Biochemical and behavioral effects of PDE10A inhibitors: Relationship to target site occupancy

Li, Yuwen; Seager, Matthew A.; Wojcik, Trevor; Heman, Karen L.; Molski, Thaddeus F.; Fernandes, Alda; Langdon, Shaun; Pendri, Annapurna; Gerritz, Samuel W.; Tian, Yuan; Yang, Hong; Gallagher, Lizbeth; Merritt, J. Robert; Zhang, Chongwu; Westphal, Ryan S.; Zaczek, Robert; Macor, John E.; Bronson, Joanne J.; Lodge, Nicholas J.

doi:10.1016/j.neuropharm.2015.10.037

Cited by 17 publications

(5 citation statements)

References 49 publications

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“…However, even if this is not the case, PDE inhibition could still influence the overall signaling in a therapeutic direction. Currently, researchers are just beginning to unravel the precise subcellular localization and the role of functional compartmentalization in physiological and pathological conditions of the fronto-striatal circuits (e.g., PDE10A: Russwurm et al, 2015; Li et al, 2016b; MacMullen et al, 2016). Another important consideration is that, in general, PDE-I research involving fronto-striatal disorders is based on the classical view of basal ganglia direct and indirect pathway functioning.…”

Section: Resultsmentioning

confidence: 99%

Phosphodiesterase Inhibition and Regulation of Dopaminergic Frontal and Striatal Functioning: Clinical Implications

Heckman

Duinen

Bollen

et al. 2016

IJNPPY

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Background:The fronto-striatal circuits are the common neurobiological basis for neuropsychiatric disorders, including schizophrenia, Parkinson’s disease, Huntington’s disease, attention deficit hyperactivity disorder, obsessive-compulsive disorder, and Tourette’s syndrome. Fronto-striatal circuits consist of motor circuits, associative circuits, and limbic circuits. All circuits share 2 common features. First, all fronto-striatal circuits consist of hyper direct, direct, and indirect pathways. Second, all fronto-striatal circuits are modulated by dopamine. Intracellularly, the effect of dopamine is largely mediated through the cyclic adenosine monophosphate/protein kinase A signaling cascade with an additional role for the cyclic guanosine monophosphate/protein kinase G pathway, both of which can be regulated by phosphodiesterases. Phosphodiesterases are thus a potential target for pharmacological intervention in neuropsychiatric disorders related to dopaminergic regulation of fronto-striatal circuits.Methods:Clinical studies of the effects of different phosphodiesterase inhibitors on cognition, affect, and motor function in relation to the fronto-striatal circuits are reviewed.Results:Several selective phosphodiesterase inhibitors have positive effects on cognition, affect, and motor function in relation to the fronto-striatal circuits.Conclusion:Increased understanding of the subcellular localization and unraveling of the signalosome concept of phosphodiesterases including its function and dysfunction in the fronto-striatal circuits will contribute to the design of new specific inhibitors and enhance the potential of phosphodiesterase inhibitors as therapeutics in fronto-striatal circuits.

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Section: Resultsmentioning

confidence: 99%

Phosphodiesterase Inhibition and Regulation of Dopaminergic Frontal and Striatal Functioning: Clinical Implications

Heckman

Duinen

Bollen

et al. 2016

IJNPPY

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“…DSR-141562 does not induce any sign of catalepsy at even 100 mg/kg, which is a 33-times higher dose than the effective dose on methamphetamine-induced locomotor hyperactivity. This is quite in contrast to the concept that antipsychotic candidate PDE10A inhibitors typically operate within a narrow dose range because of extrapyramidal side effects in mice, rats, monkeys, and humans (Schmidt et al, 2008;Grauer et al, 2009;Uthayathas et al, 2014;Li et al, 2016b;Goldsmith et al, 2017). Since the extrapyramidal side effects were dose limiting in clinical studies with D 2 receptor antagonists and PDE10A inhibitors, the wide safety margin of the DSR-141562 dose for catalepsy would be of great benefit in schizophrenia treatment.…”

Section: Pde1 Inhibitor Is Effective In Schizophrenia Modelsmentioning

confidence: 89%

A Novel Phosphodiesterase 1 Inhibitor DSR-141562 Exhibits Efficacies in Animal Models for Positive, Negative, and Cognitive Symptoms Associated with Schizophrenia

Enomoto

Tatara

Goda

et al. 2019

J Pharmacol Exp Ther

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In our drug discovery program, we identified a novel orally available and brain-penetrant phosphodiesterase (PDE) 1 inhibitor, 3-methyl-7-(tetrahydro-2H-pyran-4-yl)-2-{[trans-4-(trifluoromethyl)cyclohexyl]-methoxy}imidazo[5,1-f][1,2,4]triazin-4(3H)-one (DSR-141562). In the present study, we characterized the preclinical profile of DSR-141562. This compound has preferential selectivity for predominantly brain-expressed PDE1B over other PDE1 family members, and high selectivity for the PDE1 family over other PDE families and 65 other tested biologic targets. Oral administration of DSR-141562 at 10 mg/kg slightly elevated the cGMP concentration, and it potently enhanced the increase of cGMP induced by a dopamine D 1 receptor agonist in mouse brains. The cGMP level in monkey cerebrospinal fluid was also elevated after treatment with DSR-141562 at 30 and 100 mg/kg and could be used as a translational biomarker. Since PDE1B is believed to regulate dopaminergic and glutamatergic signal transduction, we evaluated the effects of this compound using schizophreniarelated behavioral assays. DSR-141562 at 3-30 mg/kg potently inhibited methamphetamine-induced locomotor hyperactivity in rats, while it had only minimal effects on the spontaneous locomotor activity. Furthermore, DSR-141562 at 1-100 mg/kg did not induce any signs of catalepsy in rats. DSR-141562 at 0.3-3 mg/kg reversed social interaction and novel object recognition deficits induced by repeated treatment with an N-methyl-D-aspartate receptor antagonist, phencyclidine, in mice and rats, respectively. In common marmosets, DSR-141562 at 3 and 30 mg/kg improved the performance in object retrieval with detour tasks. These results suggest that DSR-141562 is a therapeutic candidate for positive, negative, and cognitive symptoms in schizophrenia. SIGNIFICANCE STATEMENT This is the first paper showing that a phosphodiesterase 1 inhibitor is efficacious in animal models for positive and negative symptoms associated with schizophrenia. Furthermore, we demonstrated that this compound improved cognitive function in the common marmoset, a nonhuman primate.

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“…Inhibitors of phosphodiesterase 10 (PDE10) have a preclinical profile consistent with possessing functional dopamine D 2 receptor antagonism (Grauer et al 2009) in the absence of any significant affinity for that receptor, and yet in clinical trials no beneficial antipsychotic action has been detected. Many laboratories working on this target have agreed that like all proven antipsychotics, all examples of PDE10 inhibitors inhibit conditioned active avoidance responses in rodents (Li et al 2016b). Fortunately, a clinically equivalent response suitable for use in a MRI scanner has now been designed (Gillan et al 2015) so this response could now be measured clinically, although we do not know whether the behaviour is deficient in schizophrenia.…”

Section: Principle 8: Learn and Reflectmentioning

confidence: 99%

Time to re-engage psychiatric drug discovery by strengthening confidence in preclinical psychopharmacology

et al. 2021

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Background There is urgent need for new medications for psychiatric disorders. Mental illness is expected to become the leading cause of disability worldwide by 2030. Yet, the last two decades have seen the pharmaceutical industry withdraw from psychiatric drug discovery after costly late-stage trial failures in which clinical efficacy predicted pre-clinically has not materialised, leading to a crisis in confidence in preclinical psychopharmacology. Methods Based on a review of the relevant literature, we formulated some principles for improving investment in translational neuroscience aimed at psychiatric drug discovery. Results We propose the following 8 principles that could be used, in various combinations, to enhance CNS drug discovery: (1) consider incorporating the NIMH Research Domain Criteria (RDoC) approach; (2) engage the power of translational and systems neuroscience approaches; (3) use disease-relevant experimental perturbations; (4) identify molecular targets via genomic analysis and patient-derived pluripotent stem cells; (5) embrace holistic neuroscience: a partnership with psychoneuroimmunology; (6) use translational measures of neuronal activation; (7) validate the reproducibility of findings by independent collaboration; and (8) learn and reflect. We provide recent examples of promising animal-to-human translation of drug discovery projects and highlight some that present re-purposing opportunities. Conclusions We hope that this review will re-awaken the pharma industry and mental health advocates to the opportunities for improving psychiatric pharmacotherapy and so restore confidence and justify re-investment in the field.

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Biochemical and behavioral effects of PDE10A inhibitors: Relationship to target site occupancy

Cited by 17 publications

References 49 publications

Phosphodiesterase Inhibition and Regulation of Dopaminergic Frontal and Striatal Functioning: Clinical Implications

Phosphodiesterase Inhibition and Regulation of Dopaminergic Frontal and Striatal Functioning: Clinical Implications

A Novel Phosphodiesterase 1 Inhibitor DSR-141562 Exhibits Efficacies in Animal Models for Positive, Negative, and Cognitive Symptoms Associated with Schizophrenia

Time to re-engage psychiatric drug discovery by strengthening confidence in preclinical psychopharmacology

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