Phosphodiesterase 10A Inhibitors Research Articles

Inhibition of Phosphodiesterase 10A Alleviates Pain-like Behavior in Mice.

Emerging evidence indicates that cyclic nucleotide phosphodiesterases exert distinct functions in pain processing and that targeting phosphodiesterases might be a novel strategy for pain relief. This study hypothesized that the phosphodiesterase isoform PDE10A might be a target for analgesic therapy. In situ hybridization, immunostaining, cyclic nucleotide enzyme immunoassays, real-time cyclic guanosine monophosphate imaging, and real-time quantitative reverse transcription polymerase chain reaction were performed to investigate the expression and activity of PDE10A in the dorsal root ganglia and spinal cord. Mice of both sexes were assessed in multiple pain models after the administration of specific PDE10A inhibitors. PDE10A is distinctly expressed in nociceptive neurons in the dorsal root ganglia and spinal cord of mice. Incubation of cultured sensory neurons with the PDE10A inhibitor, TAK-063 (150 nM), increased cyclic guanosine monophosphate levels in enzyme immunoassays and real-time imaging at the single-cell level. Strikingly, treatment with TAK-063 (0.3 mg/kg intraperitoneal) ameliorated the pain-like behavior of female and male mice in models of acute nociceptive pain after intraplantar injection of capsaicin (mean ± SD; 8.87 ± 8.78 s [TAK-063] vs. 51.24 ± 36.36 s [vehicle], P = 0.020) or allyl isothiocyanate (2.46 ± 3.43 s [TAK-063] vs. 10.36 ± 4.87 s [vehicle]; P = 0.018). Furthermore, TAK-063 (0.3 mg/kg intraperitoneal) reduced established pain-like behavior in models of inflammatory pain induced by intraplantar injection of zymosan (Two-way ANOVA, group, F(1, 18) = 48.51, TAK-063 vs. vehicle; P ≤ 0.0001) or complete Freund's adjuvant (F(1, 14) = 46.10, TAK-063 vs. vehicle; P ≤ 0.0001), without the development of antinociceptive tolerance. The antinociceptive effects were recapitulated using the PDE10A inhibitor PF-2545920. Collectively, our data support the idea that PDE10A is a suitable target for the development of efficacious analgesic drugs.

Preclinical Evaluation of MK-8189: A Novel Phosphodiesterase 10A Inhibitor for the Treatment of Schizophrenia.

MK-8189 is a novel phosphodiesterase 10A (PDE10A) inhibitor being evaluated in clinical studies for the treatment of schizophrenia. PDE10A is a cyclic nucleotide phosphodiesterase enzyme highly expressed in medium spiny neurons of the striatum. MK-8189 exhibits sub-nanomolar potency on the PDE10A enzyme and has excellent pharmaceutical properties. Oral administration of MK-8189 significantly increased cGMP and pGluR1 in rat striatal tissues. Activation of the dopamine D1 direct and D2 indirect pathways was demonstrated by detecting significant elevation of mRNA encoding substance P (Sub P) and enkephalin (ENK) after MK-8189 administration. The PDE10A tracer [3H]MK-8193 was used determine the PDE10A enzyme occupancy (EO) required for efficacy in behavioral models. In the rat conditioned avoidance responding assay, MK-8189 significantly decreased avoidance behavior at PDE10A EO greater than ~48%. MK-8189 significantly reversed an MK-801-induced deficit in pre-pulse inhibition at PDE10A EO of ~47% and higher. Target engagement of MK-8189 in rhesus monkeys was examined with [11C]MK-8193 in PET studies and plasma concentrations of 127nM MK-8189 yielded ~50% EO in the striatum. The impact of MK-8189 on cognitive symptoms was evaluated using the objective retrieval task in rhesus monkeys. MK-8189 significantly attenuated a ketamine-induced deficit in object retrieval performance at exposure that yielded ~29% PDE10A EO. These findings demonstrate the robust impact of MK-8189 on striatal signaling and efficacy in preclinical models of symptoms associated with schizophrenia. Data from these studies were used to establish the relationship between preclinical efficacy, plasma exposures, and PDE10A EO to guide dose selection of MK-8189 in clinical studies. Significance Statement We describe the primary pharmacology of MK-8189 a PDE10A inhibitor under evaluation for the treatment of schizophrenia. We report efficacy in preclinical models that have been used to characterize other PDE10A inhibitors and atypical antipsychotics. The PDE10A occupancy achieved by MK-8189 in behavioral studies was used to support dose selection in clinical trials. This work provides evidence to support exploration of higher levels of PDE10A occupancy in clinical trials to determine if this translates to improved efficacy in patients.

Inhibition of phosphodiesterase 10A mitigates neuronal injury by modulating apoptotic pathways in cold-induced traumatic brain injury

Brain injury develops from a complex series of pathophysiological phases, resulting in acute necrotic or delayed apoptotic cell death after traumatic brain injury (TBI). Inhibition of apoptotic cell death is critical for the treatment of acute neurodegenerative disorders, such as TBI. Here, we investigated the role of phosphodiesterase 10A (PDE10A) in the development of neuronal injury, particularly in apoptotic cell death. Using the PDE10A inhibitor TAK-063, we found that PDE10A inhibition is associated with decreased brain injury, brain swelling, and blood brain barrier disruption 48 h after cold-induced TBI. Furthermore, a particularly notable result was observed with 3 mg/kg TAK-063, which reduced disseminated neuronal injury. Protein abundance analysis revealed that PDE10A inhibition activates survival kinases AKT and ERK-1/-2, which were associated with the decreased activation of MMP-9 and PTEN. Additionally, iNOS and nNOS levels significantly reduced in the TAK-063 group, playing roles in inflammation and apoptosis. A planar surface immunoassay was performed for in-depth analyses of the apoptotic signaling pathways. We observed that inhibition of PDE10A resulted in the decreased expression of TNFRSF1A, TNFRSF10B, and TNFRSF6 receptors, particularly inducing apoptotic cell death. Moreover, these findings correlated with reduced levels of pro-apoptotic proteins, including PTEN, p27, Cytochrome-c, cleaved Caspase-3, Bad, and p53. Interestingly, TAK-063 treatment reduced levels of anti-apoptotic proteins or enzymes, including XIAP, Claspin, and HIF1α, without affecting Bcl-x, MCL-1, SMAC, HO-1, HO-2, HSP27, HSP60, and HSP70. The findings suggest that PDE10A regulates cellular signaling predominantly pro-apoptotic pathways, and inhibition of this protein is a promising approach for the treatment of acute brain injury.

PDE9A Inhibition Improves Coronary Microvascular Rarefaction and Left Ventricular Diastolic Dysfunction in the ZSF1 Rat Model of HFpEF.

Heart failure with preserved ejection fraction (HFpEF) commonly arises from comorbid diseases, such as hypertension, obesity, and diabetes mellitus. Selective inhibition of phosphodiesterase 9A (PDE9A) has emerged as a potential therapeutic approach for treating cardiometabolic diseases. Coronary microvascular disease (CMD) is one of the key mechanisms contributing to the development of left ventricular (LV) diastolic dysfunction in HFpEF. Our study aimed to investigate the mechanisms by which PDE9A inhibition could ameliorate CMD and improve LV diastolic function in HFpEF. The obese diabetic Zucker fatty/spontaneously hypertensive heart failure F1 hybrid (ZSF1) rat model of HFpEF was employed in which it was found that a progressively developing coronary microvascular rarefaction is associated with LV diastolic dysfunction when compared to lean, nondiabetic hypertensive controls. Obese ZSF1 rats had an increased cardiac expression of PDE9A. Treatment of obese ZSF1 rats with the selective PDE9A inhibitor, PF04447943 (3 mg/kg/day, oral gavage for 2 weeks), improved coronary microvascular rarefaction and LV diastolic dysfunction, which was accompanied by reduced levels of oxidative and nitrosative stress markers, hydrogen peroxide, and 3-nitrotyrosine. Liquid chromatography-mass spectrometry (LC-MS) proteomic analysis identified peroxiredoxins (PRDX) as downregulated antioxidants in the heart of obese ZSF1 rats, whereas Western immunoblots showed that the protein level of PRDX5 was significantly increased by the PF04447943 treatment. Thus, in the ZSF1 rat model of human HFpEF, PDE9A inhibition improves coronary vascular rarefaction and LV diastolic dysfunction, demonstrating the usefulness of PDE9A inhibitors in ameliorating CMD and LV diastolic dysfunction through augmenting PRDX-dependent antioxidant mechanisms.

Structural insight into the lead identification of a dual inhibitor of PDE1B and PDE10A: Integrating pharmacophore-based virtual screening, molecular docking, and structure-activity-relationship approaches

Schizophrenia is a chronic neuropsychiatric disorder affecting more than 1% of the world's population. Current antipsychotic treatments show inadequacy in mitigating the negative and cognitive symptoms of schizophrenia. In addition, these medications cause undesirable extrapyramidal side effects. According to the studies, inhibition of phosphodiesterase (PDE) 1B and PDE10A simultaneously can alleviate positive, negative, and cognitive symptoms of schizophrenia. Thus, this study aims to identify new dual inhibitors of PDE1B and PDE10A using ligand-based pharmacophore modelling, virtual screening, and molecular docking studies. Accordingly, the generated pharmacophore models of PDE1B and PDE10A comprised hydrogen bond acceptor, aromatic ring, and hydrophobic features. These features were essential for retrieving the active hits from the Universal Natural Product Database in the virtual screening. Additional filters were subsequently employed to identify potential hits that could be developed into central nervous system-active compounds. Hits meeting all the screening criteria were subjected to docking studies with PDE1B and PDE10A. Among these hits, UNPD167314 exhibited significant binding affinities for the target receptors. It occupied the P-clamp and displayed hydrophobic, aromatic, and hydrogen bond interactions with the active site residues of both receptors, thus selected as a lead compound for the design of potent and selective dual inhibitors. The structural modifications of UNPD167314 resulted in the design of 35 novel inhibitors. Out of 35, four compounds exhibited high and comparable binding affinities for both PDE1B and PDE10A, making them promising candidates for further evaluation and optimisation.

Increased cGMP improves microvascular exercise training adaptations independent of endothelial nitric oxide synthase.

Impaired microvascular function is a hallmark of pre-diabetes. With development of atherosclerosis this impaired microvascular function can result in diminished capacity for ambulation and is a risk factor for Type 2 Diabetes. Dynamic changes in vascular tone are determined, in large part, by the eNOS/NO/cGMP axis. We used gain of function of the eNOS/NO/cGMP axis in diet-induced obese (DIO) mice and reduced function in lean mice to test the hypothesis that functionality of this vascular control mechanism parallels the benefits of an exercise training regimen. DIO mice have lower exercise capacity than lean mice and were used for pharmacological gain of function. The PDE-5a inhibitor - sildenafil - increases cGMP and was administered to DIO mice daily. In sedentary mice, we find that sildenafil does not improve exercise capacity. In contrast, it amplifies the microcirculatory effects of exercise training. Sildenafil synergizes with exercise training to improve performance during an incremental exercise test. Improved exercise performance was accompanied by increased skeletal muscle capillary flow velocity and capillary density measured via intravital microscopy. Loss of function was tested in lean mice hemizygous for endothelial cell (EC) specific eNOS creating an EC-eNOS knockdown (KD). EC-eNOS KD decreases capillary density and exercise tolerance in sedentary mice; however, it did not prevent exercise-training induced improvements in endurance capacity. These data show that 1) increasing cGMP with sildenafil enhances microcirculatory function and exercise work tolerance that results from training; 2) eNOS KD does not prevent the microcirculatory or improvements in exercise tolerance with training. PDE-5a inhibitors combined with physical exercise are a potential mechanism for improving ambulation in patients with circulatory limitations.

Exploring dimethoxy naphthalenyl methoxyphenyl quinazolinyl amine as a PDE10A inhibitor: In-silico studies, synthesis and binding interactions with serum albumin

Phosphodiesterase 10A (PDE10A) inhibitors stand out as key players in the quest for effective treatments against neurological disorders. Among them, Papaverine has gained attention for its ability to activate striatal output, hinting at potential antipsychotic properties. A thorough computational analysis of 28 alkoxy quinazoline derivatives derived from Papaverine led to the discovery of Dimethoxynaphthalenyl methoxyphenyl quinazolinyl amine (QPhN), addressing its exceptional docking score (-27.71) and binding energy (−44 kJ/mol). The main contributors of this binding were Gln716 and Phe719. Absorption, Distribution, Metabolism, Excretion (ADME) and Toxicity analysis predicted its drug likeness, bioavailability and highest CNS scoring (0.0409). Notably, its synthesis involved two-step process, first cyclic addition of dimethoxy quinazolinyl chloride and dioxaborolanyl phenol took place along with alkylation with bromomethyl naphthalene. To better understand the ADME profile of QPhN, its interaction with serum albumin (SA) was analyzed with the help of Photo physical studies. Fluorescence emission of SA was quenched to reveal the subtle shifts (distinct red shift of around 20 nm) in the protein’s microenvironment. Through static quenching analysis, a binding constant value in the range (K = 104 M−1) underscored the prevalence of non-covalent interactions between QPhN and SA with involvement of one binding site. Additionally, the interaction between QPhN and SA was enthalpically and entropically compelled to sub domain IIA with ΔH (−72.2 kJ/mol), ΔS (−210.37 J mol−1 K−1) and ΔG (−9.62 kJ/mol) values. The binding represents weak perturbation (1–3 %) of α-helix content of SA with increasing concentration of QPhN. The study highlighted the importance of QPhN as a promising marker for PDE10A.

Phosphodiesterase 9A inhibition improves aging-related increase in pulmonary vascular resistance in mice.

As individuals age, there is a gradual decline in cardiopulmonary function, often accompanied by cardiac pump dysfunction leading to increased pulmonary vascular resistance (PVR). Our study aims to investigate the changes in cardiac and pulmonary vascular function associated with aging. Additionally, we aim to explore the impact of phosphodiesterase 9A (PDE9A) inhibition, which has shown promise in treating cardiometabolic diseases, on addressing left ventricle (LV) dysfunction and elevated PVR in aging individuals. Young (3 months old) and aged (32 months old) male C57BL/6 mice were used. Aged mice were treated with the selective PDE9A inhibitor PF04447943 (1 mg/kg/day) through intraperitoneal injections for 10 days. LV function was evaluated using cardiac ultrasound, and PVR was assessed in isolated, ventilated lungs perfused under a constant flow condition. Additionally, changes in PVR were measured in response to perfusion of the endothelium-dependent agonist bradykinin or to nitric oxide (NO) donor sodium nitroprusside (SNP). PDE9A protein expression was measured by Western blots. Our results demonstrate the development of LV diastolic dysfunction and increased PVR in aged mice. The aged mice exhibited diminished decreases in PVR in response to both bradykinin and SNP compared to the young mice. Moreover, the lungs of aged mice showed an increase in PDE9A protein expression. Treatment of aged mice with PF04447943 had no significant effect on LV systolic or diastolic function. However, PF04447943 treatment normalized PVR and SNP-induced responses, though it did not affect the bradykinin response. These data demonstrate a development of LV diastolic dysfunction and increase in PVR in aged mice. We propose that inhibitors of PDE9A could represent a novel therapeutic approach to specifically prevent aging-related pulmonary dysfunction.

A novel phosphodiesterase inhibitor for the treatment of chronic liver injury and metabolic diseases.

Chronic liver disease (CLD) leads to approximately two million deaths annually. Cyclic adenosine monophosphate (cAMP) signaling has long been studied in liver injury, particularly in the regulation of fatty acid (FA) β-oxidation and pro-inflammatory polarization of tissue-resident lymphocytes. Phosphodiesterase 4B (PDE4B) inhibition has been explored as a therapeutic modality, but these drugs have had limited success and are known to cause significant adverse effects. The PDE4 inhibitor 2-(4-([2-(5-Chlorothiophen-2-yl)-5-ethyl-6-methylpyrimidin-4-yl]amino)phenyl)acetic acid) (known as A-33) has yet to be explored for the treatment of metabolic diseases. Herein, we evaluated the efficacy of A-33 in the treatment of animal models of alcohol-associated liver disease (ALD) and steatotic liver disease (SLD). We demonstrated that A-33 effectively ameliorated the signs and symptoms of CLD, resulting in significant decreases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, decreased overall fat and collagen deposition in the liver, decreased intrahepatic triglyceride (TG) concentrations, and normalized expression of genes related to β-oxidation of fatty acids, inflammation, and extracellular matrix (ECM) deposition. We also designed and synthesized a novel analog of A-33, termed MDL3, which inhibited both PDE4B and PDE5A and was more effective in ameliorating pathophysiological signs and symptoms of liver injury and inflammation. In addition, MDL3 re-sensitized obese mice to glucose and significantly inhibited the pathological remodeling of adipose tissue, which was not observed with A-33 administration. In conclusion, we synthesized and demonstrated that MDL3, a novel PDE4B and PDE5A inhibitor, presents a promising avenue of exploration for treating CLD.

Reversed-phase thin-layer chromatography and ultra-performance liquid chromatography/mass spectrometry to estimate the drug likeness of phosphodiesterase 10A inhibitors with phthalimide core

Lipophilicity is a physicochemical parameter well known as a decisive factor for predicting the successful development of a drug. Thus, a balance between potency and physicochemical properties during medicinal chemistry optimization is needed. In this study, the lipophilicity of isoindole-1,3(2H)-dione derivatives designed as phosphodiesterase 10A (PDE10A) inhibitors was determined by chromatographic [reversed-phase thin-layer chromatography (RP-TLC) and ultra-performance liquid chromatography/mass spectrometry (UPLC/MS)] and in silico methods. To assess the correlation between the obtained lipophilicity parameters, principal component analysis (PCA) was performed. logP values obtained by chromatographic (logPRP-TLC and logPUPLC/MS) and in silico methods were compared using the PCA method. The results of PCA revealed that logPUPLC/MS and in silico clogP provided by the ChemDraw program were highly correlated. Compounds’ drug likeness was screened, and the pharmacokinetic properties were predicted. All the investigated compounds displayed drug-likeness properties, and they met the criteria of Lipinski’s rule of five, which predicted the oral bioavailability of drug candidates. Analysis of the influence of physicochemical properties on the biological activity showed that the compounds with increased potency on PDE10A had significantly higher topological polar surface area (TPSA) values. The blood‒brain barrier permeability and the hemolytic activity of model compound 18 were examined. The model compound 18 displayed no toxicity effect on erythrocytes in the hemolytic assay and good parallel artificial membrane permeability. The results showed that phthalimide compounds with benzimidazole moiety are a source of compound-targeted inhibition of PDE10A with balanced physicochemical and drug-likeness properties.

Abstract 146: Phosphodiesterase 10A Mediates Arterial Calcification Through A P38/MAPK-MMP3 Signaling

Background: Vascular calcification is prevalent in patients with atherosclerosis, chronic kidney disease (CKD), diabetes, and peripheral artery disease (PAD). When located in the arterial media, it is strongly associated with increased cardiovascular morbidity and mortality. The cyclic nucleotides cAMP and cGMP play important regulatory roles in a variety of human diseases that are controlled by distinct phosphodiesterase (PDE) isozymes. We have recently found that PDE10A is the most highly induced isoform in a rodent model of arterial calcification. The function and underlying mechanisms of PDE10A in medial artery calcification, however, remain unknown. Methods: Vascular smooth muscle cell (VSMC) calcification was mediated by a high phosphate media. Medial artery calcification was induced by vitamin D 3 injection and 5/6 nephrectomy calcification models. Vascular calcification was assessed by calcium assay and Von Kossa staining. Results: PDE10A was markedly increased in calcifying VSMCs in vitro , calcified arteries in vivo , and calcified human tibial arteries from patients with PAD. Knockdown or inhibition of PDE10A markedly attenuated phosphate-induced VSMC osteogenic transformation and calcification in VSMCs. Conversely, overexpression of PDE10A increased VSMC calcification. Deficiency and inhibition of PDE10A significantly decreased arterial calcification in vivo . Several labs including our own have demonstrated that matrix metallopeptidases (MMPs) are involved in vascular calcification. Using bioinformatics analysis and loss-of-function strategy, we found that MMP-3 could be regulated by PDE10A in calcifying VSMCs. Our further mechanistic studies showed that knockdown or inhibition of PDE10A decreased activated p38 MAPK and that inhibition of p38 MAPK attenuated MMP-3 upregulation under a calcifying condition. These data suggest that PDE10A mediates arterial calcification through a p38 MAPK-MMP-3 signaling pathway. Conclusion: PDE10A is a key regulator in the development of medial artery calcification. Our findings provide insight into the use of PDE10A inhibition strategies to reduce arterial calcification in patients with CKD and PAD.

Discovery of 3-trifluoromethyl-substituted pyrazoles as selective phosphodiesterase 10A inhibitors for orally attenuating isoprenaline-induced cardiac hypertrophy

Recently, MP-10, a previous drug candidate with potent inhibition of phosphodiesterase 10A (PDE10A) in clinical phase II trials for schizophrenia or Alzheimer's disease, has shown significant potential in preventing and treating cardiovascular diseases. However, its poor metabolic stability and high permeability across the blood-brain barrier (BBB) make it unsuitable for preventing and treating peripheral cardiovascular diseases. Herein, the hit-to-lead optimization was performed to discover novel 3-trifluoromethyl-substituted pyrazole derivatives as potent and selective PDE10A inhibitors. The structure-activity relationships, biological characterization, molecular mechanism, and drug-like evaluation were discussed to identify compound C7 which showed potent inhibition against PDE10A (half maximal inhibitory concentration, IC50 = 11.9 nmol/L), more than 840-fold selectivity over other PDE subtypes, enhanced liver microsomes stability (T1/2 = 239 min) compared to MP-10 and low BBB permeability. Importantly, oral pretreatment with C7·3HCl at a dose of 5.0 mg/kg significantly attenuated the pathological and functional changes induced by isoprenaline (ISO)-induced pathological cardiac hypertrophy in mice, particularly suppressing increase of cardiac weight, atrial natriuretic peptide (ANP) and β-myosin heavy chain (β-MHC) hypertrophic markers along with cardiac fibrosis. These findings further support that targeting PDE10A provides an innovative therapeutic approach for preventing and treating cardiac diseases.

Identification of Novel Quinolone and Quinazoline Alkaloids as Phosphodiesterase 10A Inhibitors for Parkinson's Disease through a Computational Approach.

Phosphodiesterases (PDEs) are vital in signal transduction, specifically by hydrolyzing cAMP and cGMP. Within the PDE family, PDE10A is notable for its prominence in the striatum and its regulatory function over neurotransmitters in medium-spiny neurons. Given the dopamine deficiency in Parkinson's disease (PD) that affects striatal pathways, PDE10A inhibitors could offer therapeutic benefits by modulating D1 and D2 receptor signaling. This study was motivated by the successful history of quinazoline/quinazoline scaffolds in the inhibition of PDE10A. This study involved detailed in silico evaluations through docking followed by pharmacological, pharmacophoric, and pharmacokinetic analyses, prioritizing central nervous system (CNS)-active drug criteria. Seven cyclic peptides, those featuring the quinazoline/quinazoline moiety at both termini, exhibited notably enhanced docking scores compared to those of the remaining alkaloids within the screened library. We identified 7 quinolines and 1 quinazoline including Lepadin G, Aspernigerin, CJ-13536, Aurachin A, 2-Undecyl-4(1H)-quinolone, Huajiaosimuline 3-Prenyl-4-prenyloxyquinolin-2-one, and Isaindigotone that followed the standard CNS active drug criteria. The dominant quinoline ring in our study and its related quinazoline were central to our evaluations; therefore, the pharmacophoric features of these scaffolds were highlighted. The top alkaloids met all CNS-active drug properties; while nonmutagenic and without PAINS alerts, many indicated potential hepatotoxicity. Among the compounds, Huajiaosimuline was particularly significant due to its alignment with lead-likeness and CNS-active criteria. Aspernigerin demonstrated its affinity for numerous dopamine receptors, which signifies its potential to alter dopaminergic neurotransmission that is directly related to PD. Interestingly, the majority of these alkaloids had biological targets primarily associated with G protein-coupled receptors, critical in PD pathophysiology. They exhibit superior excretion parameters and toxicity end-points compared to the standard. Notably, selected alkaloids demonstrated stability in the binding pocket of PDE10A according to the molecular dynamic simulation results. Our findings emphasize the potential of these alkaloids as PDE10A inhibitors. Further experimental studies may be necessary to confirm their actual potency in inhibiting PDE10A before exploring their therapeutic potential in PD.

Trifluoromethyl Rhodium-Carbynoid in [2+1+2] Cycloadditions.

Trifluoromethyl cationic carbyne (CF3 C+ :) possessing dual carbene-carbocation behavior emulated as trifluoromethyl metal-carbynoid (CF3 C+ =M) has not been explored yet, and its reaction characteristics are unknown. Herein, a novel α-diazotrifluoroethyl sulfonium salt was prepared and used in Rh-catalyzed three-component [2+1+2] cycloadditions for the first time with commercially available N-fused heteroarenes and nitriles, yielding a series of imidazo[1,5-a] N-heterocycles that are of interest in medicinal chemistry, in which the insertion of trifluoromethyl Rh-carbynoid (CF3 C+ =Rh) into C=N bonds of N-fused heteroarenes was involved. This strategy demonstrates synthetic applications in late-stage modification of pharmaceuticals, construction of CD3 -containing N-heterocycles, gram-scale experiments, and synthesis of phosphodiesterase 10A inhibitor analog. These highly valuable and modifiable imidazo[1,5-a] N-heterocycles exhibit good antitumor activity in vitro, thus demonstrating their potential applications in medicinal chemistry.

Trifluoromethyl Rhodium‐Carbynoid in [2+1+2] Cycloadditions

AbstractTrifluoromethyl cationic carbyne (CF3C+:) possessing dual carbene‐carbocation behavior emulated as trifluoromethyl metal‐carbynoid (CF3C+=M) has not been explored yet, and its reaction characteristics are unknown. Herein, a novel α‐diazotrifluoroethyl sulfonium salt was prepared and used in Rh‐catalyzed three‐component [2+1+2] cycloadditions for the first time with commercially available N‐fused heteroarenes and nitriles, yielding a series of imidazo[1,5‐a] N‐heterocycles that are of interest in medicinal chemistry, in which the insertion of trifluoromethyl Rh‐carbynoid (CF3C+=Rh) into C=N bonds of N‐fused heteroarenes was involved. This strategy demonstrates synthetic applications in late‐stage modification of pharmaceuticals, construction of CD3‐containing N‐heterocycles, gram‐scale experiments, and synthesis of phosphodiesterase 10A inhibitor analog. These highly valuable and modifiable imidazo[1,5‐a] N‐heterocycles exhibit good antitumor activity in vitro, thus demonstrating their potential applications in medicinal chemistry.

Effects of the Phosphodiesterase 10A Inhibitor MR1916 on Alcohol Self-Administration and Striatal Gene Expression in Post-Chronic Intermittent Ethanol-Exposed Rats.

Alcohol use disorder (AUD) requires new neurobiological targets. Problematic drinking involves underactive indirect pathway medium spiny neurons (iMSNs) that subserve adaptive behavioral selection vs. overactive direct pathway MSNs (dMSNs) that promote drinking, with a shift from ventromedial to dorsolateral striatal (VMS, DLS) control of EtOH-related behavior. We hypothesized that inhibiting phosphodiesterase 10A (PDE10A), enriched in striatal MSNs, would reduce EtOH self-administration in rats with a history of chronic intermittent ethanol exposure. To test this, Wistar rats (n = 10/sex) with a history of chronic intermittent EtOH (CIE) vapor exposure received MR1916 (i.p., 0, 0.05, 0.1, 0.2, and 0.4 µmol/kg), a PDE10A inhibitor, before operant EtOH self-administration sessions. We determined whether MR1916 altered the expression of MSN markers (Pde10a, Drd1, Drd2, Penk, and Tac1) and immediate-early genes (IEG) (Fos, Fosb, ΔFosb, and Egr1) in EtOH-naïve (n = 5-6/grp) and post-CIE (n = 6-8/grp) rats. MR1916 reduced the EtOH self-administration of high-drinking, post-CIE males, but increased it at a low, but not higher, doses, in females and low-drinking males. MR1916 increased Egr1, Fos, and FosB in the DLS, modulated by sex and alcohol history. MR1916 elicited dMSN vs. iMSN markers differently in ethanol-naïve vs. post-CIE rats. High-drinking, post-CIE males showed higher DLS Drd1 and VMS IEG expression. Our results implicate a role and potential striatal bases of PDE10A inhibitors to influence post-dependent drinking.

Tolerance to paradoxical increase in motor activity caused by inhibition of phosphodiesterase 10a in a model of hypodopaminergy

Tolerance to paradoxical increase in motor activity caused by inhibition of phosphodiesterase 10a in a model of hypodopaminergy

Association Analysis of Common Structural Variants in the Alzheimer’s Disease Sequencing Project

AbstractBackgroundStructural variants (SV), genomic rearrangements of >50 base pairs, are an important source of genetic variation and have a great impact on gene expression and protein function. However, their contribution to the genetic architecture of Alzheimer’s Disease (AD) has not been comprehensively investigated. Identification of SVs by short‐read alignment can be inaccurate and biased. We used a novel SV calling pipeline that leverages assembly‐based methods and graph‐based representation, to identify SVs with high accuracy in the diverse sample of the Alzheimer’s Disease Sequencing Project (ADSP). We further examined the association of common SVs with AD.MethodsWe applied Biograph for SV calling on the ADSP 17K whole genome sequence data. After filtering out low‐quality SVs and performing sample‐level quality control, we identified 222,956 deletions, 177,139 insertions, and 10,558 inversions in 12,908 individuals (6,304 AD cases; 6,604 controls). We performed association analyses of common SVs (MAF > 1%) with AD using a logistic mixed‐effects model adjusting for sex, technical covariates, principal components, and relatedness. Statistical significance was evaluated using a Bonferroni‐corrected threshold (P< 9.19.x10−7).ResultsThere were 28,634 deletions, 25,522 insertions, and 198 inversions with MAF > 1%. We identified 2 intronic deletions significantly associated with AD. The first deletion is located in CCDC88B, encoding a protein that regulates T‐cell maturation and inflammation. The second deletion is located in CCDC11, predicted to be part of the spliceosomal complex. Among 11 insertions significantly associated with AD, 3 mapped to exonic sequences. A relatively common insertion located in an exon of FOXO6 showed the most significant association with AD (P = 1.41×10−12). FOXO6 is a member of Forkhead transcription factors that have been implicated in aging. Along with its high level of expression in the hippocampus, mice lacking FOXO6 had impaired memory consolidation. We identified one inversion suggestively associated with AD (P = 3.32×10−6) and located in an intron of PDE5A. PDE5A inhibitors have been reported as potential therapeutic targets for AD.ConclusionUsing novel data structures and algorithms to call SV, we discovered 14 SVs significantly associated with AD. Validation and gene prioritization of these findings are warranted.

Prediction of molecular interaction of Phosphodiesterase 10A inhibition by natural compounds: insights from structure-based screening and molecular dynamics simulations

Phosphodiesterase 10 A (PDE10A) is an enzyme that regulates cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) levels in the brain, particularly in the striatum, which plays a critical role in movement control and reward processing. Inhibition of PDE10A can increase cAMP and cGMP levels, improving neuronal signaling and reducing symptoms of neuropsychiatric disorders such as schizophrenia, Huntington’s disease, and Parkinson’s disease. In this study, a structure-based virtual screening was conducted to identify potential anti-neuropsychiatric disorders compounds from phytoconstituents in the IMPPAT database. The ligands were docked against PDE10A, resulting in 40 compounds with appreciable docking scores. These 40 compounds underwent further ADMET predictions and drug likeliness, resulting in five potential compounds. Finally, based on the specific interactions, two compounds (Colladonin and Isopongachromene), were subjected to molecular dynamics (MD) simulation and MM-PBSA studies. The MM-PBSA analysis validated and captured the intermolecular interactions, indicating that Colladonin and Isopongachromene had appreciable binding affinities of −155.60 kJ.mol−1 and −108.28 kJ.mol−1, respectively and were promising candidates against neuropsychiatric disorders, targeting PDE10A. Overall, this study provides insight into the potential of PDE10A inhibitors as therapeutic agents for treating neuropsychiatric disorders, and Colladonin and Isopongachromene are promising compounds for further development. Communicated by Ramaswamy H. Sarma

Identification of selective inhibitors for phosphodiesterase 5A using e-pharmacophore modelling and large-scale virtual screening-based structure guided drug discovery approaches

The inhibition of Phosphodiesterase 5A (PDEA5) has the potential to modulate pulmonary arterial hypertension and cardiovascular diseases. Exploring the cross-reactivity of clinically available PDE5A therapeutics with PDE6A is intriguing in order to develop highly selective PDE5A compounds in cardiovascular arena. In the current study, we leveraged e-pharmacophore based screening and molecular dynamics (MD) simulation to discover more selective PDE5A inhibitors as compared to the PDE6A catalytic domain. e-Pharmacophore based mapping of the CoCoCo database (7 million compounds: ∼ 150,000,000 conformers), followed by Glide docking, MM-GBSA, and protein–inhibitor interaction analysis, revealed 1536427, 4832637 and 6788240 as stable, tight binders of PDE5A instead of PDE6A. These compounds adhere to Lipinski Rule of Five (RO5) and ADME/Tox criteria. MD simulations analysis showed that 1536427 stays stable and tightly binds to catalytic (Q-region) core of PDE5A catalytic domain as compared to sildenafil. Pronounced inward motions of the hydrophobic (H-region) and Lid region indicate the closure of PDE5A-1536427 complex, whereas this region in PDE6A-1536427 is more open. Significant differences in the interactions, stability, and dynamics of 1536427 were observed in the catalytic domain of PDE6A, demonstrating less specificity for PDE6A in comparison to PDE5A. After lead optimization and therapeutic interventions, this proposed lead may emerge as a promising PDE5A selective inhibitor. Communicated by Ramaswamy H. Sarma