vedomostiregmedРегуляторные исследования и экспертиза лекарственных средствRegulatory Research and Medicine Evaluation3034-30623034-3453Federal State Budgetary Institution ‘Scientific Centre for Expert Evaluation of Medicinal Products’ of the Ministry of Health of the Russian Federation (FSBI ‘SCEEMP’)10.30895/1991-2919-2025-723vedomostiregmed-723Research ArticleРАЗРАБОТКА ЛЕКАРСТВЕННЫХ СРЕДСТВ: ОТ ИДЕИ ДО ПРИМЕНЕНИЯPHARMACEUTICAL DEVELOPMENT: FROM AN IDEA TO THE FINAL P RODUCTФосфодиэстераза 10А как терапевтическая мишень в нейропсихофармакологии: обзорPhosphodiesterase 10A as a Therapeutic Target in Neuropsychopharmacology: A Reviewhttps://orcid.org/0000-0003-1142-6325ДоротенкоА. Р.DorotenkoA. R.

Доротенко Артем Романович

Ул. Льва Толстого, д. 6–8, Санкт-Петербург, 197022

Artem R. Dorotenko

6–8 Lev Tolstoy St., Saint Petersburg 197022

a.r.dorotenko@gmail.comhttps://orcid.org/0000-0001-9251-9923СухановИ. М.SukhanovI. M.

Суханов Илья Михайлович - д-р мед. наук.

Ул. Льва Толстого, д. 6–8, Санкт-Петербург, 197022

Ilya M. Sukhanov - Dr. Sci. (Med.)

6–8 Lev Tolstoy St., Saint Petersburg 197022

ilia.sukhanov@gmail.comhttps://orcid.org/0009-0009-9985-0286ИскаревскийГ. В.IskarevskiiG. V.

Искаревский Григорий Вячеславович 

Олимпийский просп., д. 1, Краснодарский край, федеральная территория «Сириус», 354340

Grigorii V. Iskarevskii

1 Olimpiysky Ave, Sirius Federal Territory 354340

esscar78@yandex.ruhttps://orcid.org/0000-0003-3011-1812УлитинаА. С.UlitinaA. S.

Улитина Анна Сергеевна - канд. мед. наук.

 Ул. Льва Толстого, д. 6–8, Санкт-Петербург, 197022; ул. Аккуратова, д. 2, Санкт-Петербург, 197341

Anna S. Ulitina - Cand. Sci. (Med.)

6–8 Lev Tolstoy St., St Petersburg 197022; 2 Akkuratov St., St Petersburg 197341

anna.s.ulitina@yandex.ruhttps://orcid.org/0000-0001-5851-9102СавченкоА. А.SavchenkoA. A.

Савченко Артем Алексеевич

Ул. Льва Толстого, д. 6–8, Санкт-Петербург, 197022

Artem A. Savchenko

6–8 Lev Tolstoy St., Saint Petersburg 197022

savcenkoartem334@gmail.comТурМ. А.TurM. А.

Тур Маргарита Алексеевна. Scopus: https://www.scopus.com/authid/detail.uri?authorId=57190949656

Ул. Льва Толстого, д. 6–8, Санкт-Петербург, 197022

Margarita А. Tur. Scopus: https://www.scopus.com/authid/detail.uri?authorId=57190949656

6–8 Lev Tolstoy St., Saint Petersburg 197022

vol4onok_07@mail.ruФедеральное государственное бюджетное образовательное учреждение высшего образования «Первый Санкт-Петербургский государственный медицинский университет имени академика И.П. Павлова» Министерства здравоохранения Российской ФедерацииРоссияAcademician I.P. Pavlov First St Petersburg State Medical UniversityRussian FederationАвтономная некоммерческая образовательная организация высшего образования «Научно-технологический университет «Сириус»РоссияSirius University of Science and TechnologyRussian FederationФедеральное государственное бюджетное образовательное учреждение высшего образования «Первый Санкт-Петербургский государственный медицинский университет имени академика И.П. Павлова» Министерства здравоохранения Российской Федерации; Федеральное государственное бюджетное учреждение «Национальный медицинский исследовательский центр имени В.А. Алмазова» Министерства здравоохранения Российской ФедерацииРоссияAcademician I.P. Pavlov First St Petersburg State Medical University; V.A. Almazov National Medical Research CenterRussian Federation202501052025152148167Copyright © Доротенко А.Р., Суханов И.М., Искаревский Г.В., Улитина А.С., Савченко А.А., Тур М.А., 20252025Доротенко А.Р., Суханов И.М., Искаревский Г.В., Улитина А.С., Савченко А.А., Тур М.А.Dorotenko A.R., Sukhanov I.M., Iskarevskii G.V., Ulitina A.S., Savchenko A.A., Tur M.А.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.vedomostincesmp.ru/jour/article/view/723ВВЕДЕНИЕ

ВВЕДЕНИЕ. Фосфодиэстеразы (ФДЭ) — ферменты, регулирующие внутриклеточный сигналинг путем гидролиза циклических нуклеотидов. Коммерческий успех селективных ингибиторов ФДЭ5 при эректильной дисфункции и ФДЭ4 при респираторных и кожных заболеваниях привлек пристальное внимание фармацевтических компаний и к другим ФДЭ. Отдельного внимания заслуживает ФДЭ10А — перспективная мишень в психофармакологии, для которой характерна экспрессия в среднеразмерных шипиковых нейронах (MSNs) полосатого тела.

ЦЕЛЬ

ЦЕЛЬ. Анализ существующих доклинических и клинических данных о применении ингибиторов ФДЭ10А и оценка возможных трудностей, возникающих при разработке лекарственных препаратов данного класса в нейропсихофармакологии.

ОБСУЖДЕНИЕ

ОБСУЖДЕНИЕ. Результаты доклинических исследований ингибиторов ФДЭ10А, повышающих уровень аденозин-3’,5’-циклофосфата (цАМФ) и гуанозин-3’,5’-циклофосфата (цГМФ) в MSNs, продемонстрировали, что фармакологические агенты данной группы обладают антипсихотическим и противопаркинсоническим, а также прокогнитивным действием. Несмотря на многообещающие результаты доклинических испытаний, клинические исследования ингибиторов ФДЭ10А не достигли успеха. В обзоре проанализированы возможные причины этих неудач, включая недостаточное понимание функции стриатальных ФДЭ в норме и патологии, потенциальное развитие толерантности к некоторым из эффектов, сложное взаимодействие внутриклеточных сигнальных путей цАМФ и цГМФ, а также особенности функционирования кортико-стриато-таламо-кортикальных путей.

ВЫВОДЫ

ВЫВОДЫ. Для полного раскрытия терапевтического потенциала ингибиторов ФДЭ10А необходимы дальнейшие исследования, направленные на более детальное изучение механизма действия ФДЭ, активности MSNs и кортико-стриато-таламо-кортикальных путей. Новые данные на всех этих трех уровнях изучения (субклеточный, клеточный и системный) позволят создать условия для дальнейшей разработки ингибиторов ФДЭ10А.

INTRODUCTION

INTRODUCTION. Phosphodiesterases (PDEs) are enzymes that regulate intracellular signalling by catalysing the hydrolysis of cyclic nucleotides. The commercial success of selective PDE5 inhibitors for erectile dysfunction and PDE4 inhibitors for respiratory and skin diseases has drawn the close attention of pharmaceutical companies to other PDEs as well. PDE10A, which is expressed in medium spiny neurons (MSNs) of the striatum, deserves special attention as a promising target in psychopharmacology.

AIM

AIM. This study aimed to analyse existing preclinical and clinical data on the use of PDE10A inhibitors and to assess possible barriers to the development of medicinal products of this class in neuropsychopharmacology.

DISCUSSION

DISCUSSION. Preclinical studies have shown that PDE10A inhibitors, which increase the levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in MSNs, have antipsychotic and antiparkinsonian properties. Some researchers also believe that PDE10A inhibitors improve cognitive functions. Despite the promising results of preclinical studies, clinical trials of PDE10A inhibitors have not been successful. This review analyses the possible reasons for these failures, including a poor understanding of the function of striatal PDEs in both normal and pathological conditions, the possible development of tolerance to some effects of PDEs, the complex interactions of intracellular cAMP and cGMP signalling pathways, and the intricate workings of the cortico-striato-thalamo-cortical (CSTC) circuits.

CONCLUSIONS

CONCLUSIONS. Further research is needed to fully assess the therapeutic potential of PDE10A inhibitors, with a more detailed investigation of the mechanism of action of PDEs, the activity of MSNs, and the CSTC circuits. New data at these three levels of study (subcellular, cellular, and systemic) will create conditions for further development of PDE10A inhibitors.

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The authors declare that there are no conflicts of interest present.