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Based on pyrroloquinoline scaffold bearing 5-HT 2C agonists, a series of arylsulfonamide derivatives of 1 H -pyrrolo[2,3- f ]quinoline and 1 H- pyrrolo[3,2- h ]quinoline, substituted at position 3 with tetrahydropyridine, were synthesized and evaluated in vitro for their affinity for 5-HT 6 receptors. A structure–activity relationship study showed that the 1 H- pyrrolo[3,2- h ]quinoline scaffold was more favorable for 5-HT 6 R binding than the 1 H -pyrrolo[2,3- f ]quinoline one, suggesting dependence upon the type of condensation of the pyrrole and quinoline rings. As revealed by quantum-chemical calculations and molecular dynamic studies, position of the quinoline nitrogen atom in the planar pyrroloquinoline skeleton might affect the spatial orientation of the arylsulfonyl fragment, as a result of structure stabilization by internal hydrogen bonds. [ABSTRACT FROM AUTHOR]

This paper presents a computer-aided insight into the receptor-ligand interaction for novel analogs of the lead structure 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione ( 1, MF-8), as part of the search for potent and selective serotonin 5-HT 7 receptor (5-HT 7 R) agents. New hydantoin derivatives ( 4 - 19 ) were designed and synthesized. For 5-phenyl-3-(2-hydroxy-3-(4-(2-ethoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione ( 4 ), its crystal structure was determined experimentally. Molecular modeling studies were performed, including both pharmacophore and structure-based approaches. New compounds were investigated in radioligand binding assays (RBA) for their affinity toward 5-HT 7 R and selectivity over 5-HT 1A R, dopamine D 2 R and α 1 -, α 2 -and β-adrenoceptors. Selected compounds ( 5 - 8 ) were assessed for their antidepressant and anxiolytic effects in vivo in mice. Most of the tested compounds displayed potent affinity and selectivity for 5-HT 7 R in RBA, in particular seven compounds ( 4, 5, 7, 8 and 10-12, K i  ≤ 10 nM). Antidepressant-like activity in vivo for all tested compounds ( 5 - 8 ) was confirmed. SAR analysis based on both crystallography-supported molecular modeling and RBA results indicated that mono -phenyl substituents at both hydantoin and piperazine are more favorable for 5-HT 7 R affinity than the di -phenyl ones. [ABSTRACT FROM AUTHOR]

The work describes a discovery of new chemical family of potent ligands for the 5-HT 6 serotonin receptors. During the search for new histamine H 4 receptor antagonists among 1,3,5-triazine derivatives, compound 2 (4-benzyl-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine) was found. Compound 2 , weakly active for the H 4 receptor but fitted in 3/4 of pharmacophore features of the 5-HT 6 R ligand, occurred to be a moderate 5-HT 6 R agent, useful as a lead structure for further modifications. A series of new derivatives ( 3 – 19 ) of the lead 2 was synthesized, evaluated in the radioligand binding assay (RBA) and explored in comprehensive molecular modelling, including both pharmacophore- and structure-based approaches with docking to the homology model of 5-HT 6 R. The most active compounds displayed a potent affinity for the 5-HT 6 R in the nanomolar range (K i = 20–30 nM), some of them ( 4 , 11 and 19 ) were tested in the rat forced swim test that revealed their antidepressant-like effect. SAR-analysis on the basis of both, RBA and docking results, indicated that action on the receptor is related to the hydrophobicity and the size of aromatic moiety substituted by a methylene linker at the position 4 of 1,3,5-triazine. [ABSTRACT FROM AUTHOR]

A series of azinesulfonamides of long-chain arylpiperazine derivatives with semi-rigid alkylene spacer was designed, synthesized, and biologically evaluated using in vitro methods for their affinity for dopaminergic D 2 and serotoninergic 5-HT 1A , 5-HT 2A , 5-HT 6 and 5-HT 7 receptors. Docking to homology models revealed a possible halogen bond formation in complexes of the most potent ligands and the target receptors. The study allowed for the identification of compound 5-({4-(2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl)piperidin-1-yl}sulfonyl)quinoline ( 21 ), which behaved as D 2 , 5-HT 1A and 5-HT 7 receptor antagonist. In preliminary in vivo studies, compound 21 displayed distinct antipsychotic properties in the MK-801-evoked hyperactivity test in mice at a dose of 10 mg/kg, and exerted antidepressant-like effect in a forced swim test in mice (MED = 0.625 mg/kg, i.p .). [ABSTRACT FROM AUTHOR]

A series of 39 arylsulfonamide/amide derivatives of (aryloxy)ethyl alkyl amines, was designed with the support of the Virtual Combinatorial Library-Virtual Screening protocol, and synthesized using solid-phase methodologies. Representative compounds were biologically evaluated for their affinity for 5-HT 7 Rs and for their selectivity over related 5-HTRs (5-HT 1A Rs, 5-HT 2A Rs, 5-HT 6 Rs), dopamine D 2 Rs and adrenergic α 1 Rs. The study identified the derivatives 27 (3-fluoro-N-{1-[2-(2-cyclopentylphenoxy)ethyl]piperidin-4-yl}-benzenesulfonamide; PZ-1417) and 35 (4-fluoro-N-(1-{2-[(propan-2-yl)phenoxy]ethyl}-8-azabicyclo[3.2.1]octan-3-yl)-benzenesulfonamide; PZ-1150) as being potent 5-HT 7 R antagonists with antidepressant and anxiolytic properties in the forced swim test (0.625–5 mg/kg and 0.625 mg/kg, respectively), the tail suspension test (0.625 mg/kg and 0.625 mg/kg, respectively), and in four plate test (0.625 mg/kg and 1.25–2.5 mg/kg, respectively) in mice. It has to be stressed that new compounds displayed higher activity than that of SB-269970, a reference 5-HT 7 R antagonist. Finally, the study provided valuable insight into the development of potential therapeutic agents for the treatment of CNS disorders. [ABSTRACT FROM AUTHOR]

The N -alkylation of the sulfonamide moiety, in a group of arylsulfonamide derivatives of (aryloxy)ethyl piperidines, may be considered as a strategy for the design of selective 5-HT 7 receptor ligands or multifunctional agents to extend a polypharmacological approach to the treatment of complex diseases. The study allowed for the identification of 31 (1-methyl- N -{1-[2-(2-( t -butyl)phenoxy)ethyl]piperidin-4-yl}- N -cyclopropylmethyl-1 H -pyrazole-4-sulfonamide), a potent and selective 5-HT 7 receptor antagonist and 33 (1-methyl- N -{1-[2-(biphenyl-2-yloxy)ethyl]piperidin-4-yl}- N -cyclopropylmethyl-1 H -pyrazole-4-sulfonamide), as multimodal 5-HT/dopamine receptor ligand, as 5-HT 2A /5-HT 7 /D 2 receptor antagonists. Both selected compounds were evaluated in vivo in a forced swim test (FST) in mice and in a novel object recognition (NOR) task in rats, demonstrating distinct antidepressant-like and pro-cognitive properties (MED = 1.25 mg/kg and 1 mg/kg, ip, respectively). These findings warrant further studies to explore the therapeutic potential of N -alkylated arylsulfonamides for the treatment of CNS disorders. [ABSTRACT FROM AUTHOR]

Virtual screening towards the search of new 5-HT 6 R ligands was carried out with three different fingerprints used for molecules representation. Two structurally new compounds were found to be characterized by a significant 5-HT 6 R activity ( K i of 119 and 670 nM). The compounds do not possess a positive ionizable group in their structures and therefore they belong to the group of atypical, non-basic 5-HT 6 R ligands. The obtained hits were proved to fit well in the 5-HT 6 R binding cavity by docking and molecular dynamic simulation experiments. Moreover, an in silico evaluation of the ADMET properties of these compounds predicted their drug-like character. [ABSTRACT FROM AUTHOR]

A 26-membered library of novel long-chain arylpiperazines, which contained primary and tertiary amides of cyclic amino acids (proline and 1,2,3,4-tetrahydroisoquinoline-3-carboxamide) in the terminal fragment was synthesized and biologically evaluated for binding affinity for 5-HT 7 and 5-HT 1A receptors. Docking studies confirmed advantages of Tic-amide over Pro-amide fragment for interaction with 5-HT 7 receptors. Selected compounds 32 and 28 , which behaved as 5-HT 7 Rs antagonist and 5-HT 1A partial agonist, respectively, produced antidepressant-like effects in the forced swim test in mice after acute treatment in doses of 10 mg/kg ( 32 ) and 1.25 mg/kg ( 28 ). Compound 32 reduced immobility in a manner similar to the selective 5-HT 7 antagonist SB-269970. [ABSTRACT FROM AUTHOR]

Abstract: An analysis of the virtual combinatorial library was used for refining a pilot set of 34 derivatives and designing a targeted 38-member library of the arylamide and arylsulfonamide derivatives of aryloxyethyl- and arylthioethyl- piperidines and pyrrolidines. All compounds 24–95 were synthesized according to an elaborated parallel solid-phase method and were biologically evaluated for their affinity for 5-HT7R. Additionally, the targeted library members were tested for 5-HT1A, 5-HT6, and D2 receptors. Selected compounds of particular interest were examined for their intrinsic activity at 5-HT7R in vitro employing a cAMP assay. The study allowed us to identify compound 68 (4-fluoro-N-(1-{2-[(propan-2-yl)phenoxy]ethyl}piperidin-4-yl) benzenesulfonamide) as a potent 5-HT7R ligand (K i = 0.3 nM) with strong antagonistic properties (K b = 1 nM) and a 1450-fold selectivity over 5-HT1ARs. [Copyright &y& Elsevier]

Abstract: The two main groups of antidepressant drugs, the tricyclic antidepressants (TCAs) and the selective serotonin reuptake inhibitors (SSRIs), as well as several other compounds, act by inhibiting the serotonin transporter (SERT). However, the binding mode and molecular mechanism of inhibition in SERT are not fully understood. In this study, five classes of SERT inhibitors were docked into an outward-facing SERT homology model using a new 4D ensemble docking protocol. Unlike other docking protocols, where protein flexibility is not considered or is highly dependent on the ligand structure, flexibility was here obtained by side chain sampling of the amino acids of the binding pocket using biased probability Monte Carlo (BPMC) prior to docking. This resulted in the generation of multiple binding pocket conformations that the ligands were docked into. The docking results showed that the inhibitors were stacked between the aromatic amino acids of the extracellular gate (Y176, F335) presumably preventing its closure. The inhibitors interacted with amino acids in both the putative substrate binding site and more extracellular regions of the protein. A general structure–docking-based pharmacophore model was generated to explain binding of all studied classes of SERT inhibitors. Docking of a test set of actives and decoys furthermore showed that the outward-facing ensemble SERT homology model consistently and selectively scored the majority of active compounds above decoys, which indicates its usefulness in virtual screening. [Copyright &y& Elsevier]

Abstract: In an attempt to identify new ligands for the 5-HT7 receptor (5-HT7R), we developed and tested a hierarchical multi-step strategy of virtual screening (VS) based on two-dimensional (2D) pharmacophore similarity, physicochemical scalar descriptors, an ADME/Tox filter, three-dimensional (3D) pharmacophore searches and a docking protocol. Six chemical classes of 5-HT7R antagonists were used as query structures in a double-path virtual screening scheme. The Enamine screening database, consisting of approximately 730,000 commercially available drug-like compounds, was adopted and used as a source of structures. A biological evaluation of 26 finally selected virtual hits resulted in finding two benzodioxane derivatives with significant affinity (K i =197 and 265nM). The approach described in this case study can be easily used as a general rational drug design tool for other biological targets. [Copyright &y& Elsevier]

A virtual screening campaign aimed at finding structurally new compounds active at 5-HT 6 R 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-HT 6 R K i = 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. Synthetic efforts, supported by molecular modelling, provided 43 compounds representing different substitution patterns. The derivative 42, 4-(5-{[(2-{5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)amino]methyl}furan-2-yl)phenol (5-HT 6 R K i = 25, 5-HT 2A R K i = 32 nM), was selected as a lead and showed a good brain/plasma concentration profile, and it reversed phencyclidine-induced memory impairment. Considering the unique activity profile, the obtained series might be a good starting point for the development of a novel antipsychotic or antidepressant with pro-cognitive properties. Image 1 • Serotonin receptor ligands with a unique activity profile have been synthesized. • The selected hit showed a dual 5-HT6/5-HT2A receptor activity. • Synthesized compound showed procognitive properties in vivo. [ABSTRACT FROM AUTHOR]

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-HT 6 R antagonists obtained by coupling variously substituted 2-aminoimidazole moieties to the well established 1-benzenesulfonyl-1 H -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. This molecular switch may be responsible for the observed differences in 5-HT 6 R activity of the studied chemotypes with different amine-like fragments. Considering the multiple functionalization sites of the embedded guanidine fragment, diverse libraries were constructed, and the relationships between the structure and activity, metabolic stability, and solubility were established. Compounds from the N -(1 H -imidazol-2-yl)acylamide chemotype (10a – z) exhibited high affinity for 5-HT 6 R and very high selectivity over 5-HT 1A , 5-HT 2A , 5-HT 7 and D 2 receptors (negligible binding), which was attributed to their very weak basicity. The lead compound in the series 4-methyl-5-[1-(naphthalene-1-sulfonyl)-1 H -indol-3-yl]-1 H -imidazol-2-amine (9i) was shown to reverse the cognitive impairment caused by the administration of scopolamine in rats indicating procognitive potential. Image 1 • The first synthetic aminergic GPCR ligands built around the 2-aminoimidazole fragment. • Several differently functionalized 2-aminoimidazole based fragments tested. • Potent and very selective 5-HT 6 R antagonists revealed. • A significant conformational change occurs upon protonation of the amidine fragment. • Compound 9i (AHN-208) exhibited procognitive properties in NOR assay. [ABSTRACT FROM AUTHOR]

A series of novel combretastatin A-4 (CA-4) thio derivatives containing different molecular cores, namely α-phenylcinnamic acids (core 1), ( Z )-stilbenes (core 2), 4,5-disubstituted oxazoles (core 3), and 4,5-disubstituted N-methylimidazoles (core 4), as cis -restricted analogues were designed and synthesized. They were selected with the use of a parallel virtual screening protocol including the generation of a virtual combinatorial library based on an elaborated synthesis protocol of CA-4 analogues. The selected compounds were evaluated for antiproliferative activity against a panel of six human cancer cell lines (A431, HeLa, MCF7, MDA-MB-231, A549 and SKOV) and two human non-cancer cell lines (HaCaT and CCD39Lu). Moreover, the effect of the test compounds on the inhibition of tubulin polymerization in vitro was estimated. In the series studied here, oxazole-bridged analogues exhibited the most potent antiproliferative activity. Compounds 23a , 23e , and 23i efficiently inhibited tubulin polymerization with IC 50 values of 0.86, 1.05, and 0.85 μ M, respectively. Thio derivative 23i , when compared to its oxygen analogue 23j , showed a 5-fold higher inhibitory impact on tubulin polymerization. Compounds 23e and 23i , which showed both best cytotoxic and antitubulin activity, were further studied in terms of their effect on cell cycle distribution and proapoptotic activity. Compound 23e induced a statistically significant block of the cell cycle at the G2/M phase in A431, HaCaT, HeLa, MCF-7, MDA-MB-231, and SKOV-3 cells to an extent comparable to that observed in CA-4. In HeLa and SKOV-3 cells incubated with 23i , a concentration-dependent block of the G2/M phase was observed. The proapoptotic effect of 23e and 23i in A431, HaCaT, MCF-7, MDA-MB-231, and SKOV-3 was demonstrated with ELISA assay and double staining with Annexin V-FITC/PI. The results indicated that compound 23e and 23i may serve as novel lead compounds in research on more effective anticancer agents. [ABSTRACT FROM AUTHOR]

A novel series of arylsulfonamide derivatives of (aryloxy)propyl piperidines was designed to obtain potent 5-HT 7 R antagonists. Among the compounds evaluated herein, 3-chloro- N -{1-[3-(1,1-biphenyl-2-yloxy)2-hydroxypropyl]piperidin-4-yl}benzenesulfonamide ( 25 ) exhibited antagonistic properties at 5-HT 7 R and showed selectivity over selected serotoninergic and dopaminergic receptors, as well as over serotonin, noradrenaline and dopamine transporters. Compound 25 demonstrated significant antidepressant-like activity in the forced swim test (0.625–2.5 mg/kg, i . p .) and in the tail suspension test (1.25 mg/kg, i . p .), augmented the antidepressant effect of inactive doses of escitalopram (selective serotonin reuptake inhibitor) and bupropion (dopamine reuptake inhibitor) in the FST in mice, and similarly to SB-269970, exerted pro-cognitive properties in the novel object recognition task in cognitively unimpaired conditions in rats (0.3 mg/kg, i . p .). Such an extended pharmacological profile, especially the augmentation effect of the identified 5-HT 7 R antagonist on SSRI activity, seems promising regarding the complexity of affective disorders and potentially improved outcomes, including mnemonic performance. [ABSTRACT FROM AUTHOR]

The serotonin type 6 receptor (5-HT 6 R) displays a strong constitutive activity, suggesting it participates largely in the physiological and pathological processes controlled by the receptor. The active states of 5-HT 6 R engage particular signal transduction pathways that lead to different biological responses. In this study, we present the development of 5-HT 6 R neutral antagonists at Gs signaling built upon the 2-phenylpyrrole scaffold. Using molecular dynamics simulations, we outline the relationship between the exposure of the basic center of the molecules and their ability to target the agonist-activated state of the receptor. Our study identifies compound 30 as a potent and selective neutral antagonist at 5-HT 6 R-operated Gs signaling. Furthermore, we demonstrate the cytoprotective effects of 30 and structurally diverse 5-HT 6 R neutral antagonists at Gs signaling in C8-D1A cells and human astrocytes exposed to rotenone. This effect is not observed for 5-HT 6 R agonists or inverse agonists. In light of these findings, we propose compound 30 as a valuable molecular probe to study the biological effects associated with the agonist-activated state of 5-HT 6 R and provide insight into the glioprotective properties of 5-HT 6 R neutral antagonists at Gs signaling. [Display omitted] • A novel framework for 5-HT 6 R ligands derived from 2-phenylpyrrole. • Exposure of the basic center is cricial to target different active states of 5-HT 6 R. • Compound 30 behaves as neutral antagonist at 5-HT 6 R-operated Gs signaling. • 5-HT 6 R neutral antagonists show cytoprotective effect in C8-D1A and human astrocytes. • Agonists and inverse agonists of 5-HT 6 R produce no cytoprotective effect. [ABSTRACT FROM AUTHOR]

Abstract: A 47-membered library of novel long-chain arylpiperazines, which contained cyclic amino acid amides in the terminal fragment (pyrrolidine-2-carboxamide and 1,2,3,4-tetrahydroisoquinoline-3-carboxamide), was synthesized on Rink-amide resin and biologically evaluated for binding affinity for 5-HT7 and 5-HT1A receptors. Surprisingly, members of the designed series containing piperidine-2-carboxamide fragments underwent hydrolysis, which occurred during the acidic treatment for release from the solid-support, to their respective pipecolic acid analogs. Representative compounds from the library displayed high-to-low affinity for 5-HT7 (K i = 18–3134 nM) and 5-HT1A (K i = 0.5–6307 nM) sites. The possible interactions implicated in binding of the studied compounds to the 5-HT7 receptor were supported by molecular modeling. Research was also applied to support the exploration of the influence of the amide fragment, the length of alkylene spacer, and arylpiperazine substituents on the receptor's affinity and selectivity. [Copyright &y& Elsevier]

The complex etiology of Alzheimer's disease has initiated a quest for multi-target ligands to address the multifactorial causes of this neurodegenerative disorder. In this context, we designed dual-acting 5-HT 6 receptor (5-HT 6 R) antagonists/MAO-B inhibitors using pharmacophore hybridization strategy. Our approach involved linking priviliged scaffolds of 5-HT 6 R with aryloxy fragments derived from reversible and irreversible MAO-B inhibitors. The study identified compound 48 that acts as an inverse agonist of 5-HT 6 R at G s signaling and an irreversible MAO-B inhibitor. Compound 48 showed moderate metabolic stability in rat microsomal assay, artificial membrane permeability, no hepatotoxicity, and it was well distributed to the brain. Additionally, 48 showed glioprotective properties in a model of cultured astrocytes using 6-OHDA as the cytotoxic agent. Finally, compound 48 (MED = 1 mg/kg, p.o.) fully reversed memory deficits in the NOR task induced by scopolamine in rats. A better understanding of effects exerted by dual-acting 5-HT 6 R/MAO-B modulators may impact the future development of neurodegenerative-directed treatment strategies. Image 1 • Multi-target directed ligands against Alzheimer's disease. • First dual-acting 5-HT 6 R inverse agonist at G s signaling/irreversible MAO-B inhibitor. • Glioprotective properties of 48 in 6-OHDA-induced toxicity. • Reversal of scopolamine-included memory deficits of 48 in the NOR test in rats. [ABSTRACT FROM AUTHOR]

In the light of recent lines of evidence, 5-HT 6 R ligands are a promising tool for future treatment of memory impairment. Hence, this study has supplied highly potent 5-HT 6 R agents with procognitive effects, which represent an original chemical class of 1,3,5-triazines, different from widely studied sulfone and indole-like 5-HT 6 R ligands. The new compounds were rationally designed as modifications of lead, 4-(1-(2-chlorophenoxy)ethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (1), involving an introduction of: (i) two chlorines at benzene ring and (ii) varied linkers joining the triazine ring to aromatic ethers. Synthesis, in vitro and in vivo biological tests and computer-aided SAR analysis for 19 new compounds were carried out. Most of the new triazines displayed high affinity (K i < 100 nM) and selectivity towards 5-HT 6 R, with respect to 5-HT 2A R, 5-HT 7 R and D 2 R. The crystallography-supported docking studies, including quantum-polarized ligand docking (QPLD), indicated that chlorine atoms may be involved in different type of halogen bonding, however, the linker properties seem to predominately affect the 5-HT 6 R affinity. 4-[1-(2,5-Dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (9), which displayed: the highest affinity (K i = 6 nM), very strong 5-HT 6 R antagonistic action (K B = 27 pM), procognitive effects in vivo in novel object recognition (NOR) test in rats, a very good permeability in PAMPA model and satisfying safety in vitro , was identified as the most potent 1,3,5-triazine agent so far, useful as a new lead for further research. Image 1 • Design and synthesis of 19 new (dichloro)phenyloxy derivatives of 1,3,5-triazine. • Radioligand binding assays for 5-HT 6 R target and 5-HT 2A R, 5-HT 7 R, D 2 R. • X-ray crystallography and molecular docking to 5-HT 6 R, including QPLD method. • Functional cAMP assays and drug-like profile in vitro. • Behavioral tests on procognitive effects (NOR and NOL) in vivo in rats. [ABSTRACT FROM AUTHOR]

This research has provided the most active 5-HT 6 R agents among 1,3,5-triazine derivatives investigated to date and has also identified the world's first selenium-containing 5-HT 6 R ligands. The studies are focused on design, synthesis, biological evaluation and docking-supported SAR analysis for novel 5-HT 6 R agents as derivatives of lead structure 4-(4-methylpiperazin-1-yl)-6-(phenoxymethyl)-1,3,5-triazin-2-amine (7). The lead modifications included an introduction of: (i) various small substituents at benzene ring, (ii) a branched ether linker or (iii) the ether oxygen replacement with other chalcogen (S, Se) or sulfonyl moiety. Hence, a series of new compounds (7 – 24) was synthesized and examined on their affinities for 5-HT 6 R and selectivity, in respect to the 5-HT 1A R, 5-HT 2A R, 5-HT 7 R and dopamine D 2 receptor, in the radioligand binding assays. For representative most active compounds functional bioassays and toxicity profile in vitro and antidepressant-like activity in vivo were examined. The 2-isopropyl-5-methylphenyl derivative (10) was found as the most active triazine 5-HT 6 R antagonist (K i = 11 nM). SAR analysis indicated, that an exchange of oxygen to selenium (7 vs. 22), and especially, to sulfur (7 vs. 19) was beneficial to increase both affinity and antagonistic action for 5-HT 6 R. Surprisingly, an introduction of SO 2 caused a drastic decrease of the 5-HT 6 R affinity, which was explained at a molecular level based on docking studies. All in vivo tested compounds (10 , 18 and 21) did not show any risk of toxicity in the safety studies in vitro. Image 1 • Synthesis of new phenyl – (O, S or Se)ether derivatives of 1,3,5-triazine. • Affinity and selectivity for 5-HT 6 R in radioligand binding assay. • Docking studies using the homology model of 5-HT 6 receptor. • Functional profile and toxicity in vitro for most active 5-HT 6 R agents. • Antidepressant-like activity in behavioral tests in vivo for selected compounds. [ABSTRACT FROM AUTHOR]

Abstract The 5-HT 7 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-1 H -imidazol-5-yl)-1 H -indoles as a new generation of selective 5-HT 7 receptor agonists. A potent and drug-like agonist, 3-(1-ethyl-1 H -imidazol-5-yl)-5-iodo-4-fluoro-1 H -indole (AGH-192, 35 , K i 5-HT7 R = 4 nM), was identified by optimizing the halogen bond formation with Ser5.42 as the supposed partner. The compound was characterized by excellent water solubility, high selectivity over related CNS targets, high metabolic stability, oral bioavailability and low cytotoxicity. Rapid absorption into the blood, medium half-life and a high peak concentration in the brain C max = 1069 ng/g were found after i.p. (2.5 mg/kg) administration in mice. AGH-192 may thus serve as the long-sought tool compound in the study of 5-HT 7 receptor function, as well as a potential analgesic, indicated by the antinociceptive effect observed in a mouse model of neuropathic pain. Graphical abstract Image 1 Highlights • AGH-192 is a selective, orally bioavailable, water-soluble 5-HT 7 R agonist. • AGH-192 alleviates the symptoms of neuropathic pain in a mouse model. • AGH-192 is metabolically stable and crosses blood-brain barrier to a high extent. • Slight hyperthermia was observed in the neuropathic mice after AGH-192 injection. • Fluorine plays a dual role in ligand binding, primarily as a halogen bond enhancer. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), a neurodegenerative disorder with a complex aetiology, is the most common memory dysfunction particularly affecting the elderly. Various protein targets have been classified to be involved in the AD treatment, including 5-HT 6 receptor (5-HT 6 R). So far, the 5-HT 6 R ligands obtained by our research group have become a good basis for hydrophobicity modulation to give a chance for more effective action toward AD by additional influence on target enzymes, e.g. cyclin-dependent kinase 5 (CDK5). In the search for 5-HT 6 R agents with additional inhibitory action on the enzyme, a series of 25 new 1,3,5-triazines (7-31) as modifications of lead, 4-[1-(2,5-dichlorophenoxy)propyl]-6-(4-methylpiperazin- 1-yl)-1,3,5-triazine-2-amine (6), was rationally designed. Molecular modelling, synthesis, crystallographic studies, in vitro biological assays and behavioral studies in vivo were performed. The new triazines showed high affinity (K i < 100 nM) and selectivity for 5-HT 6 R. The most effective one, 4-[1-(2,5-difluorophenoxy)propyl]-6-(4-methylpiperazin- 1-yl)-1,3,5-triazine-2-amine (8), exhibited the strong antagonistic action towards 5-HT 6 R (K i = 5 nM, pK b = 8.16), had an impact on the memory processes in the Novel Object Recognition test and displayed anxiolytic-like activity in the Elevated Plus Maze test in rats. Moreover, it had the antiplatelet effect as well as very good permeability (PAMPA model), high metabolic stability (RLMs) and satisfactory safety in vitro. Although the CDK5 inhibitory effects in vitro for the tested compounds (8 , 10 , 14 , 18 , 26-31) missed the potency expected from in silico simulations, the novel antagonist (8) with a very satisfying pharmacological and ADMET profile can serve as a new lead structure in further searches for innovative therapy against AD with accompanying symptoms. [Display omitted] • Computer-aided design and synthesis of 2- and/or 4-substituted 1,3,5-triazines. • Radioligand binding assays for 5-HT 6 R target and 5-HT 1A R, 5-HT 2A R, 5-HT 7 R, D 2 R. • X-ray crystallography and docking to 5-HT 6 R and to CDK5 enzyme. • Functional cAMP studies, CDK5, MAO-B assays and drug-like profile in vitro. • Behavioral NOR, EPM, FST tests for the most active agent 8 in vivo in rats. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is becoming a growing problem increasing at a tremendous rate. Serotonin 5-HT 6 receptors appear to be a particularly attractive target from a therapeutic perspective, due to their involvement not only in cognitive processes, but also in depression and psychosis. In this work, we present the synthesis and broad biological characterization of a new series of 18 compounds with a unique 1,3,5-triazine backbone, as potent 5-HT 6 receptor ligands. The main aim of this research is to compare the biological activity of the newly synthesized sulfur derivatives with their oxygen analogues and their N -demethylated O- and S-metabolites obtained for the first time. Most of the new triazines displayed high affinity (K i < 200 nM) and selectivity towards 5-HT 6 R, with respect to 5-HT 2A R, 5-HT 7 R, and D 2 R, in the radioligand binding assays. For selected, active compounds crystallographic studies, functional bioassays, and ADME-Tox profile in vitro were performed. The exciting novelty is that the sulfur derivatives exhibit an agonistic mode of action contrary to all other compounds obtained to date in this chemical class herein and previously reported. Advanced computational studies indicated that this intriguing functional shift might be caused by presence of chalcogen bonds formed only by the sulfur atom. In addition, the N -demethylated derivatives have emerged highly potent antioxidants and, moreover, show a significant improvement in metabolic stability compared to the parent structures. The cholinesterase study present micromolar inhibitory AChE and BChE activity for both 5-HT 6 agonist 19 and potent antagonist 5. Finally, the behavioral experiments of compound 19 demonstrated its antidepressant-like properties and slight ability to improve cognitive deficits, without inducing memory impairments by itself. Described pharmacological properties of both compounds (5 and 19) allow to give a design clue for the development of multitarget compounds with 5-HT 6 (both agonist and antagonist)/AChE and/or BChE mechanism in the group of 1,3,5-triazine derivatives. [Display omitted] • Synthesis of (thio)ether-1,3,5-triazine derivatives and their metabolites. • Radioligand binding assays for 5-HT 6 R, off-targets and enzymatic assays for ChEs. • X-ray crystallography and molecular modelling with emphasis on molecular dynamics. • Functional cAMP studies and drug-like profile in vitro. • Behavioral NOR, EPM, FST tests for the most active agent 19 in rats. [ABSTRACT FROM AUTHOR]

Based on our earlier studies of structure activity relationships on 4-substituted piperazine derivatives, in this work we synthesized a novel set of long-chain arylpiperazines with the purpose of elucidating if some structural modifications in the terminal fragment could affect the binding affinity for the 5-HT 7 and 5-HT 1A receptors. In this new series, the quinazolinone system of the previous derivatives was replaced by a 6-phenylpyrimidine or a 2-methylquinazoline, which were used as versatile building blocks for the preparation of new compounds. A 4-arylpiperazine moiety through a five methylene chain was anchored at the nitrogen or oxygen atom of the heterocyclic scaffolds. The substituents borne by the piperazine nucleus were phenyl, phenylmethyl, 3- or 4-chlorophenyl, and 2-ethoxyphenyl. Binding tests, performed on human cloned 5-HT 7 and 5-HT 1A receptors, showed that, among the newly synthesized derivatives, 4-[5-[4-(2-ethoxyphenyl)-1-piperazinyl]pentoxy]-6-phenyl-pyrimidine ( 13 ) and 3-[5-[4-(2-ethoxyphenyl)-1-piperazinyl]pentyl]-2-methyl-4(3 H )-quinazolinone ( 20 ) displayed the best affinity values, K i = 23.5 and 8.42 nM for 5-HT 7 and 6.96 and 2.99 nM for 5-HT 1A receptors, respectively. Moreover, the functional properties for both compounds were further evaluated using the cAMP assay. Finally, a molecular modeling study has been performed for 5-HT 7 and 5-HT 1A receptor homology models to investigate the binding mode of N - and O -alkylated pyrimidinones/pyrimidines 4 – 13 , 2-methylquinazolinones/quinazolines 17 – 22 , and previously reported 2- and 3-substituted quinazolinones 23 – 30 . [ABSTRACT FROM AUTHOR]

The incorporation of the fluorine motif is a strategy widely applied in drug design for modulating the activity, physicochemical parameters, and metabolic stability of chemical compounds. In this study, we attempted to reduce the affinity for ether-à-go-go-related gene (h ERG) channel by introducing fluorine atoms in a group of 1 H -pyrrolo[3,2- c ]quinolines that are capable of inhibiting monoamine oxidase type B (MAO-B). A series of structural modifications guided by in vitro evaluation of MAO-B inhibition and antitargeting for h ERG channels were performed, which led to the identification of 1-(3-chlorobenzyl)-4-(4,4-difluoropiperidin-1-yl)-1 H -pyrrolo[3,2- c ]quinoline (26). Compound 26 acted as a reversible MAO-B inhibitor exhibiting selectivity over 45 targets, enzymes, transporters, and ion channels, and showed potent glioprotective properties in cultured astrocytes. In addition, the compound demonstrated good metabolic stability in rat liver microsomes assay, a favorable safety profile, and brain permeability. It also displayed procognitive effects in the novel object recognition test in rats and antidepressant-like activity in forced swim test in mice. The findings of the study suggest that reversible MAO-B inhibitors can have potential therapeutic applications in Alzheimer's disease. [Display omitted] • Fluorine atoms in diminishing the undesirable h ERG affinity. • Six water molecules important for MAO-B inhibitor binding based on MD simulations. • Glioprotective properties of selective reversible MAO-B inhibitors. • Procognitive properties of selective reversible MAO-B inhibitor 26 in NOR test. • Antidepressant-like activity of reversible MAO-B inhibitor 26 in FST. [ABSTRACT FROM AUTHOR]

A novel series of arylpiperazinylalkyl 2-benzoxazolones and 2-benzothiazolones 18 – 38 was designed, synthesized and tested to evaluate their affinity for the 5-HT 7 and 5-HT 1A receptors. Compounds with a 2-benzothiazolone nucleus generally had affinity values higher than the corresponding 2-benzoxazolone compounds. In particular, derivatives possessing a six or seven carbon chain linker between 2-benzothiazolone and arylpiperazine had K i values in the subnanomolar range for the 5-HT 1A receptor and in the low nanomolar range for the 5-HT 7 receptor, indicating that they may be interesting dual ligands. Molecular modeling studies revealed different docking poses for the investigated compounds in homology models of 5-HT 1A and 5-HT 7 receptors, which explained their experimentally determined affinities and general low selectivity. Additionally, structural interaction fingerprints analysis identified the important amino acid residues for the specific interactions of long-chain arylpiperazines within the binding pockets of both serotonin receptors. [ABSTRACT FROM AUTHOR]

Abstract: The one-step synthesis of positional isomers of N,N-dimethylsulfamoylquinoline are presented. Seven newly synthesized compounds have been characterized by elemental analyses, MS, 1H and 15N NMR spectral data. The long-range correlations between the ring protons and the endocyclic nitrogen atoms were observed in the gHMBC experiments. The spectral positions of the nitrogen atoms from the sulfonamide groups were drawn from the 1D spectra of the 15N-labeled sulfonamide isotopomers. Correlations between the experimentally determined chemical shifts and GIAO calculated isotropic shielding constants were found. The GIAO calculations were based on HF-, MP2-, and B3LYP-optimized geometries and were performed at the HF, BLYP, and B3LYP levels of theory. [Copyright &y& Elsevier]

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., bromine and iodine. To elucidate the role of halogen atoms in the binding of SSRIs to SERT, we designed a series of 22 fluoxetine and fluvoxamine analogs substituted with fluorine, chlorine, bromine, and iodine atoms, differently arranged on the phenyl ring. The obtained biological activity data, supported by a thorough in silico binding mode analysis, allowed the identification of two partners for halogen bond interactions: the backbone carbonyl oxygen atoms of E493 and T497. Additionally, compounds with heavier halogen atoms were found to bind with the SERT via a distinctly different binding mode, a result not presented elsewhere. The subsequent analysis of the prepared XSAR sets showed that E493 and T497 participated in the largest number of formed halogen bonds. The XSAR library analysis led to the synthesis of two of the most active compounds (3,4-diCl-fluoxetine 42 , SERT K i = 5 nM and 3,4-diCl-fluvoxamine 46 , SERT K i = 9 nM, fluoxetine SERT K i = 31 nM, fluvoxamine SERT K i = 458 nM). We present an example of the successful use of a rational methodology to analyze binding and design more active compounds by halogen atom introduction. 'XSAR library analysis', a new tool in medicinal chemistry, was instrumental in identifying optimal halogen atom substitution. [Display omitted] • Fluorine-halogen substitution increase activity of SERT ligands. • Halogens interact through a hybrid halogen-hydrogen bonds. • XSAR methodology identified the best halogen substitution pattern. [ABSTRACT FROM AUTHOR]

Complexes of 10-methylthiocolchicine with monovalent cations have been obtained and characterized by spectroscopic methods, PM5 study and molecular modelling. The cytotoxic and fungicidal activities of the 10-methylthiocolchicine complexes were tested. The 10-methylthiocolchicine complexes were shown to be more active against SKOV-3 cancer than colchicine. • Complexes of 10-methylthiocolchicine with lithium, sodium, potassium, rubidium and cesium iodides and perchlorates. • PM5 study and molecular modelling of 10-methylthiocolchicine complexes. • The cytotoxic and fungicidal activities of 10-methylthiocolchicine complexes were tested. Thiocolchicine (10-methylthiocolchicine) is a semi-synthetic alkaloid with notable cytotoxic activity. Complexes of 10-methylthiocolchicine with Li+, Na+, K+, Rb+ and Cs+ monovalent cations of perchlorates and iodides have been obtained and characterized by spectroscopic methods, semi-empirical studies and molecular modelling. An explanation of the chemical nature of complexes formed between this alkaloid and monovalent metal cations of perchlorate and iodide salts which are present in human daily life is important. Their activities as cytotoxic and antifungal agents were also tested against the SKOV-3 cancer cell line and for eight selected microfungi species, respectively. Biological tests indicated no antifungal properties for 10-methylthiocolchicine. Complexation of 10-methylthiocolchicine with monovalent metal cations significantly improved the anticancer potency (~IC 50 = 4 nM) against the SKOV-3 cancer cell line. [ABSTRACT FROM AUTHOR]