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Memory impairments constitute a significant problem worldwide, and the COVID-19 pandemic dramatically increased the prevalence of cognitive deficits. Patients with cognitive deficits, specifically memory disturbances, have underlying comorbid conditions such as schizophrenia, anxiety, or depression. Moreover, the available treatment options have unsatisfactory effectiveness. Therefore, there is a need to search for novel procognitive and anti-amnesic drugs with additional pharmacological activity. One of the important therapeutic targets involved in the modulation of learning and memory processes are serotonin receptors, including 5-HT1A, 5-HT6, and 5-HT7, which also play a role in the pathophysiology of depression. Therefore, this study aimed to assess the anti-amnesic and antidepressant-like potential of JJGW08, a novel arylpiperazine alkyl derivative of salicylamide with strong antagonistic properties at 5-HT1A and D2 receptors and weak at 5-HT2A and 5-HT7 receptors in rodents. First, we investigated the compound’s affinity for 5-HT6 receptors using the radioligand assays. Next, we assessed the influence of the compound on long-term emotional and recognition memory. Further, we evaluated whether the compound could protect against MK-801-induced cognitive impairments. Finally, we determined the potential antidepressant-like activity of the tested compound. We found that JJGW08 possessed no affinity for 5-HT6 receptors. Furthermore, JJGW08 protected mice against MK-801-induced recognition and emotional memory deficits but showed no antidepressant-like effects in rodents. Therefore, our preliminary study may suggest that blocking serotonin receptors, especially 5-HT1A and 5-HT7, might be beneficial in treating cognitive impairments, but it requires further investigation.

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.

Rationale MK-801 (dizocilpine) is a non-competitive NMDA receptor antagonist originally explored for anticonvulsant potential. Despite its original purpose, its amnestic properties led to the development of pivotal models of various cognitive impairments widely employed in research and greatly impacting scientific progress. MK-801 offers several advantages; however, it also presents drawbacks, including inducing dose-dependent hyperlocomotion or ambiguous effects on anxiety, which can impact the interpretation of behavioral research results. Objectives The present review attempts to summarize and discuss the effects of MK-801 on different types of memory and cognitive functions in animal studies. Results A plethora of behavioral research suggests that MK-801 can detrimentally impact cognitive functions. The specific effect of this compound is influenced by variables including developmental stage, gender, species, strain, and, crucially, the administered dose. Notably, when considering the undesirable effects of MK-801, doses up to 0.1 mg/kg were found not to induce stereotypy or hyperlocomotion. Conclusion Dizocilpine continues to be of significant importance in preclinical research, facilitating the exploration of various procognitive therapeutic agents. However, given its potential undesirable effects, it is imperative to meticulously determine the appropriate dosages and conduct supplementary evaluations for any undesirable outcomes, which could complicate the interpretation of the findings.

Arrhythmia, an irregular heartbeat, might be a life-threatening condition but also a risk factor for stroke or worsen the prognosis after myocardial infarction. The limited efficacy and proarrhythmic potential of the available drugs require searching for new, more effective, and safer pharmacotherapies. Studies indicate that the blockade of α1-adrenoceptors could be effective in treating heart rhythm abnormalities. In this study, we aimed to assess the antiarrhythmic and hypotensive potential of HBK-10, a novel 2-methoxyphenylpiperazine derivative, as well as its binding to the selected adrenergic receptors. Radioligand binding studies demonstrated that HBK-10 showed a high affinity for α1 but not for α2 or β1 receptors. Next, we evaluated the ability of HBK-10 to protect against an adrenaline-induced arrhythmia in rats. The compound showed potent prophylactic antiarrhythmic properties in this arrhythmia model. Notably, the compound did not show proarrhythmic potential in normotensive rats since it did not influence the ECG parameters at antiarrhythmic doses. Finally, the compound showed hypotensive properties in rats, which were not observed after coadministration with adrenaline, noradrenaline, or methoxamine, which suggests α1-adrenolytic properties of HBK-10. Our results confirm that compounds with a 2-methoxyphenylpiperazine group show a high affinity for α1-adrenoceptors and a significant antiarrhythmic effect. Given the promising results of our study, further evaluation of HBK-10 is necessary to unravel the mechanisms behind its pharmacological effects and evaluate the safety profile.

Depression, anxiety, and schizophrenia may coexist in psychiatric patients. Moreover, these disorders are very often associated with cognitive impairments. However, pharmacotherapy of these conditions remains challenging due to limited drug effectiveness or numerous side effects. Therefore, there is an urgent need to develop novel multimodal compounds that can be used to treat depression, anxiety, and schizophrenia, as well as memory deficits. Thus, this study aimed to evaluate the potential antidepressant-like, anxiolytic-like, antipsychotic-like effects, and anti-amnesic properties, of the novel arylpiperazine derivative of salicylamide, JJGW07, with an affinity towards serotonin 5-HT1A, 5-HT2A, and 5-HT7 and dopamine D2 receptors. Firstly, we investigated the compound’s affinity for 5-HT6 receptors and its functional activity by using in vitro assays. JJGW07 did not bind to 5-HT6 receptors and showed antagonistic properties for 5-HT1A, 5-HT2A, 5-HT7, and D2 receptors. Based on the receptor profile, we performed behavioral studies in mice to evaluate the antidepressant-like, anxiolytic-like, and antipsychotic-like activity of the tested compound using forced swim and tail suspension tests; four-plate, marble-burying, and elevated plus maze tests; and MK-801- and amphetamine-induced hyperlocomotion tests, respectively. JJGW07 revealed antidepressant-like properties in the tail suspension test, anxiolytic-like effects in the four-plate and marble-burying tests, and antipsychotic-like activity in the MK-801-induced hyperlocomotion test. Importantly, the tested compound did not induce catalepsy and motor impairments or influence locomotor activity in rodents. Finally, to assess the potential procognitive and anti-amnesic properties of JJGW07, we used passive avoidance and object recognition tests in mice. JJGW07 demonstrated positive effects on long-term emotional memory and also ameliorated MK-801-induced emotional memory impairments in mice, but showed no procognitive properties in the case of recognition memory. Our results encourage the search for new compounds among salicylamide derivatives, which could be model structures with multitarget mechanisms of action that could be used in psychiatric disorder therapy.

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.

Studies proved that among all α1-adrenoceptors, cardiac myocytes functionally express only α1A- and α1B-subtype. Scientists indicated that α1A-subtype blockade might be beneficial in restoring normal heart rhythm. Therefore, we aimed to determine the role of α1-adrenoceptors subtypes (i.e., α1A and α1B) in antiarrhythmic effect of six structurally similar derivatives of 2-methoxyphenylpiperazine. We compared the activity of studied compounds with carvedilol, which is β1- and α1-adrenoceptors blocker with antioxidant properties. To evaluate the affinity for adrenergic receptors, we used radioligand methods. We investigated selectivity at α1-adrenoceptors subtypes using functional bioassays. We tested antiarrhythmic activity in adrenaline-induced (20 μg/kg i.v.), calcium chloride-induced (140 and 25 mg/kg i.v.) and barium chloride-induced (32 and 10 mg/kg i.v.) arrhythmia models in rats. We also evaluated the influence of studied compounds on blood pressure in rats, as well as lipid peroxidation. All studied compounds showed high affinity toward α1-adrenoceptors but no affinity for β1 receptors. Biofunctional studies revealed that the tested compounds blocked α1A-stronger than α1B-adrenoceptors, but except for HBK-19 they antagonized α1A-adrenoceptor weaker than α1D-subtype. HBK-19 showed the greatest difference in pA2 values-it blocked α1A-adrenoceptors around seven-fold stronger than α1B subtype. All compounds showed prophylactic antiarrhythmic properties in adrenaline-induced arrhythmia, but only the activity of HBK-16, HBK-17, HBK-18, and HBK-19 (ED50 = 0.18-0.21) was comparable to that of carvedilol (ED50 = 0.36). All compounds reduced mortality in adrenaline-induced arrhythmia. HBK-16, HBK-17, HBK-18, and HBK-19 showed therapeutic antiarrhythmic properties in adrenaline-induced arrhythmia. None of the compounds showed activity in calcium chloride- or barium chloride-induced arrhythmias. HBK-16, HBK-17, HBK-18, and HBK-19 decreased heart rhythm at ED84. All compounds significantly lowered blood pressure in normotensive rats. HBK-18 showed the strongest hypotensive properties (the lowest active dose: 0.01 mg/kg). HBK-19 was the only compound in the group, which did not show hypotensive effect at antiarrhythmic doses. HBK-16, HBK-17, HBK-18, HBK-19 showed weak antioxidant properties. Our results indicate that the studied 2-methoxyphenylpiperazine derivatives that possessed stronger α1A-adrenolytic properties (i.e., HBK-16, HBK-17, HBK-18, and HBK-19) were the most active compounds in adrenaline-induced arrhythmia. Thus, we suggest that the potent blockade of α1A-receptor subtype is essential to attenuate adrenaline-induced arrhythmia.

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 α1-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 α1-adrenergic receptors. First, using radioligand binding studies, we demonstrated that S-61 and S-73 did not bind with β1-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 α1-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.

Anxiety is a common mental disorder, and its prevalence has lately increased because of the COVID-19 pandemic. Unfortunately, the available anxiolytics are often ineffective, and most possess addictive potential. Thus, searching for novel compounds is essential. In our previous studies, we selected a multimodal compound, HBK-15, which showed a fast antidepressant-like effect in animal models of depression. HBK-15 demonstrated a high affinity for serotonin 5-HT 1A receptors and moderate for 5-HT 7 , dopamine D 2 , and α 1 -adrenoceptors. Based on the receptor profile and preliminary studies, we aimed to investigate the anxiolytic potential of HBK-15 using the conditioned-response rat model of anxiety, i.e., the Vogel drinking test. We performed hot plate and free-drinking tests to exclude false positive results in the Vogel test. Using radioligand binding studies, we also investigated the affinity of the compound for the selected biological targets, which play a role in anxiety. Our experiments revealed that HBK-15 showed an anxiolytic-like effect in rats (5 mg/kg) without influencing the pain threshold or the amount of water consumed in the free-drinking test. Furthermore, the tested compound did not show a significant affinity for the selected biological targets, which suggests that its anxiolytic-like mechanism of action could be connected with the interaction with other receptors. This study indicates that multimodal compounds with a receptor profile similar to HBK-15 could be an attractive therapeutic option for patients with a generalized anxiety disorder. However, more studies are required to determine the exact mechanism of action of HBK-15 and its safety profile.

Cardiovascular diseases remain one of the leading causes of death worldwide. Unfortunately, the available pharmacotherapeutic options have limited effectiveness. Therefore, developing new drug candidates remains very important. We selected six novel arylpiperazine alkyl derivatives of salicylamide to investigate their cardiovascular effects. Having in mind the beneficial role of α1-adrenergic receptors in restoring sinus rhythm and regulating blood pressure, first, using radioligand binding assays, we evaluated the affinity of the tested compounds for α-adrenergic receptors. Our experiments revealed their high to moderate affinity for α1- but not α2-adrenoceptors. Next, we aimed to determine the antiarrhythmic potential of novel derivatives in rat models of arrhythmia induced by adrenaline, calcium chloride, or aconitine. All compounds showed potent prophylactic antiarrhythmic activity in the adrenaline-induced arrhythmia model and no effects in calcium chloride- or aconitine-induced arrhythmias. Moreover, the tested compounds demonstrated therapeutic antiarrhythmic activity, restoring a normal sinus rhythm immediately after the administration of the arrhythmogen adrenaline. Notably, none of the tested derivatives affected the normal electrocardiogram (ECG) parameters in rodents, which excludes their proarrhythmic potential. Finally, all tested compounds decreased blood pressure in normotensive rats and reversed the pressor response to methoxamine, suggesting that their hypotensive mechanism of action is connected with the blockade of α1-adrenoceptors. Our results confirm the antiarrhythmic and hypotensive activities of novel arylpiperazine derivatives and encourage their further investigation as model structures for potential drugs.