Paweł Zajdel, Mikołaj Matłoka, Jolanta Konieczny, Tomasz Kos, Josie C Lammers, Natalie G Cavalco, Allison A Clark, Tomasz Lenda, Grzegorz Satała, Vittorio Canale, Katarzyna Grychowska, Martyna Krawczyk, Agnieszka Nikiforuk, Anna Partyka, Magdalena Jastrzębska-Więsek, Klemencja Berghauzen-Maciejewska, Dominika Biała, Monika Janicka, Artur Janusz, Radosław Piast, Krzysztof Mulewski, Damian Smuga, Jerzy Pieczykolan, Maciej Wieczorek, Rafał Moszczyński-Pętkowski, Krzysztof Dubiel, Krystyna Ossowska, Andrzej J Bojarski, Krzysztof Kamiński, John D McCorvy, Piotr Popik
{"title":"Simultaneous 5-HT<sub>1B</sub>R agonist/5-HT<sub>6</sub>R antagonist action as a potential treatment of Parkinson's disease and its comorbidities.","authors":"Paweł Zajdel, Mikołaj Matłoka, Jolanta Konieczny, Tomasz Kos, Josie C Lammers, Natalie G Cavalco, Allison A Clark, Tomasz Lenda, Grzegorz Satała, Vittorio Canale, Katarzyna Grychowska, Martyna Krawczyk, Agnieszka Nikiforuk, Anna Partyka, Magdalena Jastrzębska-Więsek, Klemencja Berghauzen-Maciejewska, Dominika Biała, Monika Janicka, Artur Janusz, Radosław Piast, Krzysztof Mulewski, Damian Smuga, Jerzy Pieczykolan, Maciej Wieczorek, Rafał Moszczyński-Pętkowski, Krzysztof Dubiel, Krystyna Ossowska, Andrzej J Bojarski, Krzysztof Kamiński, John D McCorvy, Piotr Popik","doi":"10.1016/j.jpet.2024.100055","DOIUrl":null,"url":null,"abstract":"<p><p>Parkinson's disease (PD) treatment focuses mainly on the augmentation of dopamine transmission, but to alleviate adverse motor effects accompanying L-DOPA use, additional treatments with serotonergic (5-HT) medications may be considered. We propose a novel concept based on the simultaneous activation of 5-HT<sub>1B</sub>R and 5-HT<sub>6</sub>R blockade as a putative therapeutic option for PD treatment. We have developed PZKKN-94, a dual human 5-HT<sub>1B</sub>R agonist (EC<sub>50</sub> = 39 nM) and human 5-HT<sub>6</sub>R antagonist (K<sub>B</sub> = 7.7 nM), with selectivity over 43 targets, favorable drug-like properties, and brain penetration. Importantly, PZKKN-94 potency was increased or retained at rat 5-HT<sub>1B</sub> and 5-HT<sub>6</sub> orthologs but not at mouse 5-HT<sub>6</sub>. Therefore, PZKKN-94 was tested in 2 rat disease models: haloperidol-induced catalepsy and 6-hydroxydopamine-induced sensorimotor deficits in rats, showing antiparkinsonian-like effects in both. Of note, PZKKN-94 did not affect the therapeutic effects of L-DOPA and attenuated L-DOPA-induced motor fluctuation (\"on-off\" phenomena) in the stepping and vibrissae tests. PZKKN-94 had no effect on L-DOPA-induced contralateral rotation, suggesting no impact on dopamine-mimetic medication effects. In addition, PZKKN-94 reversed scopolamine-, phencyclidine-, and aged-induced learning deficits in the rat novel object recognition test, increased cognitive flexibility in the attention set-shifting task, and displayed antidepressant-like actions in the forced swim test in rats. Our data suggest that dual-acting 5-HT<sub>1B</sub>R agonists/5-HT<sub>6</sub>R antagonists provide a novel therapeutic approach to alleviate both motor symptoms and accompanying cognitive and depression comorbidities in PD. Our present findings highlight the dual 5-HT<sub>1B</sub>R agonist/5-HT<sub>6</sub>R antagonist strategy to simultaneously spare L-DOPA's action and alleviate motor fluctuations related to L-DOPA treatment. SIGNIFICANCE STATEMENT: The commonly used L-DOPA-based medications for Parkinson's disease, though effective in alleviating initial disease states, are limited in long-term use due to the motor (dyskinesia and on-off phenomena) and nonmotor (psychotic-like) side effects. A novel nondopaminergic strategy for treatment of Parkinson's disease based on simultaneous activation of the 5-HT<sub>1B</sub> receptor and blockade of the 5-HT<sub>6</sub> receptor is proposed. The compound PZKKN-94 produces an antiparkinsonian-like effect and attenuates motor fluctuations, preserving the efficacy of L-DOPA. In addition, PZKKN-94 demonstrates procognitive and antidepressant-like properties.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 2","pages":"100055"},"PeriodicalIF":3.1000,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Pharmacology and Experimental Therapeutics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.jpet.2024.100055","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/12/9 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
Abstract
Parkinson's disease (PD) treatment focuses mainly on the augmentation of dopamine transmission, but to alleviate adverse motor effects accompanying L-DOPA use, additional treatments with serotonergic (5-HT) medications may be considered. We propose a novel concept based on the simultaneous activation of 5-HT1BR and 5-HT6R blockade as a putative therapeutic option for PD treatment. We have developed PZKKN-94, a dual human 5-HT1BR agonist (EC50 = 39 nM) and human 5-HT6R antagonist (KB = 7.7 nM), with selectivity over 43 targets, favorable drug-like properties, and brain penetration. Importantly, PZKKN-94 potency was increased or retained at rat 5-HT1B and 5-HT6 orthologs but not at mouse 5-HT6. Therefore, PZKKN-94 was tested in 2 rat disease models: haloperidol-induced catalepsy and 6-hydroxydopamine-induced sensorimotor deficits in rats, showing antiparkinsonian-like effects in both. Of note, PZKKN-94 did not affect the therapeutic effects of L-DOPA and attenuated L-DOPA-induced motor fluctuation ("on-off" phenomena) in the stepping and vibrissae tests. PZKKN-94 had no effect on L-DOPA-induced contralateral rotation, suggesting no impact on dopamine-mimetic medication effects. In addition, PZKKN-94 reversed scopolamine-, phencyclidine-, and aged-induced learning deficits in the rat novel object recognition test, increased cognitive flexibility in the attention set-shifting task, and displayed antidepressant-like actions in the forced swim test in rats. Our data suggest that dual-acting 5-HT1BR agonists/5-HT6R antagonists provide a novel therapeutic approach to alleviate both motor symptoms and accompanying cognitive and depression comorbidities in PD. Our present findings highlight the dual 5-HT1BR agonist/5-HT6R antagonist strategy to simultaneously spare L-DOPA's action and alleviate motor fluctuations related to L-DOPA treatment. SIGNIFICANCE STATEMENT: The commonly used L-DOPA-based medications for Parkinson's disease, though effective in alleviating initial disease states, are limited in long-term use due to the motor (dyskinesia and on-off phenomena) and nonmotor (psychotic-like) side effects. A novel nondopaminergic strategy for treatment of Parkinson's disease based on simultaneous activation of the 5-HT1B receptor and blockade of the 5-HT6 receptor is proposed. The compound PZKKN-94 produces an antiparkinsonian-like effect and attenuates motor fluctuations, preserving the efficacy of L-DOPA. In addition, PZKKN-94 demonstrates procognitive and antidepressant-like properties.
期刊介绍:
A leading research journal in the field of pharmacology published since 1909, JPET provides broad coverage of all aspects of the interactions of chemicals with biological systems, including autonomic, behavioral, cardiovascular, cellular, clinical, developmental, gastrointestinal, immuno-, neuro-, pulmonary, and renal pharmacology, as well as analgesics, drug abuse, metabolism and disposition, chemotherapy, and toxicology.