PROMISING DIRECTIONS FOR THE APPLICATION OF PIPERIDINE DERIVATIVES AS STRUCTURAL COMPONENTS OF NEUROTROPIC DRUGS

Piperidine is one of the most common heterocycles, and its derivatives are found in many pharmacological groups, including neurotropic drugs. These compounds are numerous among analgesics, and, in addition to “classical” promedol, fentanyl and its derivatives, the paper presents the results of studying new compounds with analgesic activity and piperidine cycle. Reviews of such piperidine antipsychotics as haloperidol and risperidone have been considered, and new compounds showing antipsychotic activity through their effects on dopamine and serotonin receptors have been elucidated. The data on the influence of methylphenidate on the brain in case of attention deficit/ hyperactivity disorder (ADHD) have been analyzed, which help to understand the disturbances occurring in this disease. Tiagabine has been considered as an antiepileptic agent reducing the number of seizures in resistant forms of partial epilepsy, as well as the activation of microglia and may be effective in neurodegenerative diseases. The last section is devoted to drugs for the treatment of Alzheimer’s disease (AD), namely donepezil, its modifications, and some new compounds potentially capable of inhibiting AD progression through the inhibition of Aβ42 protein synthesis.

Docking of highly selective peptide ligands of 5HT2A/C receptors with antipsychotic activity

Search for new ligands selective to various 5HT2 receptor subtypes is an important scientific and practical problem for experimental psychopharmacology and clinical medicine. Most of existing antagonists of the 5HT2A- and 5HT2C- subtypes have necessary anti-anxiety and antipsychotic properties, but they are partially selective to 5HT2B receptors. The activation of the latter ones leads to cardiotoxic side effects, so it significantly limits clinical use of these drugs. For the search of new highly selective ligands of 5HT2A/C receptors an in silico screening algorithm was proposed using PScore.Max and Affinity.maxPScore indices, taking into account the affinity of low molecular weight compounds to each of 5HT2 receptor subtype. Cyclic physiologically active substances of peptide nature have been proposed as new promising drugs with antipsychotic activity. Based on the CXXC library, a number of cyclopeptides with a high selectivity of the structure to the target binding sites were selected for further in vitro studies by extending the peptide chain.It was also found that a promising direction for increasing the selectivity of peptide ligands to 5HT2A/C receptors is the introduction of non-proteinogenic amino acids during the formation of a starting docking library. Their choice will be stipulated by the nature of interactions between the reference ligands and amino acid residues of the binding site.

PDE10A Inhibitors—Clinical Failure or Window Into Antipsychotic Drug Action?

PDE10A, a phosphodiesterase that inactivates both cAMP and cGMP, is a unique signaling molecule in being highly and nearly exclusively expressed in striatal medium spiny neurons. These neurons dynamically integrate cortical information with dopamine-signaled value to mediate action selection among available behavioral options. Medium spiny neurons are components of either the direct or indirect striatal output pathways. Selective activation of indirect pathway medium spiny neurons by dopamine D2 receptor antagonists is putatively a key element in the mechanism of their antipsychotic efficacy. While PDE10A is expressed in all medium spiny neurons, studies in rodents indicated that PDE10A inhibition has behavioral effects in several key assays that phenocopy dopamine D2 receptor inhibition. This finding gave rise to the hypothesis that PDE10A inhibition also preferentially activates indirect pathway medium spiny neurons, a hypothesis that is consistent with electrophysiological, neurochemical, and molecular effects of PDE10A inhibitors. These data underwrote industry-wide efforts to investigate and develop PDE10A inhibitors as novel antipsychotics. Disappointingly, PDE10A inhibitors from 3 companies failed to evidence antipsychotic activity in patients with schizophrenia to the same extent as standard-of-care D2 antagonists. Given the notable similarities between PDE10A inhibitors and D2 antagonists, gaining an understanding of why only the latter class is antipsychotic affords a unique window into the basis for this therapeutic efficacy. With this in mind, we review the data on PDE10A inhibition as a step toward back-translating the limited antipsychotic efficacy of PDE10A inhibitors, hopefully to inform new efforts to develop better therapeutics to treat psychosis and schizophrenia.

The Antipsychotic D2AAK1 as a Memory Enhancer for Treatment of Mental and Neurodegenerative Diseases

The treatment of memory impairments associated with the central nervous system diseases remains an unmet medical need with social and economic implications. Here we show, that a multi-target ligand of aminergic G protein-coupled receptors with antipsychotic activity in vivo (D2AAK1) stimulates neuron growth and survival and promotes neuron integrity. We focused on the multilevel evaluation of the D2AAK1-related effects on neurons in terms of behavioral, cellular, molecular, and biochemical features in vivo and in vitro, such as memory-related responses, locomotor activity, tissue sections analysis, metabolic activity, proliferation level, neurons morphology, and proteins level involved in intracellular signaling pathways. In silico studies indicate that activation of calcium/calmodulin-dependent protein kinase I (CaMKI) may underline some of the observed activities of the compound. Furthermore, the compound increases hippocampal neuron proliferation via the activation of neurotrophic factors and cooperating signals responsible for cell growth and proliferation. D2AAK1 improves memory and learning processes in mice after both acute and chronic administration. D2AAK1 also causes an increase in the number of hippocampal pyramidal neurons after chronic administration. Because of its neuroprotective properties and pro-cognitive activity in behavioral studies D2AAK1 has the potential for the treatment of memory disturbances in neurodegenerative and mental diseases.

Designed proteinoid polymers and nanoparticles encapsulating risperidone for enhanced antipsychotic activity

Background Nanoparticles (NPs) incorporating drug formulations can be used to facilitate passage through biological barriers including the blood–brain barrier (BBB) and increase drug delivery and bioavailability. Hence, NP-based administration may enhance the efficiency of current antipsychotics. Encapsulation within NPs can resolve aqueous solubility problems that not only reduce permeability through the BBB but also affect targeting. The present study describes a new drug delivery system based on proteinoid NPs to explore the possibility of improving drug efficacy. Risperidone (RSP) is a commonly used atypical antipsychotic medication, and was therefore selected for encapsulation by proteinoid NPs. Results Proteinoid polymers with high molecular weight and low polydispersity were synthesized from l-amino acids and poly-l-lactic acid (PLLA) by thermal step-growth polymerization mechanism. RSP-loaded proteinoid NPs were then prepared using a self-assembly process in the presence of RSP, followed by PEGylation. The optimal PEGylated RSP-loaded NPs were characterized in terms of diameter and size distribution, drug loading, ζ-potential, cytotoxicity, biodistribution, and psychopharmacological effects. The findings indicate significantly higher antipsychotic activity of drug-loaded proteinoid NPs compared to free RSP. Conclusions Proteinoid NPs enhance RSP delivery and may potentially increase drug efficiency by reducing dosage and side effects.

One Pot Synthesis and Pharmacological Evaluation of Aryl Substituted Imidazoles as Potential Atypical Antip

Background: Second generation or ‘‘atypical’’ antipsychotics demonstrate an improved therapeutic profile over conventional neuroleptics. These are effective in both positive and negative symptoms of the disease and have a lower propensity to induce adverse symptoms. Objective: Main objective of the research was in silico design and synthesis of potential atypical antipsychotics with combined antiserotonergic / antidopaminergic effect. Method: A one pot synthesis of aryl substituted imidazole derivatives was carried out in green solvent PEG-400 and the prepared compounds were evaluated for atypical antipsychotic activity in animal models for dopaminergic and serotonergic antagonism. The compounds were designed based on their 3D similarity studies to standard drugs and in silico (docking studies) with respect to 5-HT2A and D2 receptors. Results and Discussion: Results from the docking studies with respect to 5-HT2A and D2 receptors suggested a potential atypical antipsychotic profile for the test compounds. Theoretical ADME profiling of the compounds based on selected physicochemical parameters suggested an excellent compliance with Lipinski’s rules. The potential of these compounds to penetrate the blood brain barrier (log BB) was computed through an online software program and the values obtained for the compounds suggested a good potential for brain permeation. Reversal of apomorphine induced mesh climbing behaviour coupled with inactivity in the stereotypy assay indicates antidopaminergic effect and a potential atypical profile for the test compounds 1-5. Further, activity of compounds in DOI assay indicated a 5-HT2 antagonistic profile (5-HT2 antagonism). Conclusion: Compound 5 emerged as important lead compound showing combined antidopaminergic and antiserotonergic (5-HT2A) activity with potential atypical antipsychotic profile.

Proteinoid Nanocapsules as Drug Delivery System for Improving Antipsychotic Activity of Risperidone

Risperidone (RSP) is an atypical antipsychotic drug widely used to treat schizophrenia and bipolar disorder. Nanoparticles (NPs) are being developed as in vivo targeted drug delivery systems, which cross the blood-brain barrier and improve pharmacokinetics and drug effectiveness. Here, biodegradable proteinoids were synthesized by thermal step-growth polymerization from the amino acids l-glutamic acid, l-phenylalanine and l-histidine and poly (l-lactic acid). Proteinoid NPs containing RSP were then formed by self-assembly, overcoming the insolubility of the drug in water, followed by PEGylation (poly ethylene glycol (PEG) conjugation to increase the stability of the NPs in the aqueous continuous phase. These NPs are biodegradable owing to their peptide and ester moieties. They were characterized in terms of diameter, size distribution, drug loading, and long-term storage. Behavioral studies on mice found enhanced antipsychotic activity compared to free RSP.

Translational Development Strategies for TAK-063, a Phosphodiesterase 10A Inhibitor

Background TAK-063 is an inhibitor of phosphodiesterase 10A (PDE10A), an enzyme highly expressed in medium spiny neurons of the striatum. PDE10A hydrolyzes both cyclic adenosine monophosphate and cyclic guanosine monophosphate and modulates dopamine signaling downstream of receptor activation in both direct and indirect pathways of the striatum. TAK-063 exhibited antipsychotic-like effects in animal models; however, the translatability of these models to the clinical manifestations of schizophrenia and the meaningfulness for new targets such as PDE10A has not been established. Methods The TAK-063 phase 1 program included a comprehensive translational development strategy with the main objective of determining whether the antipsychotic-like pharmacodynamic effects seen in nonclinical models would translate to human subjects. To evaluate this objective, we conducted a single-rising dose study (84 healthy subjects), a positron emission tomography (PET) study (12 healthy subjects), a functional magnetic resonance imaging blood oxygen level-dependent (BOLD) study (27 healthy subjects), and a multiple-rising dose study that included people with schizophrenia (30 healthy Japanese subjects and 47 subjects with stable schizophrenia). In addition, assessments of cognition and electroencephalography (27 healthy subjects and 47 subjects with stable schizophrenia) were included. Results PDE10A engagement by TAK-063 was verified with a novel PET radiotracer for use in primates and humans. TAK-063 showed favorable pharmacokinetic and safety profiles in humans, and TAK-063 reduced ketamine-induced changes in electroencephalography and BOLD signaling in animal models and healthy human subjects. In addition, analogous effects on cognition were observed in animal models and human subjects. Conclusions Overall, the phase 1 results showed some consistent evidence of antipsychotic activity. This translational strategy may be valuable for the future development of novel therapeutic approaches, even when relevant nonclinical models are not available.