Effective Techniques for Multimodal Data Fusion: A Comparative Analysis.

Data processing in robotics is currently challenged by the effective building of multimodal and common representations. Tremendous volumes of raw data are available and their smart management is the core concept of multimodal learning in a new paradigm for data fusion. Although several techniques for building multimodal representations have been proven successful, they have not yet been analyzed and compared in a given production setting. This paper explored three of the most common techniques, (1) the late fusion, (2) the early fusion, and (3) the sketch, and compared them in classification tasks. Our paper explored different types of data (modalities) that could be gathered by sensors serving a wide range of sensor applications. Our experiments were conducted on Amazon Reviews, MovieLens25M, and Movie-Lens1M datasets. Their outcomes allowed us to confirm that the choice of fusion technique for building multimodal representation is crucial to obtain the highest possible model performance resulting from the proper modality combination. Consequently, we designed criteria for choosing this optimal data fusion technique.

Structure-Based Design and Optimization of FPPQ, a Dual-Acting 5-HT3 and 5-HT6 Receptor Antagonist with Antipsychotic and Procognitive Properties.

In line with recent clinical trials demonstrating that ondansetron, a 5-HT3 receptor (5-HT3R) antagonist, ameliorates cognitive deficits of schizophrenia and the known procognitive effects of 5-HT6 receptor (5-HT6R) antagonists, we applied the hybridization strategy to design dual-acting 5-HT3/5-HT6R antagonists. We identified the first-in-class compound FPPQ, which behaves as a 5-HT3R antagonist and a neutral antagonist 5-HT6R of the Gs pathway. FPPQ shows selectivity over 87 targets and decent brain penetration. Likewise, FPPQ inhibits phencyclidine (PCP)-induced hyperactivity and displays procognitive properties in the novel object recognition task. In contrast to FPPQ, neither 5-HT6R inverse agonist SB399885 nor neutral 5-HT6R antagonist CPPQ reversed (PCP)-induced hyperactivity. Thus, combination of 5-HT3R antagonism and 5-HT6R antagonism, exemplified by FPPQ, contributes to alleviating the positive-like symptoms. Present findings reveal critical structural features useful in a rational polypharmacological approach to target 5-HT3/5-HT6 receptors and encourage further studies on dual-acting 5-HT3/5-HT6R antagonists for the treatment of psychiatric disorders.

Estimation of the lipophilicity of purine-2,6-dione-based TRPA1 antagonists and PDE4/7 inhibitors with analgesic activity.

Lipophilicity is one of the principal QSAR parameters which influences among others the pharmacodynamics and pharmacokinetic properties of a drug candidates. In this paper, the lipophilicity of 14 amide derivatives of 1,3-dimethyl-2,6-dioxopurin-7-yl-alkylcarboxylic acids as multifunctional TRPA1 channel antagonists and phosphodiesterase 4/7 inhibitors with analgesic activity were investigated, using reversed-phase thin-layer chromatography method. It was observed that the retention behavior of the analyzed compounds was dependent on their structural features i.e. an aliphatic linker length, a kind of substituent at 8 position of purine-2,6-dione scaffold as well as on a substitution in a phenyl group. The experimental parameters (RM0) were compared with computationally calculated partition coefficient values by Principal Component Analysis (PCA). To verify the influence of lipophilic parameter of the investigated compounds on their biological activity the Kruskal-Wallis test was performed. The lowest lipophilicity was observed for the compounds with weak PDE4/7 inhibitory potency. The differences between the lipophilicity of potent inhibitors and inactive compounds were statistically significant. It was found that the presence of more lipophilic propoxy- or butoxy- substituents as well as the elongation of the aliphatic chain to propylene one between the purine-2,6-dione core and amide group were preferable for desired multifunctional activity.

Neuropathic pain-alleviating activity of novel 5-HT6 receptor inverse agonists derived from 2-aryl-1H-pyrrole-3-carboxamide.

The diverse signaling pathways engaged by serotonin type 6 receptor (5-HT6R) together with its high constitutive activity suggests different types of pharmacological interventions for the treatment of CNS disorders. Non-physiological activation of mTOR kinase by constitutively active 5-HT6R under neuropathic pain conditions focused our attention on the possible repurposing of 5-HT6R inverse agonists as a strategy to treat painful symptoms associated with neuropathies of different etiologies. Herein, we report the identification of compound 33 derived from the library of 2-aryl-1H-pyrrole-3-carboxamides as a potential analgesic agent. Compound 33 behaves as a potent 5-HT6R inverse agonist at Gs, Cdk5, and mTOR signaling. Preliminary ADME/Tox studies revealed preferential distribution of 33 to the CNS and placed it in the low-risk safety space. Finally, compound 33 dose-dependently reduced tactile allodynia in spinal nerve ligation (SNL)-induced neuropathic rats.

Novel serotonin 5-HT2A receptor antagonists derived from 4-phenylcyclohexane-5-spiro-and 5-methyl-5-phenyl-hydantoin, for use as potential antiplatelet agents.

BACKGROUND: Antiplatelet drugs have been used in the treatment of acute coronary syndromes and for the prevention of recurrent events. Unfortunately, many patients remain resistant to the available antiplatelet treatment. Therefore, there is a clinical need to synthesize novel antiplatelet agents, which would be associated with different pathways of platelet aggregation, to develop an alternative or additional treatment for resistant patients. Recent studies have revealed that 5-HT2A receptor antagonists could constitute alternative antiplatelet therapy. METHODS: Based on the structures of the conventional 5-HT2A receptor ligands, two series of compounds with 4-phenylcyclohexane-5-spiro- or 5-methyl-5-phenyl-hydantoin core linked to various arylpiperazine moieties were synthesized and their affinity for 5-HT2A receptor was assessed. Further, we evaluated their antagonistic potency at 5-HT2A receptors using isolated rat aorta and cells expressing human 5-HT2A receptors. Finally, we studied their anti-aggregation effect and compared it with ketanserin and sarpogrelate, the reference 5-HT2A receptor antagonists. Moreover, the structure-activity relationships were studied following molecular docking to the 5-HT2A receptor model. RESULTS: Functional bioassays revealed some of the synthesized compounds to be moderate antagonists of 5-HT2A receptors. Among them, 13, 8-phenyl-3-(3-(4-phenylpiperazin-1-yl)propyl)-1,3-diazaspiro[4.5]decane-2,4-dione, inhibited collagen stimulated aggregation (IC50 = 27.3 µM) being more active than sarpogrelate (IC50 = 66.8 µM) and comparable with ketanserin (IC50 = 32.1 µM). Moreover, compounds 2-5, 9-11, 13, 14 inhibited 5-HT amplified, ADP- or collagen-induced aggregation. CONCLUSIONS: Our study confirmed that the 5-HT2A antagonists effectively suppress platelet aggregation and remain an interesting option for the development of novel antiplatelet agents with an alternative mechanism of action.

2-Phenyl-1H-pyrrole-3-carboxamide as a New Scaffold for Developing 5-HT6 Receptor Inverse Agonists with Cognition-Enhancing Activity.

Serotonin type 6 receptor (5-HT6R) has gained particular interest as a promising target for treating cognitive deficits, given the positive effects of its antagonists in a wide range of memory impairment paradigms. Herein, we report on degradation of the 1H-pyrrolo[3,2-c]quinoline scaffold to provide the 2-phenyl-1H-pyrrole-3-carboxamide, which is devoid of canonical indole-like skeleton and retains recognition of 5-HT6R. This modification has changed the compound's activity at 5-HT6R-operated signaling pathways from neutral antagonism to inverse agonism. The study identified compound 27 that behaves as an inverse agonist of the 5-HT6R at the Gs and Cdk5 signaling pathways. Compound 27 showed high selectivity and metabolic stability and was brain penetrant. Finally, 27 reversed scopolamine-induced memory decline in the novel object recognition test and exhibited procognitive properties in the attentional set-shifting task in rats. In light of these findings, 27 might be considered for further evaluation as a new cognition-enhancing agent, while 2-phenyl-1H-pyrrole-3-carboxamide might be used as a template for designing 5-HT6R inverse agonists.

Multifunctional Ligands with Glycogen Synthase Kinase 3 Inhibitory Activity as a New Direction in Drug Research for Alzheimer's Disease.

Alzheimer's disease (AD) belongs to the most common forms of dementia that causes a progressive loss of brain cells and leads to memory impairment and decline of other thinking skills. There is yet no effective treatment for AD; hence, the search for new drugs that could improve memory and other cognitive functions is one of the hot research topics worldwide. Scientific efforts are also directed toward combating behavioral and psychological symptoms of dementia, which are an integral part of the disease. Several studies have indicated that glycogen synthase kinase 3 beta (GSK3ß) plays a crucial role in the pathogenesis of AD. Moreover, GSK3ß inhibition provided beneficial effects on memory improvement in multiple animal models of AD. The present review aimed to update the most recent reports on the discovery of novel multifunctional ligands with GSK3ß inhibitory activity as potential drugs for the symptomatic and disease-modifying therapy of AD. Compounds with GSK3ß inhibitory activity seem to be an effective pharmacological approach for treating the causes and symptoms of AD as they reduced neuroinflammation and pathological hallmarks in animal models of AD and provided relief from cognitive and neuropsychiatric symptoms. These compounds have the potential to be used as drugs for the treatment of AD, but their precise pharmacological, pharmacokinetic, toxicological and clinical profiles need to be defined.

New imidazopyridines with phosphodiesterase 4 and 7 inhibitory activity and their efficacy in animal models of inflammatory and autoimmune diseases.

Herein, we describe the rapid synthesis of a focused library of trisubstituted imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines from 2,4-dichloro-3-nitropyridine using the combination of solution-phase/solid-phase chemistry as new potential anti-inflammatory agents in the treatment of autoimmune diseases. Structure-activity relationship studies, followed by the structure optimization, provided hit compounds (17 and 28) which inhibited phosphodiesterase 4 (PDE4) with IC50 values comparable to rolipram and displayed different inhibitory potency against phosphodiesterase 7 (PDE7). Among them, compound 17 showed a beneficial effect in all the studied animal models of inflammatory and autoimmune diseases (concanavalin A-induced hepatitis, lipopolysaccharide-induced endotoxemia, collagen-induced arthritis, and MOG35-55-induced encephalomyelitis). In addition, compound 17 showed a favorable pharmacokinetic profile after intraperitoneal administration; it was characterized by a fast absorption from the peritoneal cavity and a relatively long terminal half-life in rats. It was found to penetrate brain barrier in mice. The performed experiments sheds light on the impact of PDE7A inhibition for the efficacy of PDE4 inhibitors in these disease conditions.

Diabetic Theory in Anti-Alzheimer's Drug Research and Development. Part 2: Therapeutic Potential of cAMP-Specific Phosphodiesterase Inhibitors.

Alzheimer's disease (AD) is one of the most prevalent age-related neurodegenerative disease that affects the cognition, behavior, and daily activities of individuals. Studies indicate that this disease is characterized by several pathological mechanisms, including the accumulation of amyloid-beta peptide, hyperphosphorylation of tau protein, impairment of cholinergic neurotransmission, and increase in inflammatory responses within the central nervous system. Chronic neuroinflammation associated with AD is closely related to disturbances in metabolic processes, including insulin release and glucose metabolism. As AD is also called type III diabetes, diverse compounds having antidiabetic effects have been investigated as potential drugs for its symptomatic and disease-modifying treatment. In addition to insulin and oral antidiabetic drugs, scientific attention has been paid to cyclic-3',5'-adenosine monophosphate (cAMP)-specific phosphodiesterase (PDE) inhibitors that can modulate the concentration of glucose and related hormones and exert beneficial effects on memory, mood, and emotional processing. In this review, we present the most recent reports focusing on the involvement of cAMP-specific PDE4, PDE7, and PDE8 in glycemic and inflammatory response controls as well as the potential utility of the PDE inhibitors in the treatment of AD. Besides the results of in vitro and in vivo studies, the review also presents recent reports from clinical trials.

Discovery of Novel pERK1/2- or ß-Arrestin-Preferring 5-HT1A Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile.

Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT1A receptors were obtained and tested in four functional assays: ERK1/2 phosphorylation, adenylyl cyclase inhibition, calcium mobilization, and ß-arrestin recruitment. Compounds 44 and 56 (2-methylaminophenoxyethyl and 2-(1H-indol-4-yloxy)ethyl derivatives, respectively) were selected as biased agonists with highly differential "signaling fingerprints" that translated into distinct in vivo profiles. In vitro, 44 showed biased agonism for ERK1/2 phosphorylation and, in vivo, it preferentially exerted an antidepressant-like effect in the Porsolt forced swimming test in rats. In contrast, compound 56 exhibited a first-in-class profile: it preferentially and potently activated ß-arrestin recruitment in vitro and potently elicited lower lip retraction in vivo, a component of "serotonergic syndrome". Both compounds showed promising developability properties. The presented 5-HT1A receptor-biased agonists, preferentially targeting various signaling pathways, have the potential to become drug candidates for distinct central nervous system pathologies and possessing accentuated therapeutic activity and reduced side effects.

Impact of N-Alkylamino Substituents on Serotonin Receptor (5-HTR) Affinity and Phosphodiesterase 10A (PDE10A) Inhibition of Isoindole-1,3-dione Derivatives.

In this study, a series of compounds derived from 4-methoxy-1H-isoindole-1,3(2H)-dione, potential ligands of phosphodiesterase 10A and serotonin receptors, were investigated as potential antipsychotics. A library of 4-methoxy-1H-isoindole-1,3(2H)-dione derivatives with various amine moieties was synthesized and examined for their phosphodiesterase 10A (PDE10A)-inhibiting properties and their 5-HT1A and 5-HT7 receptor affinities. Based on in vitro studies, the most potent compound, 18 (2-[4-(1H-benzimidazol-2-yl)butyl]-4-methoxy-1H-isoindole-1,3(2H)-dione), was selected and its safety in vitro was evaluated. In order to explain the binding mode of compound 18 in the active site of the PDE10A enzyme and describe the molecular interactions responsible for its inhibition, computer-aided docking studies were performed. The potential antipsychotic properties of compound 18 in a behavioral model of schizophrenia were also investigated.

Multifunctional 6-fluoro-3-[3-(pyrrolidin-1-yl)propyl]-1,2-benzoxazoles targeting behavioral and psychological symptoms of dementia (BPSD).

Patients suffering from dementia experience cognitive deficits and 90% of them show non-cognitive behavioral and psychological symptoms of dementia (BPSD). The spectrum of BPSD includes agitation, depression, anxiety and psychosis. Antipsychotics, e.g. quetiapine, have been commonly used off-label to control the burdensome symptoms, though they cause serious side effects and further cognitive impairment. Therefore, the development of targeted therapy for BPSD, suitable for elderly patients, remains relevant. A multitarget-directed ligand, acting on serotonin 5-HT2A and dopamine D2 receptors (R) and thus exerting anti-aggressive and antipsychotic activity, as well as on 5-HT6Rs and 5-HT7Rs (potential pro-cognitive, antidepressant and anxiolytic activity), poses a promising strategy for the treatment of BPSD. Antitargeting muscarinic M3R and hERG channel is expected to reduce the risk of side effects. We obtained a series of stereoisomeric compounds by combining 6-fluoro-1,2-benzoxazole moiety and arylsulfonamide fragment through pyrrolidin-1-yl-propyl linker. N-[(3R)-1-[3-(6-fluoro-1,2-benzoxazol-3-yl)propyl]pyrrolidin-3-yl]-1-benzothiophene-2-sulfonamide showed a substantial affinity for the targets of interest (pKi = 8.32-9.35) and no significant interaction with the antitargets. Functional studies revealed its antagonist efficacy (pKB = 7.41-9.03). The lead compound showed a promising profile of antipsychotic-like activity in amphetamine- and MK-801-induced hyperlocomotion (MED = 2.5 mg/kg), antidepressant-like, as well as anxiolytic-like activity in mice (MED = 0.312 and 1.25 mg/kg in the forced swim and four-plate tests, respectively). Notably, the novel compound didn't affect spontaneous locomotor activity, nor induced catalepsy or memory deficits (step-through passive avoidance test) in therapeutically relevant doses, which proved its benign safety profile. The overall pharmacological characteristics of the lead compound outperformed the reference drug quetiapine, making it a promising option for evaluation in the treatment of BPSD.

Multifunctional Ligands Targeting Phosphodiesterase as the Future Strategy for the Symptomatic and Disease-Modifying Treatment of Alzheimer's Disease.

Alzheimer's Disease (AD) is a chronic neurodegenerative disorder characterized by cognitive impairments such as memory loss, decline in language skills, and disorientation that affects over 46 million people worldwide. Patients with AD also suffer from behavioral and psychological symptoms of dementia that deteriorate their quality of life and lead to premature death. Currently available drugs provide modest symptomatic relief but do not reduce pathological hallmarks (senile plaques and neurofibrillary tangles) and neuroinflammation, both of which are integral parts of dementia. A large body of evidence indicates that impaired signaling pathways of cyclic-3',5'- Adenosine Monophosphate (cAMP) and cyclic-3',5'-guanosine Monophosphate (cGMP) may contribute to the development and progression of AD. In addition, Phosphodiesterase (PDE) inhibitors, commonly known as cAMP and/or cGMP modulators, were found to be involved in the phosphorylation of tau; aggregation of amyloid beta; neuroinflammation; and regulation of cognition, mood, and emotion processing. The purpose of this review was to update the most recent reports on the development of novel multifunctional ligands targeting PDE as potential drugs for both symptomatic and disease-modifying therapy of AD. This review collected the chemical structures of representative multifunctional ligands, results of experimental in vitro and in vivo pharmacological studies, and current opinions regarding the potential utility of these compounds for the comprehensive therapy of AD. Finally, the multiparameter predictions of drugability of the representative compounds were calculated and discussed.

Diabetic Theory in Anti-Alzheimer's Drug Research and Development - Part 1: Therapeutic Potential of Antidiabetic Agents.

Alzheimer's Disease (AD) is a chronic and progressive neurodegenerative disorder that affects over 46 million people worldwide. It is characterized by a decline in cognitive abilities, including memory and thinking skills. AD patients also suffer from behavioral and psychological symptoms of dementia of which depression is the most prevalent. Currently available drugs provide modest symptomatic relief and do not reduce pathological hallmarks (senile plaques and neurofibrillary tangles) and neuroinflammation, both of which are integral parts of AD. Studies suggest that AD is a type of diabetes manifested in the brain. Although AD and diabetes are currently classified as separate disease entities, they share common pathophysiological mechanisms, one of them is an increased level of cytokines involved in the inflammation and the regulation of metabolic, regenerative, and neural processes. The purpose of this review was to update the most recent reports on the discovery and development of antidiabetic agents as promising drugs for the symptomatic and diseasemodifying treatment of AD. We collected the results of in vitro and in vivo studies, and recent reports from clinical trials suggesting the utility of antidiabetic agents in memory-enhancing therapy of AD. Their beneficial effects on chronic neuroinflammation, pathological hallmarks, and neuropsychiatric symptoms co-occurring with cognitive deficits are also presented. Antidiabetic agents refer to the diabetic and inflammatory hypotheses of AD and provide hope to find an effective drug for comprehensive therapy of the disease.

Advances in the Discovery of PDE10A Inhibitors for CNS-Related Disorders. Part 2: Focus on Schizophrenia.

Schizophrenia is a debilitating mental disorder with relatively high prevalence (~1%), during which positive manifestations (such as psychotic states) and negative symptoms (e.g., a withdrawal from social life) occur. Moreover, some researchers consider cognitive impairment as a distinct domain of schizophrenia symptoms. The imbalance in dopamine activity, namely an excessive release of this neurotransmitter in the striatum and insufficient amounts in the prefrontal cortex is believed to be partially responsible for the occurrence of these groups of manifestations. Second-generation antipsychotics are currently the standard treatment of schizophrenia. Nevertheless, the existent treatment is sometimes ineffective and burdened with severe adverse effects, such as extrapyramidal symptoms. Thus, there is an urgent need to search for alternative treatment options of this disease. This review summarizes the results of recent preclinical and clinical studies on phosphodiesterase 10A (PDE10A), which is highly expressed in the mammalian striatum, as a potential drug target for the treatment of schizophrenia. Based on the literature data, not only selective PDE10A inhibitors but also dual PDE2A/10A, and PDE4B/10A inhibitors, as well as multifunctional ligands with a PDE10A inhibitory potency are compounds that may combine antipsychotic, precognitive, and antidepressant functions. Thus, designing such compounds may constitute a new direction of research for new potential medications for schizophrenia. Despite failures of previous clinical trials of selective PDE10A inhibitors for the treatment of schizophrenia, new compounds with this mechanism of action are currently investigated clinically, thus, the search for new inhibitors of PDE10A, both selective and multitarget, is still warranted.

Novel multitarget 5-arylidenehydantoins with arylpiperazinealkyl fragment: Pharmacological evaluation and investigation of cytotoxicity and metabolic stability.

On the basis of the structures of serotonin modulators or drugs (NAN-190, buspirone, aripiprazole) and phosphodiesterase 4 (PDE4) inhibitors (rolipram, RO-20-1724), a series of novel multitarget 5-arylidenehydantoin derivatives with arylpiperazine fragment was synthesized. Among these compounds, 5-(3,4-dimethoxybenzylidene-3-(4-(4-(2,3-dichlorophenyl)piperazine-1-yl)butyl)-imidazolidine-2,4-dione (13) and 5-(3-cyclopentyloxy-4-methoxybenzylidene-3-(4-(4-(2-methoxyphenyl)piperazine-1-yl)butyl)-imidazolidine-2,4-dione (18) were found to be the most promising showing very high affinity toward 5-HT1A and 5-HT7 receptors (Ki = 0.2-1.0 nM) but a negligible inhibitory effect on PDE4. The high affinity of the compounds for 5-HT1A and 5-HT7 receptors was further investigated by computer-aided studies. Moreover, compounds 13 and 18 showed no significant cytotoxicity in the MTT assay, but high clearance in the in vitro assay. In addition, these compounds behaved like 5-HT1A and 5-HT7 receptor antagonists and exhibited antidepressant-like activity, similar to the reference drug citalopram, in an animal model of depression.

Discovery and Development of Non-Dopaminergic Agents for the Treatment of Schizophrenia: Overview of the Preclinical and Early Clinical Studies.

Schizophrenia is a chronic psychiatric disorder that affects about 1 in 100 people around the world and results in persistent emotional and cognitive impairments. Untreated schizophrenia leads to deterioration in quality of life and premature death. Although the clinical efficacy of dopamine D2 receptor antagonists against positive symptoms of schizophrenia supports the dopamine hypothesis of the disease, the resistance of negative and cognitive symptoms to these drugs implicates other systems in its pathophysiology. Many studies suggest that abnormalities in glutamate homeostasis may contribute to all three groups of schizophrenia symptoms. Scientific considerations also include disorders of gamma-aminobutyric acid-ergic and serotonergic neurotransmissions as well as the role of the immune system. The purpose of this review is to update the most recent reports on the discovery and development of non-dopaminergic agents that may reduce positive, negative, and cognitive symptoms of schizophrenia, and may be alternative to currently used antipsychotics. This review collects the chemical structures of representative compounds targeting metabotropic glutamate receptor, gamma-aminobutyric acid type A receptor, alpha 7 nicotinic acetylcholine receptor, glycine transporter type 1 and glycogen synthase kinase 3 as well as results of in vitro and in vivo studies indicating their efficacy in schizophrenia. Results of clinical trials assessing the safety and efficacy of the tested compounds have also been presented. Finally, attention has been paid to multifunctional ligands with serotonin receptor affinity or phosphodiesterase inhibitory activity as novel strategies in the search for dedicated medicines for patients with schizophrenia.

Novel Aryloxyethyl Derivatives of 1-(1-Benzoylpiperidin-4-yl)methanamine as the Extracellular Regulated Kinases 1/2 (ERK1/2) Phosphorylation-Preferring Serotonin 5-HT1A Receptor-Biased Agonists with Robust Antidepressant-like Activity.

Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives were designed as "biased agonists" of serotonin 5-HT1A receptors. The compounds were tested in signal transduction assays (ERK1/2 phosphorylation, cAMP inhibition, Ca2+ mobilization, and ß-arrestin recruitment) which identified ERK1/2 phosphorylation-preferring aryloxyethyl derivatives. The novel series showed high 5-HT1A receptor affinity, >1000-fold selectivity versus noradrenergic α1, dopamine D2, serotonin 5-HT2A, histamine H1, and muscarinic M1 receptors, and favorable druglike properties (CNS-MPO, Fsp3, LELP). The lead structure, (3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(pyridin-2-yloxy)ethyl)amino)methyl)piperidin-1-yl)methanone (17, NLX-204), displayed high selectivity in the SafetyScreen44 panel (including hERG channel), high solubility, metabolic stability, and Caco-2 penetration and did not block CYP3A4, CYP2D6 isoenzymes, or P-glycoprotein. Preliminary in vivo studies confirmed its promising pharmacokinetic profile. 17 also robustly stimulated ERK1/2 phosphorylation in rat cortex and showed highly potent (MED = 0.16 mg/kg) and efficacious antidepressant-like activity, totally eliminating immobility in the rat Porsolt test. These data suggest that the present 5-HT1A receptor-biased agonists could constitute promising antidepressant drug candidates.

Advances in Discovery of PDE10A Inhibitors for CNS-Related Disorders. Part 1: Overview of the Chemical and Biological Research.

Phosphodiesterase 10A (PDE10A) is a double substrate enzyme that hydrolyzes second messenger molecules such as cyclic-3',5'-adenosine monophosphate (cAMP) and cyclic-3',5'-guanosine monophosphate (cGMP). Through this process, PDE10A controls intracellular signaling pathways in the mammalian brain and peripheral tissues. Pharmacological, biochemical, and anatomical data suggest that disorders in the second messenger system mediated by PDE10A may contribute to impairments in the central nervous system (CNS) function, including cognitive deficits as well as disturbances of behavior, emotion processing, and movement. This review provides a detailed description of PDE10A and the recent advances in the design of selective PDE10A inhibitors. The results of preclinical studies regarding the potential utility of PDE10A inhibitors for the treatment of CNS-related disorders, such as schizophrenia as well as Huntington's and Parkinson's diseases are also summarized.

Characteristics of metabolic stability and the cell permeability of 2-pyrimidinyl-piperazinyl-alkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione with antidepressant- and anxiolytic-like activities.

A series of 2-pyrimidinyl-piperazinyl-alkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione has been synthesized in an attempt to discover a new class of psychotropic agents. Compounds were evaluated for their in vitro affinity for serotonin 5-HT1A , 5-HT7 , and phosphodiesterases PDE4 and PDE10. The most potent compound 2-pyrimidinyl-1-piperazinyl-butyl-imidazo[2,1-f]purine-2,4-dione (4b) behaved as strong and selective antagonist of 5-HT1A . Molecular modeling studies revealed differences in binding mode between compound 4b and buspirone, which might reflect variation of the ligands' affinity and potency in the 5-HT1A receptor. Compound 4b in silico models demonstrated drug-likeness properties and, contrary to buspirone, showed a metabolic stability in mouse liver microsomes system. Experimentally obtained value of apparent permeability coefficient Papp for 4b in parallel artificial permeability assay indicates the possibility of binding weakly to plasma proteins and high intestinal absorption fraction. Evaluation of the antidepressant- and anxiolytic-like activities of 4b revealed both activities at the same dose of 1.25 mg/kg and seemed to be specific. The antidepressant and/or anxiolytic properties of 4b may be related to its first-pass effect.