Pemetrexed (PMX), a first-line chemotherapeutic for non-small cell lung cancer (NSCLC), has recently been identified as a ligand of peroxisome proliferator-activated receptor gamma (PPARγ). However, the structural and dynamic basis of this interaction remains unclear. In this study, docking was combined with microsecond-scale molecular dynamics (MD) simulations to characterize PMX binding to the PPARγ ligand-binding domain (LBD). PMX was observed to adopt a binding pose resembling known partial agonists, stabilized by hydrogen bonds with residues Ser289, Tyr327, and Tyr473. Energetic and conformational analyses revealed that PMX avoids deep engagement with the AF-2 surface, which is a region critical for coactivator recruitment and full transcriptional activation. Free energy landscapes, principal component analysis, and dynamic cross-correlation maps further demonstrated that PMX induces conformational dynamics consistent with a partial agonist profile. This study provides an atomistic perspective on the recognition mechanism of PMX as a PPARγ partial agonist, offering a structural foundation for designing multitarget agents that simultaneously disrupt nucleotide metabolism and transcriptional regulation in NSCLC.

Exposure-response of serum biomarkers to vamorolone, a dissociative corticosteroidal anti-inflammatory drug, in 4- to <7-year children.

Selective activation of cannabinoid receptors by cannabis terpenes.

Perospirone is a second-generation antipsychotic classified as a serotonin-dopamine antagonist that is primarily used to treat schizophrenia and bipolar disorder. While its therapeutic effects have been attributed to D2 and 5-HT2A receptor antagonism and partial 5-HT1A agonism, its potential interactions with ion channels remain unexplored. In this study, we investigated the effects of perospirone on vascular voltage-gated K+ (Kv) channels in freshly isolated rabbit coronary arterial smooth muscle cells. Perospirone inhibited vascular Kv channels in a concentration-dependent manner, with a half-maximal inhibitory concentration (IC50) of 20.54 ± 2.89 μM and a Hill coefficient of 0.92 ± 0.07. Perospirone did not change the activation or inactivation kinetics and did not exhibit use-dependent inhibition, suggesting that the interaction between the drug and the channels did not affect the voltage sensors or conformational states of the channels. Pretreatment with the Kv2.1 inhibitor guangxitoxin or the Kv7 inhibitor linopirdine did not change the extent of the perospirone-induced Kv current inhibition, whereas pretreatment with the Kv1.5 inhibitor DPO-1 partially attenuated the inhibitory effect of perospirone on Kv currents. These findings demonstrate that perospirone inhibits vascular Kv1.5 subtype channels in a concentration-dependent but use-independent manner. This previously unrecognized off-target effect suggests that perospirone can affect vascular function, highlighting its potential cardiovascular implications in clinical settings.

Discovery and characterization of quinoxaline and quinoline carboxamides as allosteric cannabinoid receptor modulators.

We pharmacologically analyzed clonidine-induced tension changes in endothelium-denuded guinea pig thoracic aorta (GP-TA). Clonidine alone produced little change in basal tension; however, in the presence of tetraethylammonium (TEA) or Ba2+, it elicited a pronounced contraction that was almost completely abolished by verapamil. In contrast, phenylephrine alone evoked a robust contraction, which was also further enhanced in the presence of Ba2+; this Ba2+-potentiated component was nearly abolished by verapamil. The Ba2+-enhanced clonidine-evoked contraction was insensitive to the α2-adrenoceptor (AR) antagonist idazoxan but was competitively inhibited by the α1-AR antagonists prazosin and tamsulosin, yielding pA2 values of 8.26 and 9.92, respectively. Clonidine competitively inhibited phenylephrine-induced contraction, with a pA2 value of 5.67 in the presence of verapamil. Moreover, clonidine suppressed the sustained component of the phenylephrine response; this inhibition was attenuated by Ba2+ but remained unchanged in the presence of verapamil. These findings indicate that, in GP-TA, clonidine acts as a biased and partial agonist primarily at α1L-ARs, promoting Ca2+ influx through L-type voltage-dependent Ca2+ channels (VDCCs). These L-type VDCC-mediated responses are negatively regulated by Ba2+-sensitive K+ channels. In addition, clonidine itself appears to directly or indirectly activate Ba2+-sensitive K+ channels, thereby suppressing the α1L-AR-L-type VDCC functional coupling.

An IL-12 partial agonist sustains intratumoral lymphocyte activation and detoxifies systemic IL-12 therapy.

Schizophrenia is a complex psychiatric disorder frequently complicated by comorbidities that contribute to functional impairment, poor treatment adherence, and elevated mortality. Among the most prevalent and burdensome are affective symptoms, sexual dysfunction, metabolic disturbances, and substance use disorders, which remain underrecognized and insufficiently addressed in routine care. This expert consensus aimed to develop comorbidity-informed pharmacological strategies for schizophrenia, grounded in real-world challenges and individualized treatment needs. A multidisciplinary panel of 10 European psychiatrists convened for an in-person meeting. Four expert-led presentations, each addressing a key comorbidity, were followed by open discussion. A modified two-round Delphi process was subsequently used to validate the consensus statements, which were thematically synthesized into actionable recommendations. Consensus-based recommendations were developed across four comorbidity domains, integrating current evidence with real-world clinical expertise. The panel emphasized the importance of individualized, patient-centered pharmacological strategies that balance efficacy, tolerability, and long-term functional outcomes. Partial dopamine agonists and other metabolically or hormonally favorable agents were identified as clinically useful across several comorbid profiles. Recommendations also addressed the optimization of antipsychotic selection, management of treatment-emergent side effects, and coordinated care for patients with dual diagnosis (also referred to as co-occurring disorders). Measurement-based monitoring and integrated service models were consistently highlighted as essential for improving outcomes. Effective management of schizophrenia requires a shift toward comorbidity-informed, recovery-oriented pharmacological care. These expert recommendations provide practical strategies to support individualized treatment planning in real-world clinical settings.

The authors report the case of a patient diagnosed and treated with schizophrenia for nearly 20 years. A rapid change in the neurological status of the patient necessitated a diagnostic revision. The patient's additional medical history included narcolepsy and psoriasis. With a stable maintenance antipsychotic combination regime, one and a half years after the last inpatient treatment for a psychotic relapse, initially mild lower limb hyperkinesis developed. At first, this hyperkinesis was hypothesized to be antipsychotic side effects. The decrease of the antipsychotic daily dose resulted in no improvement of the motor symptoms. On the contrary, the generalization of the hyperkinesis and rapid progression of the motoric status were observed. Therefore, further neurological investigation was initiated. Finally, genetic testing confirmed Huntington's disease. The neuropsychological examination at the time of the diagnosis could not confirm major cognitive impairment, however, alterations in a number of cognitive domains were present. During the follow-up period, and by use of the combination of a low-dose partial dopamine receptor agonist and clozapine, no psychotic relapse was detected. The cognitive status exhibited a mild deterioration compared to baseline. In line with the prognosis of Huntington's disease, the motor symptoms slightly progressed despite the pharmacotherapy. We present our case in the context of a literature review. Orv Hetil. 2025; 166(52): 2064-2072.

Schizophrenia is regarded as a complex and heterogeneous psychiatric disorder, characterised by diverse symptoms and comorbidities, which complicate both clinical management and drug development. Current pharmacological treatment, primarily based on dopamine D2 receptor antagonism or partial agonism, which has not markedly progressed since the emergence of chlorpromazine in the 1950s, remains inadequate in addressing the full spectrum of clinical symptoms. Despite decades of preclinical research, many novel compounds with different mechanisms that show efficacy in animal models subsequently fail in Phase II or III clinical trials. This translational gap may reflect limitations in model selection, reliance on behavioural endpoints with poor clinical correspondence and the inherent inability of rodent paradigms to capture the full heterogeneity of human schizophrenia. This review provides a systematic overview of how rodent models and behavioural assays have been applied by the pharmaceutical industry over the past 30 years to evaluate antipsychotic efficacy, both for marketed drugs and investigational compounds entering first-in-human (FIH) clinical trials. We examine the extent to which these models have informed regulatory submissions and clinical development, whilst also analysing the translational challenges that arise from their limited ability to capture the complexity and heterogeneity of schizophrenia, as well as the impact of inclusion criteria on the testing of antipsychotic drug efficacy. By highlighting these limitations, we propose key considerations for refining model selection, behavioural endpoints, and biomarker integration to strengthen the predictive value of preclinical research and improve the likelihood of success for novel antipsychotics in clinical trials.

Lactate, historically viewed as a metabolic by-product, has emerged as a signalling molecule via the G protein-coupled receptor Hydroxycarboxylic Acid Receptor 1 (HCAR1). The receptor is primarily expressed in adipocytes but also found in various other tissues. HCAR1 activation has been shown to regulate lipolysis and improve insulin sensitivity, positioning it as a promising therapeutic target for metabolic disorders such as obesity and type 2 diabetes. Despite its potential, its role in cancer progression and the limited availability of characterized ligands necessitate further investigation into its signalling mechanisms. This study aimed to broaden the pharmacological understanding of HCAR1 by investigating previously uncharacterized ligands and profiling their signalling properties. We employed enhanced bystander bioluminescence resonance energy transfer (ebBRET) assays to investigate G protein activation and β-arrestin recruitment following ligand stimulation of HCAR1. A panel of compounds was screened to identify more potent agonists and modulators of HCAR1 signalling. We identified AZ7136 as a relatively potent HCAR1 agonist, AZ2114 as a partial agonist, and GPR81 agonist 1 as an ago-positive allosteric modulator. HCAR1 preferentially activated Gαi/o and Gαs pathways without recruiting β-arrestins, revealing a distinct signalling profile. These findings expand our understanding of HCAR1 signalling and introduce new molecular tools for probing its physiological and pathological roles. The characterized ligands may support future therapeutic strategies targeting HCAR1 in metabolic disorders while informing approaches to mitigate potential oncogenic effects.

Distinct ligands for the same G-protein coupled receptor (GPCR) activate intracellular signaling partners to varying extents, but the molecular mechanisms driving these differences remain elusive. Hypothesizing that such differences in signaling efficacy may be captured structurally in intermediate states under non-equilibrium conditions, we implemented a time-resolved (TR) cryo-EM approach to visualize the GTP-induced activation of the Gαiβγ heterotrimer by the μ-opioid receptor (MOR) bound to three ligands displaying partial, full, or super-agonism on the receptor1. We resolved ensembles of conformational states along the G-protein activation pathway, including a previously unobserved intermediate state that enabled us to visualize receptor dynamics as a function of bound ligand. The results demonstrate ligand-dependent differences in state occupancy and conformational stability, with higher ligand efficacy correlating with increased dynamics of the receptor's transmembrane (TM) helices 5 and 6. Furthermore, we identify key mechanistic differences in the GTP-induced activation of Gi compared to Gs that likely underlie their distinct activation kinetics. Corroborated by molecular dynamics (MD) simulations and single-molecule fluorescence assays, these findings provide a dynamic structural landscape of GPCR-G-protein interactions for ligands of different efficacy and suggest partial agonists may produce a 'kinetic trap' during G-protein activation.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a validated therapeutic target for type 2 diabetes (T2D), but current FDA-approved agonists are limited by adverse effects. SR10171, a non-covalent partial inverse agonist with modest binding potency, improves insulin sensitivity in mice without bone loss or marrow adiposity. Here, we characterize a series of SR10171 analogs to define structure-function relationships using biochemical assays, hydrogen-deuterium exchange (HDX), and computational modeling. Analogs featuring flipped indole scaffolds with N-alkyl substitutions exhibited 10- to 100-fold enhanced binding to PPARγ while retaining inverse agonist activity. HDX and molecular dynamic simulations revealed that ligand-induced dynamics within ligand-binding pocket and AF2 domain correlate with enhanced receptor binding and differential repression. Lead analogs restored receptor activity in loss-of-function PPARγ variants and improved insulin sensitivity in adipocytes from a diabetic patient. These findings elucidate mechanisms of non-covalent PPARγ modulation establishing a framework for developing safer, next-generation insulin sensitizers for metabolic disease therapy.

Psilocybin, a naturally occurring tryptamine alkaloid found in over 200 species of fungi, has emerged as a focal point in the modern revival of psychedelic science. Once relegated to the margins of psychopharmacology due to its association with counterculture and strict legal restrictions, psilocybin is now undergoing a scientific renaissance. This transformation is driven by its unique pharmacological profile and promising therapeutic potential across a range of psychiatric and neurodegenerative conditions. This review systematically summarizes the research progress on psilocybin, covering its natural biosynthetic pathways, production technologies, mechanisms of action, and clinical applications. We first introduced its four-enzyme synthesis pathway in Psilocybe fungi and explored how synthetic biology can revolutionize its production methods through microbial heterologous expression. Pharmacologically, psilocybin acts as a prodrug that is converted in vivo into its active metabolite, dephosphorylated psilocybin (psilocin), which functions as a partial agonist of the 5-HT2A receptor. This activates neuroplasticity pathways such as BDNF and mTOR, thereby producing rapid and sustained antidepressant effects. Despite its therapeutic promise, significant challenges remain. These include methodological limitations such as functional unblinding in clinical trials, lack of diversity in study populations, and evolving regulatory frameworks. Looking forward, the integration of precision psychiatry, synthetic biology, and novel trial designs will be critical in translating psilocybin from a promising compound into a mainstream therapeutic agent. This review aims to provide a foundational understanding of psilocybin’s scientific basis and its potential to reshape modern psychiatric care, we uniquely bridge the gap between upstream biosynthetic engineering and downstream clinical efficacy, providing a holistic roadmap for the drug’s development from fungi to pharmacy. GRAPHICAL ABSTRACT HIGHLIGHTS Microbial biosynthesis enables scalable, high-titer psilocybin production. Therapeutic action is driven by 5-HT2A receptor-mediated neuroplasticity. Demonstrates rapid and sustained antidepressant efficacy in clinical trials.

Acute alcohol withdrawal encompasses somatic withdrawal signs and increased negative affect. In prolonged alcohol withdrawal the somatic withdrawal signs have resolved but the increased negative affect persists. We investigated acute and prolonged alcohol withdrawal after 9 daily injections of 2.5 g/kg alcohol plus 4-methypyrazole, an alcohol dehydrogenase inhibitor, in male and female C57BL/6J mice, and examined whether nicotinic acetylcholine receptor (nAChR) drugs could attenuate withdrawal-induced negative affect. Male mice showed changing somatic withdrawal signs over time and negative affect that persisted at least 21 days into withdrawal. Pre-treatment with mecamylamine, a non-specific nAChR antagonist, or varenicline, a nAChR partial agonist, reduced withdrawal-induced anxiety- and compulsive-like behavior in the marble-burying test during prolonged withdrawal. In contrast, female mice did not exhibit somatic withdrawal signs or anxiety- or compulsive-like behaviors. Instead, female mice showed a deficit in social interaction that was not attenuated by mecamylamine. Alcohol clearance and sedation were not different between sexes, indicating that differences in withdrawal signs and negative affect are not confounded by differences in alcohol metabolism. These findings suggest that cholinergic drugs may be a promising therapeutic for withdrawal-induced negative affect in male, but not female, mice.

A light-induced cyclization via a radical spin-center shift process that results in the direct functionalization of the indole ring at the C4-position is developed into a practical method for the synthesis of medicinally active, ring-constrained tryptamine analogs. Amino acids were coupled to tryptamine and irradiated with UV light to produce a library of lactams bridging the C3- and C4-positions of the indole nucleus. An extension to this method is introduced that employs α-acetoxy- and α-lactone-substituted tryptamides. Using optimized conditions and these easily accessed precursors, C3- to C4-bridged indoles can now be produced in good to excellent yields, free of the C2-regioisomers that are often seen using α-halo tryptamide substrates. Due to the structural similarities of the reduced lactams (azocinoindoles) with known psychoactive tryptamines, their functional activation at the serotonin 5-HT2A receptor was investigated both in silico and in vitro. These azocinoindoles show both full and partial agonist 5-HT2A Gq activation efficacies and suppress the head-twitch response in vivo, suggesting they belong to an emerging class of nonhallucinogenic 5-HT2A agonists. The azocinoindole core and the synthetic advances described here that enable its structural diversification provide a valuable platform for serotonin receptor drug discovery.

α-Ethyltryptamine (AET), a synthetic tryptamine formerly used as an antidepressant, has resurfaced as a compound of interest due to its structural and functional overlap with serotonergic psychedelics and entactogens. Here, we characterized the pharmacological properties of racemic AET and its optical isomers, R(-)-AET and S(+)-AET, focusing on their interactions with the serotonin (or 5-hydroxytryptamine) 5-HT2A receptor (5-HT2AR) and serotonin transporter (SERT). In vitro, all three compounds displaced [3H]ketanserin from 5-HT2AR with micromolar affinity; however, only S(+)-AET elicited weak partial agonist activity in calcium mobilization assays, an effect abolished by the 5-HT2AR antagonist volinanserin. In vivo, all forms of AET induced a dose-dependent effect on the head-twitch response (HTR) in mice, which was completely blocked by volinanserin, confirming the 5-HT2AR involvement. Notably, pretreatment with fluoxetine abolished AET-induced HTR without affecting responses to the classical psychedelic DOI, implicating SERT-mediated serotonin release in AET's mechanism of action. These findings indicate that AET's behavioral effects rely on a dual mechanism involving both direct 5-HT2AR activation and indirect serotonergic potentiation via SERT. This dual pharmacology distinguishes AET from classical psychedelics and places it within a unique niche alongside MDMA-like serotonergic agents, highlighting the therapeutic and neuropsychiatric potential of AET isomers for modulating mood and cognition.

Mitragynine is a psychoactive alkaloid in Mitragyna speciosa with unique polypharmacology at G protein-coupled receptors. In addition to its well-known partial agonist activity at opioid receptors, mitragynine is an antagonist at human α2A-adrenoceptors (α2ARs), as measured in an in vitro GTPγS G protein assay. Mitragynine's in vitro α2AR antagonist pharmacology contrasts with rat behavioral pharmacology studies that suggest mitragynine behaves as an in vivo agonist at rat α2Rs. This study investigates this apparent discrepancy using recombinant α-adrenoceptors and a range of orthogonal signal transducers. We evaluated whether mitragynine activates any of seven Gαi/o proteins coupled to α2A, α2B, and α2CRs, as well as Gαq and Gα11 coupled to α1AR. Additionally, we examined rat and human α2AR-mediated cAMP inhibition, α2AR-mediated β-arrestin2 recruitment, and tested α2R or α1R-mediated ERK phosphorylation in wild-type, β-arrestin 1/2 knockout, and Gαq/11 knockout cells. Finally, we report binding and enzyme-inhibition profiling results for mitragynine and its major metabolites, 7-Hydroxymitragynine and 9-Hydroxycorynantheidine, at 99 targets. The results did not support the hypothesis that mitragynine (or its primary metabolites) activates α2Rs, but, aligned with our previous GTPγS results, demonstrate that mitragynine is a low-potency, competitive α2AR antagonist at Gαi1, cAMP, and β-arrestin2 transducers. However, we show that mitragynine is a low-potency (EC50 ∼3 μM), partial agonist at α1AR-Gα11 and stimulates ERK phosphorylation via Gαq/11-coupled α1Rs, supporting in vivo studies that suggest mitragynine is an α1R agonist. Nevertheless, the agonist effects of mitragynine at α1AR-Gα11 were modest compared to clonidine, a partial agonist control that also activated all α2R transducers. Mitragynine's dual α2AR antagonist/α1R partial agonist pharmacology might contribute to mitragynine's psychostimulant-like properties.

Aripiprazole, brexpiprazole, and cariprazine have a unique pharmacology as demonstrated by their high affinity to the dopamine type-2 receptor (ie, D2 receptor). These agents may be preferred over others for the treatment of psychotic and bipolar disorders due to their lower incidence of movement disorders and sedation. When prescribed adjunctively to full antagonist agents, partial agonist antipsychotics can mitigate adverse effects such as hyperprolactinemia. However, their high affinity for the D2 receptor may interfere with the efficacy of full antagonist antipsychotics when used in combination. Some partial agonists may be less preferred in particular patient scenarios based on their demonstrated clinical efficacy. Three illustrative patient cases highlight clinical pearls related to the safe and effective use of antipsychotic polypharmacy involving partial agonist antipsychotics.

Discovery of a selective α2C-AR scaffold from a molecular hybridization approach.