wywoływał taki sam efekt. F15599, F13714 i związek 1 obniżały temperaturę ciała u myszy poprzez presynaptyczne autoreceptory 5-HT1A, a ten efekt był odwracany przez WAY-100635.Uzyskane wyniki są podstawą do podjęcia dalszych badań określających bezpieczeństwo oraz dokładny profil działania testowanych związków.The serotonergic 5-HT1A receptor is involved in the pathophysiology of many neuronal disorders due to its wide spread in brain. In order to achieve optimal therapy or to minimize the side effects there is a new group of ligands called “biased agonist”, which preferentially activate receptor subpopulations and specific signaling pathway, not affecting or even blocking another response. The aim of the study was to evaluate antidepressant- and anxiolytic-like activity and the influence on cognitive function of non-selective or biased pre-& post-synaptic 5-HT1A receptors: befiradol, F15599, F13714 and compound 1.Antidepressant-like effect was evaluated in the mouse model of depression induced by corticosterone and unpredictable chronic mild stress model, with the forced swim test as behavioral endpoint. In the four-plate test, the compounds were tested for anxiolytic-like activity, whereas the influence on cognitive function was evaluated in the novel object recognition test. To confirm presynaptic activity of tested compounds the serotonin 5-HT1A receptor-mediated hypothermia in mice was performed. F15599 and befiradol demonstrated antidepressant-like effect in both mouse models of depression, F13714 only in unpredictable chronic mild stress, whereas compound 1 was inactive in both models. All tested compounds showed anxiolytic-like activity except F13714. F15599 at all doses and compound 1 at lower doses did not affect memory consolidation process. The presynaptic serotonin 5-HT1A receptor-mediated hypothermia in mice was confirmed for F15599, F13714 and compound 1 and this effect was prevented by WAY-100635.In order to determine safety and pharmacological profile of studied compounds further research will be performed

The Calcium/Calmodulin-Dependent Kinases II and IV as Therapeutic Targets in Neurodegenerative and Neuropsychiatric Disorders

CaMKII and CaMKIV are calcium/calmodulin-dependent kinases playing a rudimentary role in many regulatory processes in the organism. These kinases attract increasing interest due to their involvement primarily in memory and plasticity and various cellular functions. Although CaMKII and CaMKIV are mostly recognized as the important cogs in a memory machine, little is known about their effect on mood and role in neuropsychiatric diseases etiology. Here, we aimed to review the structure and functions of CaMKII and CaMKIV, as well as how these kinases modulate the animals’ behavior to promote antidepressant-like, anxiolytic-like, and procognitive effects. The review will help in the understanding of the roles of the above kinases in the selected neurodegenerative and neuropsychiatric disorders, and this knowledge can be used in future drug design

The antiarrhythmic activity of novel pyrrolidin-2-one derivative S-75 in adrenaline-induced arrhythmia

Arrhythmia is a quivering or irregular heartbeat that can often lead to blood clots, stroke, heart failure, and other heart-related complications. The limited efficacy and safety of antiarrhythmic drugs require the design of new compounds. Previous research indicated that pyrrolidin-2-one derivatives possess an affinity for α1-adrenergic receptors. The blockade of α1-adrenoceptor may play a role in restoring normal sinus rhythm; therefore, we aimed to verify the antiarrhythmic activity of novel pyrrolidin-2-one derivative S-75. In this study, we assessed the influence on sodium, calcium, potassium channels, and β1-adrenergic receptors to investigate the mechanism of action of S-75. Lack of affinity for β1-adrenoceptors and weak effects on ion channels decreased the role of these adrenoceptors and channels in the pharmacological activity of S-75. Next, we evaluated the influence of S-75 on normal ECG in rats and isolated rat hearts, and the tested derivative did not prolong the QTc interval, which may confirm the lack of the proarrhythmic potential. We tested antiarrhythmic activity in adrenaline-, aconitine- and calcium chloride-induced arrhythmia models in rats. The studied compound showed prophylactic antiarrhythmic activity in the adrenaline-induced arrhythmia, but no significant activity in the model of aconitine- or calcium chloride-induced arrhythmia. In addition, S-75 was not active in the model of post-reperfusion arrhythmias of the isolated rat hearts. Conversely, the compound showed therapeutic antiarrhythmic properties in adrenaline-induced arrhythmia, reducing post-arrhythmogen heart rhythm disorders, and decreasing animal mortality. Thus, we suggest that the blockade of α1-adrenoceptor might be beneficial in restoring normal heart rhythm in adrenaline-induced arrhythmia

The antiarrhythmic and hypotensive effects of S-61 and S-73, the Pyrrolidin-2-one derivatives with alpha(1)-adrenolytic properties

Heart rhythm abnormalities are a cause of many deaths worldwide. Unfortunately, the available antiarrhythmic drugs show limited efficacy and proarrhythmic potential. Thus, efforts should be made to search for new, more effective, and safer pharmacotherapies. Several studies suggested that blocking the α(1)-adrenoceptors could restore normal heart rhythm in arrhythmia. In this study, we aimed to assess the antiarrhythmic potential of S-61 and S-73, two novel pyrrolidin-2-one derivatives with high affinity for α(1)-adrenergic receptors. First, using radioligand binding studies, we demonstrated that S-61 and S-73 did not bind with β(1)-adrenoceptors. Next, we assessed whether S-61 and S-73 could protect rats against arrhythmia in adrenaline-, calcium chloride- and aconitine-induced arrhythmia models. Both compounds showed potent prophylactic antiarrhythmic properties in the adrenaline-induced arrhythmia model, but the effect of S-61 was more pronounced. None of the compounds displayed antiarrhythmic effects in calcium chloride- or aconitine-induced arrhythmia models. Interestingly, both derivatives revealed therapeutic antiarrhythmic activity in the adrenaline-induced arrhythmia, diminishing heart rhythm irregularities. Neither S-61 nor S-73 showed proarrhythmic potential in rats. Finally, the compounds decreased blood pressure in rodents. The hypotensive effects were not observed after coadministration with methoxamine, which suggests the α(1)-adrenolytic properties of both compounds. Our results confirm that pyrrolidin-2-one derivatives possess potent antiarrhythmic properties. Given the promising results of our experiments, further studies on pyrrolidin-2-one derivatives might result in the development of a new class of antiarrhythmic drugs