Prominently selective fluorescence approach with distinctive biopharmaceutical utility for analysis of lurasidone in human plasma and urine: Application to in vitro dissolution and content uniformity testing.

A relevant approach based on the attractive inherited merits of fluorescence spectroscopy has been established for quantitative estimation of a newly approved second-generation atypical antipsychotic lurasidone (LUR) in its raw materials and pharmaceutical dosage forms. This study brings to light the strong native fluorescence of LUR at 400 nm in water after excitation at 316 nm. Different experimental parameters that may compromise the fluorescence of the drug were carefully investigated and optimized. A linear response was established between the relative fluorescence intensity and concentration over the concentration range of 50-650 ng/mL with excellent correlation (r = 0.9998). The validity of the method was evidenced in accordance with International Council for Harmonization guidelines, with minimal detection and quantification limits of 2.88 and 8.73 ng/mL, respectively. The method was effectively applied for the estimation of LUR in spiked human plasma and urine samples with acceptable recoveries. The biopharmaceutical significance of the method was heightened by its successful applications for both content uniformity and in vitro dissolution testing. Three different tools accredited the greenness character of the presented study. Eco-friendliness, effortlessness, and cost effectiveness are crucial hallmarks of our study. The presented study demonstrates potential applicability in quality control laboratories with limited resources.

Facile, eco-friendly and sensitive fluorimetric approach for detection of chlorpromazine: Application in biological fluids and tablet formulations as well as greenness evaluation of the analytical method.

Monitoring antipsychotic drugs in biological fluids, such as human serum and urine, is important for ensuring the safety and efficacy of psychiatric treatments. This process helps maintain therapeutic drug levels, minimize side effects, and optimize patient well-being. Chlorpromazine (CZ) is a widely prescribed antipsychotic drug used for conditions like schizophrenia, bipolar disorder, and acute psychosis. Almost all existing sensing techniques for CZ are either insensitive spectrophotometric methods or involve long and complex chromatographic procedures, limiting their routine use. In this work, we introduce a facile, green, and sensitive fluorimetric strategy with high reproducibility for detecting CZ in its pure form, tablet formulation, and spiked human plasma and urine without the need for derivatization reactions. The proposed method relies on the inhibition of the intramolecular photoinduced electron transfer (PET) effect by using 2.0 M acetic acid. This approach enables the linear detection of CZ from 3.0 to 600 ng/mL with remarkably low quantitation and detection limits of 1.51 and 0.49 ng/mL, respectively. Moreover, the developed method's greenness was evaluated.

Recent Advances in representative small-molecule DRD2 inhibitors: Synthetic Routes and clinical applications.

The dopamine D2 receptor (DRD2) represents a pivotal target for therapeutic intervention in the treatment of neuropsychiatric disorders, including schizophrenia, bipolar disorder, and Parkinson's disease. The successful discovery of numerous effective DRD2 inhibitors has led to their clinical application and ongoing evaluation in various clinical trials. This review explores the synthetic approaches and clinical applications of prototypical small-molecule DRD2 inhibitors that have received approval or are currently undergoing clinical trials, highlighting their therapeutic potential and challenges. The synthesis of these inhibitors employs various chemical strategies, including modifications of phenothiazine and butyrophenone structures, which have yielded significant antipsychotic agents like chlorpromazine and haloperidol. Additionally, newer classes of inhibitors, such as aripiprazole, exhibit partial agonist activity at DRD2, offering a unique therapeutic profile. Clinically, DRD2 inhibitors demonstrate efficacy in managing positive symptoms of schizophrenia, manic episodes in bipolar disorder, and dopaminergic imbalance in Parkinson's disease. However, the emergence of adverse effects, including tardive dyskinesia, extrapyramidal symptoms and metabolic syndrome, presents substantial challenges. Advances in the development of second-generation antipsychotics aim to balance efficacy with a better side effect profile by targeting additional neurotransmitter receptors. This review aims to deliver an overview of the synthesis and clinical applications of representative small-molecule DRD2 inhibitors across various clinical phases, thereby offering strategic insights for the advancement of DRD2 inhibitor development.

Contrasting the pharmacokinetic performance and gut microbiota effects of an amorphous solid dispersion and lipid nanoemulsion for a poorly water-soluble anti-psychotic.

Increasing attention is being afforded to understanding the bidirectional relationship that exists between oral drugs and the gut microbiota. Often overlooked, however, is the impact that pharmaceutical excipients exert on the gut microbiota. Subsequently, in this study, we contrasted the pharmacokinetic performance and gut microbiota interactions between two commonly employed formulations for poorly soluble compounds, namely 1) an amorphous solid dispersion (ASD) stabilised by poly(vinyl pyrrolidone) K-30, and 2) a lipid nanoemulsion (LNE) comprised of medium chain glycerides and lecithin. The poorly soluble antipsychotic, lurasidone, was formulated with ASD and LNE due to its rate-limiting dissolution, poor oral bioavailability, and significant food effect. Both the ASD and LNE were shown to facilitate lurasidone supersaturation within in vitro dissolution studies simulating the gastrointestinal environment. This translated into profound improvements in oral pharmacokinetics in rats, with the ASD and LNE exerting comparable âˆ¼ 2.5-fold improvements in lurasidone bioavailability, compared to the pure drug. The oral formulations imparted contrasting effects on the gut microbiota, with the LNE depleting the richness and abundance of the microbial ecosystem, as evidenced through reductions in alpha diversity (Chao1 index) and operational taxonomical units (OTUs). In contrast, the ASD exerted a 'gut neutral' effect, whereby a mild enrichment of alpha diversity and OTUs was observed. Importantly, this suggests that ASDs are effective solubility-enhancing formulations that can be used without comprising the integrity of the gut microbiota - an integral consideration in the treatment of mental health disorders, such as schizophrenia, due to the role of the gut microbiota in regulating mood and cognition.

In situ-gelling hydrophobized starch nanoparticle-based nanoparticle network hydrogels for the effective delivery of intranasal olanzapine to treat brain disorders.

Intranasal (IN) delivery offers potential to deliver antipsychotic drugs with improved efficacy to the brain. However, the solubilization of such drugs and the frequency of required re-application both represent challenges to its practical implementation in treating various mental illnesses including schizophrenia. Herein, we report a sprayable nanoparticle network hydrogel (NNH) consisting of hydrophobically-modified starch nanoparticles (SNPs) and mucoadhesive chitosan oligosaccharide lactate (COL) that can gel in situ within the nasal cavity and release ultra-small penetrative SNPs over time. Hydrophobization of the SNPs enables enhanced uptake and prolonged release of poorly water soluble drugs such as olanzapine from the NNH depot through mucous and ultimately into the brain via the nose-to-brain (N2B) pathway. The hydrogel shows high in vitro cytocompatibility in mouse striatal neuron and human primary nasal cell lines and in vivo efficacy in an amphetamine-induced pre-clinical rat schizophrenia model, with IN-delivered NNH hydrogels maintaining successful attenuation of locomotor activity for up to 4 h while all other tested treatments (drug-only IN or conventional intraperitoneal delivery) failed to attenuate at any time point past 0.5 h. As such, in situ-gelling NNHs represent a safe excipient for the IN delivery of hydrophobic drugs directly to the brain using customized SNPs that exhibit high penetration and drug complexing properties to maximize effective drug delivery.

Efficient and environmentally friendly spectrofluorimetric determination of cariprazine: An analytical and green chemistry approach.

Cariprazine represents a new generation of antipsychotic medication, characterized by its heightened affinity for the D3 receptor. It has recently obtained approval as an adjunctive treatment option for patients diagnosed with major depressive disorder. In this study, a novel approach utilizing fluorescence spectroscopy was developed to analyze cariprazine. The methodology involves the transformation of cariprazine into a fluorescent compound by means of chemical derivatization with 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl). Following excitation at 470 nm, the fluorescent derivative displayed peak fluorescence emission at 550 nm. The factors influencing the derivatization process were optimized. Upon reaching the optimal reaction conditions, a linear correlation (r2 = 0.9995) was observed between the fluorescence intensity and concentrations of cariprazine ranging from 20 to 400 ng/ml. Detection and quantitation limits were determined to be 5.85 and 17.74 ng/ml, respectively. The approach was accurate and precise, with percent recovery values ranging from 98.14% to 99.91% and relative standard deviations of less than 2%. Application of the method to the analysis of cariprazine in bulk and commercial capsules forms yielded accurate results. Moreover, adherence to environmentally friendly analytical practices was evident through alignment with the principles of green analysis, as demonstrated by the analytical eco-scale, AGREE, and GAPI greenness assessment tools.

Dual 5-HT2A and 5-HT2C Receptor Inverse Agonist That Affords In Vivo Antipsychotic Efficacy with Minimal hERG Inhibition for the Treatment of Dementia-Related Psychosis.

Psychosis is a distressing symptom commonly occurring in people with dementia. To treat Parkinson's disease psychosis, pimavanserin (1), a 5-HT2A receptor inverse agonist having minimal 5-HT2C receptor affinity and no dopamine D2 receptor affinity, was approved in the United States, but not for dementia-related psychosis due to limited efficacy issues. Herein, we report on the identification of a potent and dual 5-HT2A and 5-HT2C receptor inverse agonist 8 having minimal hERG inhibition, after having demonstrated the involvement of both 5-HT2A and 5-HT2C receptors to deliver antipsychotic efficacy in an MK-801-induced locomotor model and having conducted 5-HT2A and 5-HT2C occupancy studies including a surrogate method. The introduction of a spirocyclopropyl group boosting 5-HT2C affinity in 1 followed by further optimization to control lipophilicity resulted in balanced dual potency and metabolic stability, and mitigating hERG inhibition led to 8 that showed significant antipsychotic efficacy due to the involvement of both receptors.

Exploitation of erythrosine B as a fluorometric marker for lurasidone determination through electrostatic attraction; application to content uniformity test.

A recently developed antipsychotic drug, lurasidone, was determined using a simple, sensitive, and eco-friendly spectrofluorimetric approach. The suggested approach was based on the quantifiable quenching impact of lurasidone on the inherent fluorescence of erythrosine B in an acidic environment employing a Teorell-Stenhagen buffer (pH 4). Following excitation at 530 nm, the quenching of erythrosine B fluorescence was monitored at 552 nm. The system variables were systematically optimized to enhance the formation of the lurasidone-erythrosine B ion pair for analytical purposes. A linear calibration graph was built in the range of 20-600 ng mL-1 with 0.9998 as a coefficient of correlation. The quantitation and detection limits were 13.5 and 4.5 ng/mL, respectively. The analytical validity of the designed approach was assessed with respect to International Council on Harmonization (ICH) guiding principles. The proposed methodology was employed with high recoveries for assessing lurasidone in bulk powder and its therapeutic tablet dosage form. Additionally, the uniformity of tablet formulations was tested using the developed approach. Finally, the established approach was assessed for its greenness using various tools.

Electrochemical Synthesis of the In Human S-oxide Metabolites of Phenothiazine-Containing Antipsychotic Medications.

The tractable preparation of Phase I drug metabolites is a critical step to understand the first-pass behaviour of novel chemical entities (NCEs) in drug discovery. In this study, we have developed a structure-electroactivity relationship (SeAR)-informed electrochemical reaction of the parent 2-chlorophenothiazine and the antipsychotic medication, chlorpromazine. With the ability to dial-in under current controlled conditions, the formation of S-oxide and novel S,S-dioxide metabolites has been achieved for the first time on a multi-milligram scale using a direct batch electrode platform. A potential rationale for the electrochemical formation of these metabolites in situ is proposed using molecular docking to a cytochrome P450 enzyme.

Integrated spectroscopic approaches for the facile one pot quantification of olanzapine in pharmaceutical formulation and spiked human plasma.

In this work, the xanthene dye, erythrosine B, was employed as a probe for the determination of olanzapine using two fast and highly simple analytical approaches. The assay was based on the formation of a binary complex between the drug and erythrosine B in a slightly acidic aqueous buffered solution. In the first method, the absorbance of the formed product was monitored at 558 nm. The reaction stoichiometry was investigated, and the stability constant of the formed complex was estimated. The linear range of the method that obeyed Beer's law was in the concentration range of 0.6-8.0 µg/ml. The calculated detection and quantitation limits were 0.2 and 0.6 µg/mL. Upon adding the drug solution to erythrosine B, the native fluorescence of the dye was quenched and monitored at 550 nm after excitation at 528 nm. Thus, the fluorescence quenching was utilized as the quantitative signal in the spectrofluorimetric approach. The extent of quenching in the fluorescence intensity was rectilinear with the drug concentration in a range of 0.1-2.5 µg/ml with a detection limit of 0.032 µg/ml. Both approaches were analytically validated based on the guiding rules of the ICH with acceptable results, and were utilized efficiently in the analysis of olanzapine in commercial tablets containing the cited drug. In addition, owing to its high sensitivity and selectivity, the spectrofluorimetric method was applied for drug analysis in spiked human plasma with satisfactory % recoveries. Finally, the greenness of the methods was confirmed using eco-score scale and Analytical Green Evaluation metrics.

The versatile binding landscape of the TAAR1 pocket for LSD and other antipsychotic drug molecules.

Increasing global concerns about psychoactive substance addiction and psychotic disorders highlight the need for comprehensive research into the structure-function relationship governing ligand recognition between these substances and their receptors in the brain. Recent studies indicate the significant involvement of trace amine-associated receptor 1 (TAAR1) in the signaling regulation of the hallucinogen lysergic acid diethylamide (LSD) and other antipsychotic drugs. This study presents structures of the TAAR1-Gs protein complex recognizing LSD, which exhibits a polypharmacological profile, and the partial agonist RO5263397, which is a drug candidate for schizophrenia and addiction. Moreover, we elucidate the cross-species recognition and partial activation mechanism for TAAR1, which holds promising implications from a drug discovery perspective. Through mutagenesis, functional studies, and molecular dynamics (MD) simulations, we provide a comprehensive understanding of a versatile TAAR1 pocket in recognizing various ligands as well as in the ligand-free state, underpinning the structural basis of its high adaptability. These findings offer valuable insights for the design of antipsychotic drugs.

Towards in vitro - In vivo correlation models for in situ forming drug implants.

In vitro-In vivo correlation (IVIVC) is a main focus of the pharmaceutical industry, academia and the regulatory sectors, as this is an effective modelling tool to predict drug product in vivo performance based on in vitro release data and serve as a surrogate for bioequivalence studies, significantly reducing the need for clinical studies. Till now, IVIVCs have not been successfully developed for in situ forming implants due to the significantly different in vitro and in vivo drug release profiles that are typically achieved for these dosage forms. This is not unexpected considering the unique complexity of the drug release mechanisms of these products. Using risperidone in situ forming implants as a model, the current work focuses on: 1) identification of critical attributes of in vitro release testing methods that may contribute to differences in in vitro and in vivo drug release from in situ forming implants; and 2) optimization of the in vitro release method, with the aim of developing Level A IVIVCs for risperidone implants. Dissolution methods based on a novel Teflon shape controlling adapter along with a water non-dissolvable glass fiber membrane (GF/F) instead of a water dissolvable PVA film (named as GF/F-Teflon adapter and PVA-Teflon adapter, respectively), and an in-house fabricated Glass slide adapter were used to investigate the impact of: the surface-to-volume ratio, water uptake ratio, phase separation rate (measured by NMP release in 24 h post injection in vitro or in vivo), and mechanical pressure on the drug release patterns. The surface-to-volume ratio and water uptake were shown to be more critical in vitro release testing method attributes compared to the phase separation rate and mechanical pressure. The Glass slide adapter-based dissolution method, which allowed for the formation of depots with bio-mimicking surface-to-volume ratios and sufficient water uptake, has the ability to generate bio-relevant degradation profiles as well as in vitro release profiles for risperidone implants. For the first time, a Level A IVIVC (rabbit model) has been successfully developed for in situ forming implants. Release data for implant formulations with slightly different PLGA molecular weights (MWs) were used to develop the IVIVC. The predictability of the model passed external validation using the reference listed drug (RLD), Perseris®. IVIVC could not be developed when formulations with different PLGA molar ratios of lactic acid to glycolic acid (L/G) were included. The present work provides a comprehensive understanding of the impact of the testing method attributes on drug release from in situ forming implants, which is a valuable practice for level A IVIVC development.

Spectroscopic studies under properties of chlorpromazine conjugated to gold nanoparticles.

Scientific studies have demonstrated that conjugates of anticancer drugs with metal nanoparticles (MeNPs) lead to a more effective deactivation of tumor cells compared to free drugs. Similarly, it has been established that conjugates of antibiotics with MeNPs exhibit higher biocidal activity against bacteria than their unbound counterparts. However, limited information is available regarding conjugates formed from drugs other than anticancer and antibiotics. Therefore, our research aims to develop synthesis methods for conjugates of chlorpromazine (CPZ), a neuroleptic, with gold nanoparticles (AuNPs). CPZ-AuNP conjugates were prepared through a ligand exchange reaction conducted on the surface of quasi-spherical, negatively charged citrate-stabilized TC-AuNPs with an average size of 55 ± 5 nm. UV-vis spectroscopy was employed to determine the stability range of the conjugates under controlled conditions of pH and ionic strength. Based on electrokinetic measurements, it was observed that the zeta potential of CPZ-AuNP conjugates strongly depends on the amount of CPZ adsorbed on the TC-AuNP surface. Additionally, the conjugates exhibited an isoelectric point at pH 8.8. Surface-enhanced Raman spectroscopy (SERS) and surface-enhanced infrared absorption spectroscopy (SEIRA) were employed to elucidate the adsorption structure of CPZ on TC-AuNPs. The interpretation of the spectra was conducted based on the Raman and FTIR spectra of CPZ, along with calculations performed using Density Functional Theory (DFT). The results indicated that CPZ primarily interacts with the TC-AuNP surface through the angularly oriented phenothiazine ring and the propylene bridge. Furthermore, it was demonstrated that the C-N-C fragment is perpendicular to the surface of the TC-AuNP with which it interacts. The findings from this analysis suggest the potential for further research on the use of these conjugates in biomedical applications.

Aromatic linker variations in novel dopamine D2 and D3 receptor ligands.

Dopamine D2-like receptors, especially D2 and D3 receptor subtypes, are important targets of antipsychotic agents. Many of these antipsychotics share an aliphatic linker element between a protonable amine group and an acyl-like moiety. Here, we have modified this aliphatic linker into phenylmethyl and phenylethyl linkers substituted in different positions. The design, synthesis, and in vitro evaluation of 18 dopamine D2 and D3 receptor ligands were performed in this study. Using a radioligand displacement assay, all ligands were found to have modest nanomolar affinity to D2R and D3R. N-(4-{2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethyl}phenyl)acetamide (6c) demonstrates the highest D3R and D2R affinity values (pKi values of 7.83 [D2R] and 8.04 [D3R]), featuring a slight preference to D3R. This derivative can be taken as a reference structure for the development of a new class of D2R and D3R ligands.

Bioequivalence prediction with small-scale biphasic dissolution and simultaneous dissolution-permeation apparatus-An aripiprazole case study.

Both biphasic dissolution and simultaneous dissolution-permeation (D-P) systems have great potential to improve the in vitro-in vivo correlation compared to simple dissolution assays, but the assay conditions, and the evaluation methods still need to be refined in order to effectively use these apparatuses in drug development. Therefore, this comprehensive study aimed to compare the predictive accuracy of small-volume (16-20 mL) D-P system and small-volume (40-80 mL) biphasic dissolution apparatus in bioequivalence prediction of five aripiprazole (ARP) containing marketed drug products. Assay conditions, specifically dose dependence were studied to overcome the limitations of both small-scale systems. In case of biphasic dissolution the in vivo maximum plasma concentration (Cmax) prediction greatly improved with the dose reduction of ARP, while in case of the D-P setup the use of whole tablet gave just as accurate prediction as the scaled dose. With the dose reduction strategy both equipment was able to reach 100 % accuracy in bioequivalence prediction for Cmax ratio. In case of the in vivo area under the curve (AUC) prediction the predictive accuracy for the AUC ratio was not dependent on the dose, and both apparatus had a 100 % accuracy predicting bioequivalence based on AUC results. This paper presents for the first time that not only selected parameters of flux assays (like permeability, initial flux, AUC value) were used as an input parameter of a mechanistic model (gastrointestinal unified theory) to predict absorption rate but the whole in vitro flux profile was used. All fraction absorbed values estimated by Predictor Software fell within the ±15 % acceptance range during the comparison with the in vivo data.

Preparation and comparison of binary and ternary inclusion complexes of aripiprazole using L-arginine/lysine and MßCD/HPßCD by using different molar ratios.

Aripiprazole (ARI), an antipsychotic having low solubility and stability. To overcome this, formation of binary and ternary using inclusion complexes of Methyl-ß-cyclodextrin (MßCD) /Hydroxy propyl beta cyclodextrin (HPßCD) and L-Arginine (ARG)/ Lysine (LYS) are analyzed by dissolution testing and phase stability study along with their complexation efficacy and solubility constants made by physical mixing. Inclusion complexes with ARG were better than LYS and prepared by solvent evaporation and lyophilization method as well. They are characterized by Attenuated Total Reflection Fourier Transform Infrared Spectroscopy (AT-FTIR), X-ray powder diffractometry (XRD), Differential Scanning Calorimetry (DSC), Scanning electron microscopy (SEM) and Thermal gravimetric analysis (TGA). The bond shifting in AT-FTIR confirmed the molecular interactions between host and guest molecules. The SEM images also confirmed a complete change of drug morphology in case of ternary inclusion complexes prepared by lyophilization method for both the polymers. ARI: MßCD: ARG when used in the specific molar ratio of 1:1:0.27 by prepared by lyophilization method has 18 times best solubility while ARI:HPßCD:ARG was 7 times best solubility than pure drug making MßCD a better choice than HPßCD. Change in the molar ratio will cause loss of stability or solubility. Solvent evaporation gave significant level of solubility but less stability.

Design of quetiapine fumarate loaded polyethylene glycol decorated graphene oxide nanosheets: Invitro-exvivo characterization.

Quetiapine Fumarate (QF) is an atypical antipsychotic with poor oral bioavailability (9%) due to its low permeability and pH-dependent solubility. Therefore, this study aims to design QF-loaded polyethylene glycol (PEG) functionalized graphene oxide nanosheets (GON) for nasal delivery of QF. In brief, GO was synthesized using a modified Hummers process, followed by ultra-sonication to produce GON. Subsequently, PEG-functionalized GON was prepared using carbodiimide chemistry (PEG-GON). QF was then decorated onto the cage of PEG-GON using the π-π stacking phenomenon (QF@PEG-GON). The QF@PEG-GON nanocomposite underwent several spectral characterizations, in vitro drug release, mucoadhesion study, ex vivo diffusion study, etc. The surface morphology of QF@PEG-GON nanocomposite validates the cracked nature of the nanocomposite, whereas the diffractograms and thermogram of nanocomposite confirm the conversion of QF into an amorphous form with uniform distribution in PEG-GON. Moreover, an ex vivo study of PEG-GON demonstrates superior mucoadhesion capacity due to its surface functional groups and hydrophilicity. The percent drug loading content and percent entrapment efficiency of the nanocomposite were found to be 9.2±0.62% and 92.3±1.02%, respectively. The developed nanocomposite exhibited 43.82±1.65% drug release within 24h, with the Korsemeyer-Peppas model providing the best-fit release kinetics (R2: 0.8614). Here, the interlayer spacing of PEG-GON prevented prompt diffusion of the buffer, leading to a delayed release pattern. In conclusion, the anticipated QF@PEG-GON nanocomposite shows promise as a nanocarrier platform for nasal delivery of QF.

Beyond dopamine: Novel strategies for schizophrenia treatment.

Despite extensive research efforts aimed at discovering novel antipsychotic compounds, a satisfactory pharmacological strategy for schizophrenia treatment remains elusive. All the currently available drugs act by modulating dopaminergic neurotransmission, leading to insufficient management of the negative and cognitive symptoms of the disorder. Due to these challenges, several attempts have been made to design agents with innovative, non-dopaminergic mechanisms of action. Consequently, a number of promising compounds are currently progressing through phases 2 and 3 of clinical trials. This review aims to examine the rationale behind the most promising of these strategies while simultaneously providing a comprehensive survey of study results. We describe the versatility behind the cholinergic neurotransmission modulation through the activation of M1 and M4 receptors, exemplified by the prospective drug candidate KarXT. Our discussion extends to the innovative approach of activating TAAR1 receptors via ulotaront, along with the promising outcomes of iclepertin, a GlyT-1 inhibitor with the potential to become the first treatment option for cognitive impairment associated with schizophrenia. Finally, we evaluate the 5-HT2A antagonist paradigm, assessing two recently developed serotonergic agents, pimavanserin and roluperidone. We present the latest advancements in developing novel solutions to the complex challenges posed by schizophrenia, offering an additional perspective on the diverse investigated drug candidates.

M1/M4 receptors as potential therapeutic treatments for schizophrenia: A comprehensive study.

Muscarinic acetylcholine receptors (mAChRs) play a significant role in the pathophysiology of schizophrenia. Although activating mAChRs holds potential in addressing the full range of schizophrenia symptoms, clinical application of many non-selective mAChR agonists in cognitive deficits, positive and negative symptoms is hindered by peripheral side effects (gastrointestinal disturbances and cardiovascular effects) and dosage restrictions. Ligands binding to the allosteric sites of mAChRs, particularly the M1 and M4 subtypes, demonstrate activity in improving cognitive function and amelioration of positive and negative symptoms associated with schizophrenia, enhancing our understanding of schizophrenia. The article aims to critically examine current design concepts and clinical advancements in synthesizing and designing small molecules targeting M1/M4, providing theoretical insights and empirical support for future research in this field.

Revealing receptor-ligand interactions of atypical antipsychotic drugs and screening anti-schizophrenia ingredients in Magnolia officinalis based on 5-HTR2A-SNAP-Tag/CMC and DRD2-SNAP-Tag/CMC models.

Schizophrenia is a serious mental illness with unknown etiology, and shows increasing incidence and high lifetime prevalence rate. The main receptors related to the disease are DRD2 and 5-HTR2A. Thus, a comprehensive understanding of the interaction mode between antipsychotic drugs with relevant receptors is very important for developing more effective drugs. 5-HTR2A-SNAP-Tag/CMC and DRD2-SNAP-Tag/CMC models constructed in this work provided a new method for studying the interaction between atypical antipsychotics and the two receptors. The results of comparative experiments showed that the new models not only met the high selectivity and specificity of the screening requirements but were also more stable and long-lasting than the traditional CMC model. Binding assays showed that the effects of three atypical antipsychotics (including clozapine, olanzapine, and quetiapine) on 5-HTR2A were stronger than their effects on DRD2. Additionally, two potentially active components, magnolol and honokiol, were screened in Magnolia officinalis methanol extract using the 5-HTR2A-SNAP-Tag/CMCHPLC-MS system. Nonlinear chromatographic analysis and molecular docking were conducted to study the interactions between screened compounds and the two receptors. The binding constants (KA) of magnolol and honokiol with 5-HTR2A were 17,854 ± 1,117 M-1 and 38,858 ± 4,964 M-1, respectively, and KA values with DRD2 were 4,872 ± 1,618 M-1 and 20,692 ± 10,267 M-1, respectively. We concluded that the established models are reliable for studying receptor-ligand interactions and screening antagonists of schizophrenia.