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A PDE10A inhibitor CPL500036 is a novel agent modulating striatal function devoid of most neuroleptic side-effects

Background: Phosphodiesterase 10A (PDE10A) is expressed almost exclusively in the striatum and its inhibition is suggested to offer potential treatment in disorders associated with basal ganglia. We evaluated the selectivity, cytotoxicity, genotoxicity, pharmacokinetics and potential adverse effects...

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Autores principales: Matloka, Mikolaj, Janowska, Sylwia, Pankiewicz, Piotr, Kokhanovska, Sofiya, Kos, Tomasz, Hołuj, Małgorzata, Rutkowska-Wlodarczyk, Izabela, Abramski, Krzysztof, Janicka, Monika, Jakubowski, Piotr, Świątkiewicz, Maciej, Welniak-Kaminska, Marlena, Hucz-Kalitowska, Joanna, Dera, Paulina, Bojarski, Lukasz, Grieb, Paweł, Popik, Piotr, Wieczorek, Maciej, Pieczykolan, Jerzy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9681820/
https://www.ncbi.nlm.nih.gov/pubmed/36438799
http://dx.doi.org/10.3389/fphar.2022.999685
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author Matloka, Mikolaj
Janowska, Sylwia
Pankiewicz, Piotr
Kokhanovska, Sofiya
Kos, Tomasz
Hołuj, Małgorzata
Rutkowska-Wlodarczyk, Izabela
Abramski, Krzysztof
Janicka, Monika
Jakubowski, Piotr
Świątkiewicz, Maciej
Welniak-Kaminska, Marlena
Hucz-Kalitowska, Joanna
Dera, Paulina
Bojarski, Lukasz
Grieb, Paweł
Popik, Piotr
Wieczorek, Maciej
Pieczykolan, Jerzy
author_facet Matloka, Mikolaj
Janowska, Sylwia
Pankiewicz, Piotr
Kokhanovska, Sofiya
Kos, Tomasz
Hołuj, Małgorzata
Rutkowska-Wlodarczyk, Izabela
Abramski, Krzysztof
Janicka, Monika
Jakubowski, Piotr
Świątkiewicz, Maciej
Welniak-Kaminska, Marlena
Hucz-Kalitowska, Joanna
Dera, Paulina
Bojarski, Lukasz
Grieb, Paweł
Popik, Piotr
Wieczorek, Maciej
Pieczykolan, Jerzy
author_sort Matloka, Mikolaj
collection PubMed
description Background: Phosphodiesterase 10A (PDE10A) is expressed almost exclusively in the striatum and its inhibition is suggested to offer potential treatment in disorders associated with basal ganglia. We evaluated the selectivity, cytotoxicity, genotoxicity, pharmacokinetics and potential adverse effects of a novel PDE10A inhibitor, CPL500036, in vivo. Methods: The potency of CPL500036 was demonstrated by microfluidic technology, and selectivity was investigated in a radioligand binding assay against 44 targets. Cardiotoxicity in vitro was evaluated in human ether-a-go-go related gene (hERG)-potassium channel-overexpressing cells by the patch-clamp method and by assessing key parameters in 3D cardiac spheroids. Cytotoxicity was determined in H1299, HepG2 and SH-SY5Y cell lines. The Ames test was used for genotoxicity analyses. During in vivo studies, CPL500036 was administered by oral gavage. CPL500036 exposure were determined by liquid chromatography–tandem mass spectrometry and plasma protein binding was assessed. The bar test was employed to assess catalepsy. Prolactin and glucose levels in rat blood were measured by ELISAs and glucometers, respectively. Cardiovascular safety in vivo was investigated in dogs using a telemetry method. Results: CPL500036 inhibited PDE10A at an IC(50) of 1 nM, and interacted only with the muscarinic M2 receptor as a negative allosteric modulator with an IC(50) of 9.2 µM. Despite inhibiting hERG tail current at an IC(25) of 3.2 μM, cardiovascular adverse effects were not observed in human cardiac 3D spheroids or in vivo. Cytotoxicity in vitro was observed only at > 60 μM and genotoxicity was not recorded during the Ames test. CPL500036 presented good bioavailability and penetration into the brain. CPL500036 elicited catalepsy at 0.6 mg/kg, but hyperprolactinemia or hyperglycemic effects were not observed in doses up to 3 mg/kg. Conclusion: CPL500036 is a potent, selective and orally bioavailable PDE10A inhibitor with a good safety profile distinct from marketed antipsychotics. CPL500036 may be a compelling drug candidate.
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spelling pubmed-96818202022-11-24 A PDE10A inhibitor CPL500036 is a novel agent modulating striatal function devoid of most neuroleptic side-effects Matloka, Mikolaj Janowska, Sylwia Pankiewicz, Piotr Kokhanovska, Sofiya Kos, Tomasz Hołuj, Małgorzata Rutkowska-Wlodarczyk, Izabela Abramski, Krzysztof Janicka, Monika Jakubowski, Piotr Świątkiewicz, Maciej Welniak-Kaminska, Marlena Hucz-Kalitowska, Joanna Dera, Paulina Bojarski, Lukasz Grieb, Paweł Popik, Piotr Wieczorek, Maciej Pieczykolan, Jerzy Front Pharmacol Pharmacology Background: Phosphodiesterase 10A (PDE10A) is expressed almost exclusively in the striatum and its inhibition is suggested to offer potential treatment in disorders associated with basal ganglia. We evaluated the selectivity, cytotoxicity, genotoxicity, pharmacokinetics and potential adverse effects of a novel PDE10A inhibitor, CPL500036, in vivo. Methods: The potency of CPL500036 was demonstrated by microfluidic technology, and selectivity was investigated in a radioligand binding assay against 44 targets. Cardiotoxicity in vitro was evaluated in human ether-a-go-go related gene (hERG)-potassium channel-overexpressing cells by the patch-clamp method and by assessing key parameters in 3D cardiac spheroids. Cytotoxicity was determined in H1299, HepG2 and SH-SY5Y cell lines. The Ames test was used for genotoxicity analyses. During in vivo studies, CPL500036 was administered by oral gavage. CPL500036 exposure were determined by liquid chromatography–tandem mass spectrometry and plasma protein binding was assessed. The bar test was employed to assess catalepsy. Prolactin and glucose levels in rat blood were measured by ELISAs and glucometers, respectively. Cardiovascular safety in vivo was investigated in dogs using a telemetry method. Results: CPL500036 inhibited PDE10A at an IC(50) of 1 nM, and interacted only with the muscarinic M2 receptor as a negative allosteric modulator with an IC(50) of 9.2 µM. Despite inhibiting hERG tail current at an IC(25) of 3.2 μM, cardiovascular adverse effects were not observed in human cardiac 3D spheroids or in vivo. Cytotoxicity in vitro was observed only at > 60 μM and genotoxicity was not recorded during the Ames test. CPL500036 presented good bioavailability and penetration into the brain. CPL500036 elicited catalepsy at 0.6 mg/kg, but hyperprolactinemia or hyperglycemic effects were not observed in doses up to 3 mg/kg. Conclusion: CPL500036 is a potent, selective and orally bioavailable PDE10A inhibitor with a good safety profile distinct from marketed antipsychotics. CPL500036 may be a compelling drug candidate. Frontiers Media S.A. 2022-11-09 /pmc/articles/PMC9681820/ /pubmed/36438799 http://dx.doi.org/10.3389/fphar.2022.999685 Text en Copyright © 2022 Matloka, Janowska, Pankiewicz, Kokhanovska, Kos, Hołuj, Rutkowska-Wlodarczyk, Abramski, Janicka, Jakubowski, Świątkiewicz, Welniak-Kaminska, Hucz-Kalitowska, Dera, Bojarski, Grieb, Popik, Wieczorek and Pieczykolan. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Matloka, Mikolaj
Janowska, Sylwia
Pankiewicz, Piotr
Kokhanovska, Sofiya
Kos, Tomasz
Hołuj, Małgorzata
Rutkowska-Wlodarczyk, Izabela
Abramski, Krzysztof
Janicka, Monika
Jakubowski, Piotr
Świątkiewicz, Maciej
Welniak-Kaminska, Marlena
Hucz-Kalitowska, Joanna
Dera, Paulina
Bojarski, Lukasz
Grieb, Paweł
Popik, Piotr
Wieczorek, Maciej
Pieczykolan, Jerzy
A PDE10A inhibitor CPL500036 is a novel agent modulating striatal function devoid of most neuroleptic side-effects
title A PDE10A inhibitor CPL500036 is a novel agent modulating striatal function devoid of most neuroleptic side-effects
title_full A PDE10A inhibitor CPL500036 is a novel agent modulating striatal function devoid of most neuroleptic side-effects
title_fullStr A PDE10A inhibitor CPL500036 is a novel agent modulating striatal function devoid of most neuroleptic side-effects
title_full_unstemmed A PDE10A inhibitor CPL500036 is a novel agent modulating striatal function devoid of most neuroleptic side-effects
title_short A PDE10A inhibitor CPL500036 is a novel agent modulating striatal function devoid of most neuroleptic side-effects
title_sort pde10a inhibitor cpl500036 is a novel agent modulating striatal function devoid of most neuroleptic side-effects
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9681820/
https://www.ncbi.nlm.nih.gov/pubmed/36438799
http://dx.doi.org/10.3389/fphar.2022.999685
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