Uncovering the unique characteristics of different groups of 5-HTR ligands with reference to their interaction with the target protein.

Background: The serotonin 5-HT receptor has attracted much more research attention, due to the therapeutic potential of its ligands being increasingly recognized, and the possibilities that lie ahead of these findings. There is a growing body of evidence indicating that these ligands have procognitive, pro-social, and anti-depressant properties, which offers new avenues for the development of treatments that could address socially important conditions related to the malfunctioning of the central nervous system. The aim of our study was to unravel the molecular determinants for 5-HTR ligands that govern their activity towards the receptor.

Unraveling psilocybin's therapeutic potential: behavioral and neuroplasticity insights in Wistar-Kyoto and Wistar male rat models of treatment-resistant depression.

Rationale: Our study aimed to unravel the unknown mechanisms behind the exceptional efficacy of Psilocybin (PSI) in treating treatment-resistant depression (TRD). Focusing on Wistar-Kyoto (WKY) rats with a TRD phenotype and Wistar (WIS) rats as a normative comparison, we investigated behavioral and neuroplasticity-related responses to PSI, striving to shed light on the distinctive features of its antidepressant effects.

Objectives: We set out to assess the behavioral impact of acute and prolonged PSI administration on WKY and WIS rats, employing Novel Object Recognition (NORT), Social Interaction (SI), and Forced Swimming Test (FST).

Assessing health risks in bottled water: chemical compounds and their impact on human health.

Bottled mineral and spring water constitute one of the main sources of drinking water. Relevant legal acts in each country individually regulate the highest permitted concentrations of harmful substances in these waters. However, current regulations do not take into account newly emerging contaminants such as BPA.

The differential influence of PZM21, a nonrewarding μ-opioid receptor agonist with G protein bias, on behavioural despair and fear response in mice.

A growing body of evidence points out the involvement of the µ-opioid receptors in the modulation of stress-related behaviour. It has been suggested that µ-opioid receptor agonists may attenuate behavioural despair following animals' exposure to an acute, inescapable stressor. Moreover, morphine was shown to ameliorate fear memories caused by a traumatic experience.

Design and Synthesis of New Quinazolin-4-one Derivatives with Negative mGlu Receptor Modulation Activity and Antipsychotic-Like Properties.

Following the glutamatergic theory of schizophrenia and based on our previous study regarding the antipsychotic-like activity of mGlu NAMs, we synthesized a new compound library containing 103 members, which were examined for NAM mGlu activity in the T-REx 293 cell line expressing a recombinant human mGlu receptor. Out of the twenty-two scaffolds examined, active compounds were found only within the quinazolinone chemotype. 2-(2-Chlorophenyl)-6-(2,3-dimethoxyphenyl)-3-methylquinazolin-4(3)-one (, , mGlu IC = 6.

Zinc Deficiency Blunts the Effectiveness of Antidepressants in the Olfactory Bulbectomy Model of Depression in Rats.

Currently used antidepressants do not always provide the desired results, and many patients suffer from treatment-resistant depression. Clinical studies suggest that zinc deficiency (ZnD) may be an important risk factor for depression and might blunt the effect of antidepressants. This study aimed to examine whether ZnD might blunt the effectiveness of antidepressants in the olfactory bulbectomy model (OB) of depression in rats.

Effects of ketamine optical isomers, psilocybin, psilocin and norpsilocin on time estimation and cognition in rats.

Rationale: Ketamine and psilocybin belong to the rapid-acting antidepressants but they also produce psychotomimetic effects including timing distortion. It is currently debatable whether these are essential for their therapeutic actions. As depressed patients report that the "time is dragging," we hypothesized that ketamine and psilocybin-like compounds may produce an opposite effect, i.

Comparison of an Addictive Potential of μ-Opioid Receptor Agonists with G Protein Bias: Behavioral and Molecular Modeling Studies.

Among different approaches to the search for novel-safer and less addictive-opioid analgesics, biased agonism has received the most attention in recent years. Some μ-opioid receptor agonists with G protein bias, including SR compounds, were proposed to induce diminished side effects. However, in many aspects, behavioral effects of those compounds, as well as the mechanisms underlying differences in their action, remain unexplored.

New 1,2,4-oxadiazole derivatives with positive mGlu receptor modulation activity and antipsychotic-like properties.

Considering the allosteric regulation of mGlu receptors for potential therapeutic applications, we developed a group of 1,2,4-oxadiazole derivatives that displayed mGlu receptor positive allosteric modulatory activity (EC = 282-656 nM). Selectivity screening revealed that they were devoid of activity at mGlu, mGlu and mGlu receptors, but modulated mGlu and mGlu receptors, thus were classified as group III-preferring mGlu receptor agents. None of the compounds was active towards hERG channels or in the mini-AMES test.

Structure-Based Design and Optimization of FPPQ, a Dual-Acting 5-HT and 5-HT Receptor Antagonist with Antipsychotic and Procognitive Properties.

In line with recent clinical trials demonstrating that ondansetron, a 5-HT receptor (5-HTR) antagonist, ameliorates cognitive deficits of schizophrenia and the known procognitive effects of 5-HT receptor (5-HTR) antagonists, we applied the hybridization strategy to design dual-acting 5-HT/5-HTR antagonists. We identified the first-in-class compound , which behaves as a 5-HTR antagonist and a neutral antagonist 5-HTR of the Gs pathway. shows selectivity over 87 targets and decent brain penetration.

-Skatyltryptamines-Dual 5-HTR/DR Ligands with Antipsychotic and Procognitive Potential.

A series of -skatyltryptamines was synthesized and their affinities for serotonin and dopamine receptors were determined. Compounds exhibited activity toward 5-HT, 5-HT, 5-HT, and D receptors. Substitution patterns resulting in affinity/activity switches were identified and studied using homology modeling.

Tuning the activity of known drugs via the introduction of halogen atoms, a case study of SERT ligands - Fluoxetine and fluvoxamine.

The selective serotonin reuptake inhibitors (SSRIs), acting at the serotonin transporter (SERT), are one of the most widely prescribed antidepressant medications. All five approved SSRIs possess either fluorine or chlorine atoms, and there is a limited number of reports describing their analogs with heavier halogens, i.e.

Low Basicity as a Characteristic for Atypical Ligands of Serotonin Receptor 5-HT2.

Serotonin receptors are extensively examined by academic and industrial researchers, due to their vital roles, which they play in the organism and constituting therefore important drug targets. Up to very recently, it was assumed that the basic nitrogen in compound structure is a necessary component to make it active within this receptor system. Such nitrogen interacts in its protonated form with the aspartic acid from the third transmembrane helix (D3x32) forming a hydrogen bond tightly fitting the ligand in the protein binding site.

Molecular Modeling of µ Opioid Receptor Ligands with Various Functional Properties: PZM21, SR-17018, Morphine, and Fentanyl-Simulated Interaction Patterns Confronted with Experimental Data.

Molecular modeling approaches are an indispensable part of the drug design process. They not only support the process of searching for new ligands of a given receptor, but they also play an important role in explaining particular activity pathways of a compound. In this study, a comprehensive molecular modeling protocol was developed to explain the observed activity profiles of selected µ opioid receptor agents: two G protein-biased µ opioid receptor agonists(PZM21 and SR-17018), unbiased morphine, and the β-arrestin-2-biased agonist,fentanyl.

Virtual screening-driven discovery of dual 5-HT/5-HT receptor ligands with pro-cognitive properties.

A virtual screening campaign aimed at finding structurally new compounds active at 5-HTR provided a set of candidates. Among those, one structure, 4-(5-{[(2-{5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)amino]methyl}furan-2-yl)phenol (1, 5-HTR K = 91 nM), was selected as a hit for further optimization. As expected, the chemical scaffold of selected compound was significantly different from all the serotonin receptor ligands published to date.

Serotonin type 5A receptor antagonists inhibit D-lysergic acid diethylamide discriminatory cue in rats.

Purpose: Like other psychedelics, D-lysergic acid diethylamide (LSD) affects numerous serotonin receptors, and according to the current dogma, the 5-HT receptors are considered the main target for its hallucinogenic effects. LSD, however, also displays agonistic activity at the 5-HT receptors, which mediate some of LSD-induced behavioural effects.

Methods: Using male Sprague Dawley rats, we examined the effects of 5-HT and 5-HT receptor antagonists on LSD-induced stimulus control in the two-lever drug discrimination test using a FR10 schedule of reinforcement.

Functional characterization of a novel opioid, PZM21, and its effects on the behavioural responses to morphine.

Background And Purpose: The concept of opioid ligands biased towards the G protein pathway with minimal recruitment of β-arrestin-2 is a promising approach for the development of novel, efficient, and potentially nonaddictive opioid therapeutics. A recently discovered biased μ-opioid receptor agonist, PZM21, showed analgesic effects with reduced side effects. Here, we aimed to further investigate the behavioural and biochemical properties of PZM21.

2-Aminoimidazole-based antagonists of the 5-HT receptor - A new concept in aminergic GPCR ligand design.

A new strategy in the design of aminergic GPCR ligands is proposed - the use of aromatic, heterocyclic basic moieties in place of the evergreen piperazine or alicyclic and aliphatic amines. This hypothesis has been tested using a benchmark series of 5-HTR antagonists obtained by coupling variously substituted 2-aminoimidazole moieties to the well established 1-benzenesulfonyl-1H-indoles, which served as the ligands cores. The crystallographic studies revealed that upon protonation, the 2-aminoimidazole fragment triggers a resonance driven conformational change leading to a form of higher affinity.

Fluorinated indole-imidazole conjugates: Selective orally bioavailable 5-HT receptor low-basicity agonists, potential neuropathic painkillers.

The 5-HT receptor has recently gained much attention due to its involvement in multiple physiological functions and diseases. The insufficient quality of the available molecular probes prompted design of fluorinated 3-(1-alkyl-1H-imidazol-5-yl)-1H-indoles as a new generation of selective 5-HT receptor agonists. A potent and drug-like agonist, 3-(1-ethyl-1H-imidazol-5-yl)-5-iodo-4-fluoro-1H-indole (AGH-192, 35, K = 4 nM), was identified by optimizing the halogen bond formation with Ser5.

Oncotoxic Properties of Serotonin Transporter Inhibitors and 5-HT Receptor Ligands.

The cytotoxic activity of several serotonin transporter (SERT) inhibitors and subtype of serotonin receptor 1A (5-HT receptor) ligands have been examined in androgen-insensitive human PC-3 prostate and neuroblastoma SH-SY5Y cancer cells. Almost all of the studied compounds (except 5-HT receptor agonist (2)-(+)-8-Hydroxy-2-(di--propylamino)tetralin hydrobromide (8-OH-DPAT)) exhibited absolute cytotoxic activity against the examined cancer cells. The compound 4-Fluoro--[2-[4-(7-methoxy-1-naphthalenyl)-1-piperazinyl]ethyl]benzamide hydrochloride (S14506) that showed highest activity against neuroblastoma tumors was the 5-HT receptor agonist (although not alike other 5-HT receptor agonists).

5-HT1A receptor ligands and their therapeutic applications: review of new patents.

Introduction: 5-HTR was one of the first discovered serotonin receptors and is one of the most thoroughly studied. Dysfunctions associated with 5-HTR neurotransmission are linked to several psychiatric disorders, including anxiety, depression, and movement disorders.

Areas Covered: The current review covers patent literature published between January 2012 and May 2018.

Low-basicity 5-HT Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol.

A series of 5-aryl-1-alkylimidazole derivatives was synthesized using the van Leusen multicomponent reaction. The chemotype is the first example of low-basicity scaffolds exhibiting high affinity for 5-HT receptor together with agonist function. The chosen lead compounds 3-(1-ethyl-1H-imidazol-5-yl)-5-iodo-1H-indole (AGH-107, 1o, K  = 6 nM, EC = 19 nM, 176-fold selectivity over 5-HTR) and 1e (5-methoxy analogue, K  = 30 nM, EC = 60 nM) exhibited high selectivity over related CNS targets, high metabolic stability and low toxicity in HEK-293 and HepG2 cell cultures.

Inhibition of PDE5A1 guanosine cyclic monophosphate (cGMP) hydrolysing activity by sildenafil analogues that inhibit cellular cGMP efflux.

Objectives: To determine the ability of 11 sildenafil analogues to discriminate between cyclic nucleotide phosphodiesterases (cnPDEs) and to characterise their inhibitory potencies (K values) of PDE5A1-dependent guanosine cyclic monophosphate (cGMP) hydrolysis.

Methods: Sildenafil analogues were identified by virtual ligand screening (VLS) and screened for their ability to inhibit adenosine cyclic monophosphate (cAMP) hydrolysis by PDE1A1, PDE1B1, PDE2A1, PDE3A, PDE10A1 and PDE10A2, and cGMP hydrolysis by PDE5A, PDE6C, PDE9A2 for a low (1 nm) and high concentration (10 μm). Complete IC plots for all analogues were performed for PDE5A-dependent cGMP hydrolysis.