Neuropsychiatric disorders present a multifaceted challenge, characterized by cognitive, social, and motor impairments with manifold underlying mechanisms. Recent attention has turned to epigenetic mechanisms, particularly histone lysine methyltransferases (HKMTs), such as G9a, in understanding fundamental pathogenesis. This review provides a concise overview of the structural and functional features of G9a and its involvement in neuropsychiatric disorders, including neurodevelopmental disorders (NDDs) like autism spectrum disorders (ASD) and Prader‐Willi syndrome (PWS), schizophrenia (SZ), epilepsy, anxiety, depression, and Alzheimer's disease (AD). Furthermore, it highlights the biochemical mechanisms of G9a‐mediated histone methylations and explores pharmacological interventions targeting G9a for potential therapeutic avenues. This current knowledge underlines G9a's significance as a therapeutic target and sets the stage for future investigations into its role in neuropsychiatric disorders.

This study examines the properties of novel guanidines, designed and synthesized as histamine H₃R antagonists/inverse agonists with additional pharmacological targets. We evaluated their potential against two targets viz., inhibition of MDA-MB-231, and MCF-7 breast cancer cells viability and inhibition of AChE/BuChE. ADS10310 showed micromolar cytotoxicity against breast cancer cells, combined with nanomolar affinity at hH₃R, and may represent a promising target for the development of an alternative method of cancer therapy. Some of the newly synthesized compounds showed moderate inhibition of BuChE in the single-digit micromolar concentration ranges. H₃R antagonist with additional AChE/BuChE inhibitory effect might improve cognitive functions in Alzheimer’s disease. For ADS10310, several in vitro ADME-Tox parameters were evaluated and indicated that it is a metabolically stable compound with weak hepatotoxic activity and can be accepted for further studies.

Pain is a very unpleasant experience that makes life extremely uncomfortable. The histamine H₄ receptor (H₄R) is a promising target for the treatment of inflammatory and immune diseases, as well as pain. H₄R ligands have demonstrated analgesic effects in a variety of pain models, including inflammatory pain. Continuing the search for active H₄R ligands among the alkyl derivatives of 1,3,5-triazine, we obtained 19 new compounds in two series: acyclic (I) and aliphatic (II). In vitro pharmacological evaluation showed their variable affinity for H₄R. The majority of compounds showed a moderate affinity for this receptor (K_i > 100 nM), while all compounds tested in ß-arrestin and cAMP assays showed antagonistic activity. The most promising, compound 6, (4-(cyclopentylmethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine; K_i = 63 nM) was selected for further in vitro evaluation: blood-brain barrier permeability (PAMPA assay; P_e = 12.26 × 10⁻⁶ cm/s) and toxicity tests (HepG2 and SH-5YSY cells; no toxicity up to 50 µM). Next, compound 6 tested in vivo in a carrageenan-induced inflammatory pain model showed anti-inflammatory and analgesic effects (strongest at 50 mg/kg i.p.). Furthermore, in a histamine- and chloroquine-induced pruritus model, compound 6 at a dose of 25 mg/kg i.p. and 50 mg/kg i.p., respectively, reduced the number of scratch bouts. Thus, compound 6 is a promising ligand for further studies.

Background: Multitarget-directed ligands (MTDLs), particularly those combining cholinesterase inhibition with additional mechanisms, are promising candidates for Alzheimer’s disease (AD) therapy. Based on our previous identification of a dual-active coumarin derivative, we designed a new series of 7-alkoxyamino-3-(1,2,3-triazole)-coumarins. Methods: These compounds were synthesized by a new Sonogashira protocol and evaluated for AChE and BChE inhibition, enzymatic kinetics, molecular docking, neurotoxicity in SH-SY5Y cells, neuroprotection against H₂O₂-induced oxidative stress, and additional interactions with H₃R and MAOs. Results: All derivatives inhibited AChE with IC₅₀ values of 4–104 nM, displaying high selectivity over BChE (up to 686-fold). Kinetic and docking studies indicated mixed-type inhibition involving both CAS and PAS. The most potent compounds (1h, 1j, 1k, 1q) were non-neurotoxic up to 50 µM, while 1h and 1k also showed neuroprotective effects at 12.5 µM. Selected derivatives (1b, 1h, 1q) demonstrated multitarget potential, including H₃R affinity (K_i as low as 32 nM for 1b) and MAO inhibition (IC₅₀ of 1688 nM for 1q). Conclusions: This series of coumarin–triazole derivatives combines potent and selective AChE inhibition with neuroprotective and multitarget activities, highlighting their promise as candidates for AD therapy.

Autism spectrum disorder is a complex neurodevelopmental disorder. The available medical treatment options for autism spectrum disorder are very limited. While the etiology and pathophysiology of autism spectrum disorder are still not fully understood, recent studies have suggested that wide alterations in the GABAergic, glutamatergic, cholinergic, and serotonergic systems play a key role in its development and progression. Histamine neurotransmission is known to have complex interactions with other neurotransmitters that fit perfectly into the complex etiology of this disease. Multitarget-directed compounds with an affinity for the histamine H₃ receptor indicate an interesting profile of activity against autism spectrum disorder in animal models. Here, we present the results of our research on the properties of (4-piperazin-1-ylbutyl)guanidine derivatives acting on histamine H₃ receptors as potential multitarget ligands. Through the virtual screening approach, we identified promising ligands among 32 non-imidazole histamine H₃ receptor antagonists/inverse agonists with potential additional activity against the dopamine D₂ receptor and/or cholinesterases. The virtual screening protocol integrated predictions from SwissTargetPrediction, SEA, and PPB2 tools, along with molecular docking simulations conducted using GOLD 5.3 and Glide 7.5 software. Among the selected ligands, compounds 25 and 30 blocked radioligand binding to the D₂ receptor at over 50% at a screening concentration of 1 µM. Further experiments allowed us to determine the pK_i value at the D₂ receptor of 6.22 and 6.12 for compounds 25 and 30, respectively. Our findings suggest that some of the tested compounds could be promising multitarget-directed ligands for the further research and development of more effective treatments for autism spectrum disorder.

Neurodegenerative diseases are a major public health problem due to the aging population and multifaceted pathology; therefore, the search for new therapeutic alternatives is of the utmost importance. In this sense, a series of six 1-(3-phenoxypropyl)piperidines alkyl-linked to a triphenylphosphonium cation derivative were synthesized as H₃R ligands with antioxidant properties to regulate excessive mitochondrial oxidative stress and contribute to potential new therapeutic approaches for neurodegenerative diseases. Radioligand displacement studies revealed high affinity for H₃R with Ki values in the low to moderate two-digit nanomolar range for all compounds. Compound 6e showed the highest affinity (Ki H₃R = 14.1 nM), comparable to that of pitolisant. Antioxidative effects were evaluated as radical-scavenging properties using the ORAC assay, in which all derivatives showed low to moderate activity. On the other hand, cytotoxic effects in SH-SY5Y neuroblastoma cells were investigated using the colorimetric alamar blue assay, which revealed significant effects on cell viability with an unequivocally structure–toxicity relationship. Finally, docking and molecular simulation studies were used to determine the H₃R binding form, which will allow us to further modify the compounds to establish a robust structure-activity relationship and find a lead compound with therapeutic utility in neurodegenerative diseases.