Antipsychotic- and Anxiolytic-like Properties of a Multimodal Compound JJGW08 in Rodents

Żmudzka, Elżbieta; Lustyk, Klaudia; Głuch‐Lutwin, Monika; Mordyl, Barbara; Zakrzewska-Sito, Alicja; Mierzejewski, Paweł; Jaśkowska, Jolanta; Kołaczkowski, Marcin; Sapa, Jacek; Pytka, Karolina

doi:10.3390/ijms232415929

Cited by 4 publications

(8 citation statements)

References 53 publications

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“…JJGW07 showed strong antagonistic properties at dopamine D 2 and serotonin 5-HT 1A receptors, whereas it showed weak antagonistic effects towards serotonin 5-HT 2A and 5-HT 7 receptors. The obtained results agree with our previous studies of JJGW07 analog, which also showed antagonistic properties for serotonin 5-HT 1A , 5-HT 2A , and 5-HT 7 and dopamine D 2 receptors [ 6 ].…”

Section: Discussionsupporting

confidence: 92%

“…Interestingly, the pharmacological profile of JJGW07 is very similar to its chemical derivative, JJGW08—a compound with the antipsychotic-like and the anxiolytic-like activity in rodents [ 6 ], as well as the anti-amnesic properties in mice (manuscript under review). Both compounds are antagonists of serotonin 5-HT 1A , 5-HT 2A , and 5-HT 7 and dopamine D 2 receptors, with no affinity towards 5-HT 6 receptors.…”

Section: Discussionmentioning

confidence: 99%

“…The tested compound was administered at the dose range of 0.625–2.5 mg/kg. The dose range was chosen based on our previous experiments on salicylamide derivatives [ 6 ]. If the effect of the lowest dose, i.e., 0.625 mg/kg, was still statistically significant, we decreased the dose by half until antidepressant-like, anxiolytic-like, antipsychotic-like, or anti-amnesic activity disappeared.…”

Section: Methodsmentioning

confidence: 99%

“…Thus, in our search for centrally-acting compounds, we investigated arylpiperazine derivatives of salicylamide with an affinity for serotonin and dopamine receptors [ 5 ]. We have previously shown the antipsychotic-like and anxiolytic-like effects [ 6 ], as well as the memory-enhancing properties (manuscript under review), of JJGW08. In this study, we selected another arylpiperazine derivative of salicylamide, JJGW07, due to its high affinity for serotonin 5-HT 1A , moderate affinity for 5-HT 7 and D 2 , and weak affinity for 5-HT 2A receptors [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

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Novel Multimodal Salicylamide Derivative with Antidepressant-like, Anxiolytic-like, Antipsychotic-like, and Anti-Amnesic Activity in Mice

et al. 2023

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Novel Multimodal Salicylamide Derivative with Antidepressant-like, Anxiolytic-like, Antipsychotic-like, and Anti-Amnesic Activity in Mice

et al. 2023

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“…Given the optimistic assumptions, this study aimed to assess the potential anti-amnesic and anti-depressant-like effects of JJGW08, a novel arylpiperazine alkyl derivative of salicylamide, which in our earlier studies showed strong antagonistic properties at 5-HT 1A and D 2 receptors and weak at 5-HT 2A and 5-HT 7 receptors as well as the potential antipsychotic- and anxiolytic-like activity in rodents [ 53 ]. We assessed whether the compound, when given alone, affected the emotional and recognition memory using the step-through passive avoidance and object recognition tests, respectively.…”

Section: Introductionmentioning

confidence: 99%

Potential Anti-Amnesic Activity of a Novel Multimodal Derivative of Salicylamide, JJGW08, in Mice

et al. 2023

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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.

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Advances in drug design and therapeutic potential of selective or multitarget 5‐HT1A receptor ligands

Giorgioni,

Bonifazi,

Botticelli

et al. 2024

Medicinal Research Reviews

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Abstract5‐HT1A receptor (5‐HT1A‐R) is a serotoninergic G‐protein coupled receptor subtype which contributes to several physiological processes in both central nervous system and periphery. Despite being the first 5‐HT‐R identified, cloned and studied, it still represents a very attractive target in drug discovery and continues to be the focus of a myriad of drug discovery campaigns due to its involvement in numerous neuropsychiatric disorders. The structure‐activity relationship studies (SAR) performed over the last years have been devoted to three main goals: (i) design and synthesis of 5‐HT1A‐R selective/preferential ligands; (ii) identification of 5‐HT1A‐R biased agonists, differentiating pre‐ versus post‐synaptic agonism and signaling cellular mechanisms; (iii) development of multitarget compounds endowed with well‐defined poly‐pharmacological profiles targeting 5‐HT1A‐R along with other serotonin receptors, serotonin transporter (SERT), D2‐like receptors and/or enzymes, such as acetylcholinesterase and phosphodiesterase, as a promising strategy for the management of complex psychiatric and neurodegenerative disorders. In this review, medicinal chemistry aspects of ligands acting as selective/preferential or multitarget 5‐HT1A‐R agonists and antagonists belonging to different chemotypes and developed in the last 7 years (2017–2023) have been discussed. The development of chemical and pharmacological 5‐HT1A‐R tools for molecular imaging have also been described. Finally, the pharmacological interest of 5‐HT1A‐R and the therapeutic potential of ligands targeting this receptor have been considered.

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Antipsychotic- and Anxiolytic-like Properties of a Multimodal Compound JJGW08 in Rodents

Cited by 4 publications

References 53 publications

Novel Multimodal Salicylamide Derivative with Antidepressant-like, Anxiolytic-like, Antipsychotic-like, and Anti-Amnesic Activity in Mice

Novel Multimodal Salicylamide Derivative with Antidepressant-like, Anxiolytic-like, Antipsychotic-like, and Anti-Amnesic Activity in Mice

Potential Anti-Amnesic Activity of a Novel Multimodal Derivative of Salicylamide, JJGW08, in Mice

Advances in drug design and therapeutic potential of selective or multitarget 5‐HT1A receptor ligands

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