AR71, Histamine H3 Receptor Ligand-In Vitro and In Vivo Evaluation (Anti-Inflammatory Activity, Metabolic Stability, Toxicity, and Analgesic Action).

The future of therapy for neurodegenerative diseases (NDs) relies on new strategies targeting multiple pharmacological pathways. Our research led to obtaining the compound AR71 [(E)-3-(3,4,5-trimethoxyphenyl)-1-(4-(3-(piperidin-1-yl)propoxy)phenyl)prop-2-en-1-one], which has high affinity for human H3R (Ki = 24 nM) and selectivity towards histamine H1 and H4 receptors (Ki > 2500 nM), and showed anti-inflammatory activity in a model of lipopolysaccharide-induced inflammation in BV-2 cells. The presented tests confirmed its antagonist/inverse agonist activity profile and good metabolic stability while docking studies showed the binding mode to histamine H1, H3, and H4 receptors. In in vitro tests, cytotoxicity was evaluated at three cell lines (neuroblastoma, astrocytes, and human peripheral blood mononuclear cells), and a neuroprotective effect was observed in rotenone-induced toxicity. In vivo experiments in a mouse neuropathic pain model demonstrated the highest analgesic effects of AR71 at the dose of 20 mg/kg body weight. Additionally, AR71 showed antiproliferative activity in higher concentrations. These findings suggest the need for further evaluation of AR71's therapeutic potential in treating ND and CNS cancer using animal experimental models.

Dual 5-HT6/SERT ligands for mitigating neuropsychiatric symptoms of dementia exerting neuroprotection against amyloid-ß toxicity, memory preservation, and antidepressant-like properties.

In light of the biological targets alterations in dementia patients suffering from neuropsychiatric symptoms, particularly in the 5-HT6 receptor and SERT transporters, this study aimed to develop dual-acting molecules targeting both these targets. By combining a 5-substituted indole with piperazine scaffolds, we synthesized molecules with nanomolar affinities for these sites, avoiding interaction with off-targets detrimental to dementia patients. Preliminary pharmacodynamic and ADMET assays let the identification of compound 15 as a lead molecule. In vitro studies showed that 15 provided neuroprotection against Aß toxicity and reduced the levels of proapoptotic enzymes: caspase 3 and 7. In vivo, 15 reversed MK-801-induced memory deficits and exhibited antidepressant-like effects. Further studies showed that acute administration of compound 15 at a dose of 5 mg/kg increased BDNF levels, which are crucial for supporting neuronal survival and potentially slowing cognitive decline in dementia. These findings suggest 15's potential as a therapeutic for behavioral and psychological symptoms of dementia (BPSD), warranting further investigation.

4-Oxypiperidine Ethers as Multiple Targeting Ligands at Histamine H3 Receptors and Cholinesterases.

This study examines the properties of a novel series of 4-oxypiperidines designed and synthesized as histamine H3R antagonists/inverse agonists based on the structural modification of two lead compounds, viz., ADS003 and ADS009. The products are intended to maintain a high affinity for H3R while simultaneously inhibiting AChE or/and BuChE enzymes. Selected compounds were subjected to hH3R radioligand displacement and gpH3R functional assays. Some of the compounds showed nanomolar affinity. The most promising compound in the naphthalene series was ADS031, which contained a benzyl moiety at position 1 of the piperidine ring and displayed 12.5 nM affinity at the hH3R and the highest inhibitory activity against AChE (IC50 = 1.537 µM). Eight compounds showed over 60% eqBuChE inhibition and hence were qualified for the determination of the IC50 value at eqBuChE; their values ranged from 0.559 to 2.655 µM. Therapy based on a multitarget-directed ligand combining H3R antagonism with additional AChE/BuChE inhibitory properties might improve cognitive functions in multifactorial Alzheimer's disease.

First-in-Class Selenium-Containing Potent Serotonin Receptor 5-HT6 Agents with a Beneficial Neuroprotective Profile against Alzheimer's Disease.

Alzheimer's disease (AD) has a complex and not-fully-understood etiology. Recently, the serotonin receptor 5-HT6 emerged as a promising target for AD treatment; thus, here a new series of 5-HT6R ligands with a 1,3,5-triazine core and selenoether linkers was explored. Among them, the 2-naphthyl derivatives exhibited strong 5-HT6R affinity and selectivity over 5-HT1AR (13-15), 5-HT7R (14 and 15), and 5-HT2AR (13). Compound 15 displayed high selectivity for 5-HT6R over other central nervous system receptors and exhibited low risk of cardio-, hepato-, and nephrotoxicity and no mutagenicity, indicating its "drug-like" potential. Compound 15 also demonstrated neuroprotection against rotenone-induced neurotoxicity as well as antioxidant and glutathione peroxidase (GPx)-like activity and regulated antioxidant and pro-inflammatory genes and NRF2 nuclear translocation. In rats, 15 showed satisfying pharmacokinetics, penetrated the blood-brain barrier, reversed MK-801-induced memory impairment, and exhibited anxiolytic-like properties. 15's neuroprotective and procognitive-like effects, stronger than those of the approved drug donepezil, may pave the way for the use of selenotriazines to inhibit both causes and symptoms in AD therapy.