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The characterization of the native and recombinant P2X7 receptor continues to be hindered by the lack of specific and subtype-selective antagonists with a "druglike" profile. However, a tyrosine derivative named KN-62 exhibits selective P2X7 receptor-blocking properties. As a molecular simplification of KN-62, the present study was designed to evaluate the functional antagonistic properties of a novel series of glycine derivatives characterized by the presence of different phenyl-substituted piperazine moieties. Antagonistic activity of these glycine derivatives was tested on HEK293 cells transfected with the human P2X7 receptor. The most potent P2X7 receptor antagonist identified in this study (compound 4g) contains an o-fluorine substituent on the phenylpiperazine moiety and had an IC50 of 12.1 nM. The biological responses investigated were ATP-dependent Ca2+ influx across the plasma membrane and ethidium bromide uptake.

The adsorption of ciprofloxacin (CIP) as well as probe compounds, phenylpiperazine (PP) (NH) and fluorochloroquinolone carboxylic acid (FCQCA) (COOH), on palygorskite (PFl-1) obeyed the Langmuir isotherm at pH 2, 7, and 11 except the FCQCA adsorption at pH 2. The CIP and PP adsorption onto PFl-1 was 98-160 mmol/kg. In neutral solution the total amount of exchangeable cations desorbed correlated with the adsorbed amount of CIP and PP well with a slope of 0.9-1, indicating a cation-exchange mechanism. A low amount of FCQCA adsorption of 27-57 mmol/kg was observed and the amount of exchangeable cations desorbed negatively correlate with the amount of FCQCA adsorbed as influenced by surface complexation or cation bridging. FTIR band shifting due to the ring-stretch vibration of PP and the keto-carbonyl group stretching of FCQCA suggested strong interactions as PP and FCQCA absorbed on PFl-1 in neutral solution. In the interaction of CIP with PFl-1, the piperazine-amine group played an important role in cation-exchange interaction in acidic to neutral solution, while the deprotonated keto carbonyl group actively partook in cation bridging or surface complexation with metal cations adsorbed on PFl-1 when the CIP was in anionic form in alkaline solution.

The aim of this study was to further characterize pharmacological properties of two phenylpiperazine derivatives: 1-{2-[2-(2,6-dimethlphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazynine hydrochloride (HBK-14) and 2-[2-(2-chloro-6-methylphenoxy)ethoxy]ethyl-4-(2- methoxyphenyl)piperazynine dihydrochloride (HBK-15) in radioligand binding and functional in vitro assays as well as in vivo models. Antidepressant-like properties were investigated in the forced swim test (FST) in mice and rats. Anxiolytic-like activity was evaluated in the four-plate test in mice and elevated plus maze test (EPM) in rats. Imipramine and escitalopram were used as reference drugs in the FST, and diazepam was used as a standard anxiolytic drug in animal models of anxiety. Our results indicate that HBK-14 and HBK-15 possess high or moderate affinity for serotonergic 5-HT2, adrenergic α1, and dopaminergic D2 receptors as well as being full 5-HT1A and 5-HT7 receptor antagonists. We also present their potent antidepressant-like activity (HBK-14—FST mice: 2.5 and 5 mg/kg; FST rats: 5 mg/kg) and (HBK-15—FST mice: 1.25, 2.5 and 5 mg/kg; FST rats: 1.25 and 2.5 mg/kg). We show that HBK-14 (four-plate test: 2.5 and 5 mg/kg; EPM: 2.5 mg/kg) and HBK-15 (four-plate test: 2.5 and 5 mg/kg; EPM: 5 mg/kg) possess anxiolytic-like properties. Among the two, HBK-15 has stronger antidepressant-like properties, and HBK-14 displays greater anxiolytic-like activity. Lastly, we demonstrate the involvement of serotonergic system, particularly 5-HT1A receptor, in the antidepressant- and anxiolytic-like actions of investigated compounds.

The In vitro metabolism of two alpha-1A-adrenergic antagonists, RWJ-69205 and RWJ-69471 (phthalimide-phenylpiperazine analogs), was assessed after 30 and 60 min incubations with rat, dog and human hepatic S9 fractions in the presence of an NADPH-generating system. Unchanged RWJ-69205 (or = 72% of the sample in all species) plus 3 metabolites from the RWJ-69205 incubations, and unchanged RWJ-69471 (or = 60% of the sample in all species) and 7 metabolites from the RWJ-69471 incubations, were profiled, quantified, and tentatively identified on the basis of API-MS and MS/MS data. The formation of RWJ-69205 and RWJ-69471 metabolites are via the following five metabolic pathways: 1. phenylhydroxylation, 2. O-dealkylation, 3. oxidative N-dealkylation, 4. N-dephenylation, and 5. dehydration. Pathway 1 formed 2 major/moderate hydroxy-phenyl metabolites of 2 analogs (4-17%) in all species, and pathway 2 produced 2 O-desisopropyl metabolites of 2 analogs in major/moderate (7-16%) in rat and human, and in trace (1%) in dog; in conjunction with pathway 1, yielded a minor diphenolic metabolite (1-2%) in RWJ-69471. Pathway 3 formed a minor N-dealkylated metabolite, isopropoxyphenyl piperazine (1-6%) in all species of 2 analogs. Pathways 4 and 5 produced 2 minor N-desphenyl metabolite and dehydrated metabolite, respectively, in rat and human S9 (or = 1-2%) in RWJ-69471. Both RWJ-69205 and RWJ-69471 were less extensively metabolized in the dog. However, rat and human appeared to metabolize RWJ-69471 more extensively than RWJ-69205 in this hepatic system.

A series of phenylpiperazine derivatives were synthesized and evaluated for their neuropeptide Y (NPY) Y5 receptor antagonistic activities. The benzindane portion of 2 was replaced by 1-phenylpiperazine, resulting in novel urea derivative 3f. Subsequent optimization of the phenylpiperazine template by substitution of the phenyl moiety resulted in a series of (2-methanesulfonamidephenyl)piperazine derivatives that showed potent binding affinity and antagonistic activity for the Y5 receptor.

New intermediates, 4-protected-1-alkyl-2-oxo-3-phenylpiperazines (3a-e) and 1-alkyl-2-oxo-3phenylpiperazines (6a-d) for the selective synthesis of 1-alkyl-3-phenylpiperazines (5a-e) are described. First method involves the reduction of the 4-protected-1-alkyl-2-oxo-3phenylpiperazine (3a-e) followed by deprotection giving the 1-alkyl-3-phenylpiperazine (5a-e). Second method involves the deprotection of 4-protected-1-alkyl-2-oxo-3-phenylpiperazine (3ae) followed by reduction giving the 1-alkyl-3-phenylpiperazine (5a-e).

Various sulfonyl-containing compounds (e.g. sulfonamides, sulfones) bind at human 5-HT6 serotonin receptors, but it has been difficult relating the binding mode(s) of such agents to one another, even though many possess a common SO2 moiety, to identify a common pharmacophore model(s). On the basis of the hypothesis that an ergoline-type conformation might be important for the binding of some sulfonamide-containing arylalkylamines, we prepared for examination at h5-HT6 receptors a series of compounds, including phenylethylamines 6, pyrroloethylamine 7, and phenylpiperazines 9. The results (with Ki values ranging from about 1 nM to >1000 nM) suggest that many of these agents likely bind in a related fashion, and structure-affinity studies indicate that the benzenesulfonamide portion of the phenylethylamine and phenylpiperazine analogues can be "reversed", abbreviated to a sulfone, and moved to an adjacent position with relatively little impact on affinity. Although a benzenesulfonamide (or related arylsulfonamide) group might be common to various 5-HT6 ligands, there appears to be some latitude with regard to the specific constitution and location of the sulfonamide moiety even within the same arylalkylamine structural framework. A pharmacophore model is presented to account for some of the current findings.

Methyldithiocarbonyl derivative 2 of pyrazine-2-carboxylic acid N′-methyl-hydrazide 1 was synthesized by methylation of CS2 adduct. Benzylamine caused the decomposition of compound 2 to pyrazine-2-carboxylic acid benzylamide 5 and 1,3-dibenzylthiourea 6. N-methyl-N′-(pyrazine-2-carbonyl)-hydrazinecarbodithioic acid methyl ester 2 were evidenced to cyclize to 3-methyl-5-pyrazin-2-yl-3H-[1, 3, 4]oxadiazole-2-thione 8 in the presence of triethylamine. In the reactions with secondary amines such as morpholine, pyrrolidine and phenylpiperazine pyrazinoyl derivatives (9–11) of thiosemicarbazide were obtained. Hydrazine, methylhydrazine, aminoalcohols, and N-alkylamino-substituted cyclic amines reacted with cyclization to 4-substituted 1,2,4-triazole-3-thiones 12, 13, and 18–22. Synthesized compounds exhibited low tuberculostatic activity in vitro (MIC 50–100 μg/mL).

The binding properties of cationic porphyrin–phenylpiperazine hybrids to calf thymus (CT) DNA were investigated by using absorption, fluorescence and circular dichroism (CD) spectra, and the apparent affinity binding constants ( K app ) of the porphyrins for CT DNA were determined by using a competition method with ethidium bromide (EB). Intercalation of porphyrin into CT DNA occurred when two phenylpiperazines were introduced at cis position onto the periphery of cationic porphyrin. The photocleavages of pBR322 plasmid DNA by the porphyrins were consistent with the values of K app . With [porphyrin] / [DNA base pairs] ratio increased, the binding mode tended to be outside binding, and the cleavage abilities of the porphyrins varied. In the presence of sodium azide, a quencher of 1 O 2 , the cleavage of DNA by the porphyrin of intercalation was less inhibited.

Two fluoroethoxy substituted derivatives, namely 2-[4-(2-(2-fluoroethoxy)phenyl)-piperazin-1-ylmethyl]indole-5-carbonitrile (5a) and 2-[4-(4-(2-fluoroethoxy)-phenyl)piperazin-1-ylmethyl]indole-5-carbonitrile (5b) were synthesized as analogs of the selective D4 receptor ligand 2-[4-(4-fluorophenyl)piperazin-1-ylmethyl]indole-5-carbonitrile (FAUC 316). In vitro characterization using CHO-cells expressing different dopamine receptor subtypes gave Ki values of 2.1 (5a) and 9.9 nM (5b) for the dopamine D4 subtype and displayed a 420-fold D4-selectivity over D2 receptors for 5b. The para-fluoroethoxy substituted candidate 5b revealed substantially reduced α1 and serotoninergic binding affinities in comparison to the ortho-fluoroethoxy substituted compound. In order to provide potential positron emission tomography (PET) imaging probes for the dopamine D4 receptor, 18F-labelling conditions using [18F]fluoroethyl tosylate were optimized and led to radiochemical yields of 81 ± 5% ([18F]5a) and 47 ± 4% ([18F]5b) (n = 3, decay-corrected and referred to labelling agent), respectively. Thus, 18F-fluoroethylation favourably at the para position of the phenylpiperazine moiety of the 5-cyano-indole framework proved to be tolerated by D4 receptors and could also be applied to alternative scaffolds in order to develop D4 radioligand candidates for PET with improved D4 receptor affinity and selectivity. Copyright © 2005 John Wiley & Sons, Ltd.

A series of arylpiperazinylbutyl derivatives of 4,5-dihydro-1,2,4-triazine-6(1H)-ones was designed and synthesized according to the new solid-supported methodology. In this approach, triazinone scaffold was constructed from the Fmoc-protected glycine. The library representatives showed different levels of affinity for 5-HT7 and 5-HT1A receptors; compounds 13, 14 and 18-20 were classified as dual 5-HT7 /5-HT1A receptors ligands. The structure-affinity relationship analysis revealed that the receptor affinity and selectivity of the tested compounds depended on the kind of substituent in position 3 of triazinone fragment as well as substitution pattern of the phenylpiperazine moiety.

A series of tridentate ligands consisting of mixed aromatic and aliphatic amine derivatives of single amino acid chelates and phenylpiperazine have been developed, and their reactions with [NEt4]2[ReBr3(CO)3] have been investigated. The compounds [Re(CO)3{(NC5H4CH2)NCH3(C2H4)NHCH3}]Br (4), [Re(CO)3{(NC5H4CH2)NCH3(C2H4)NCH3(CH2)xCOOC2H5}]Br (x = 1, 5; x = 4, 6) [Re(CO)3{(NC5H4CH2)NH(C2H4)N(CH3)2}]Br (7), [Re(CO)3{(NC5H4CH2)N(CH 2COOC2H5)(C2H4)N(CH3)2}]Br (8) and [Re(CO)3(NC5H4CH2)(C2H4NH2)N(CH2)3–CH3Ophenpip]Br (9) (phenpip: phenylpiperazine, –C6H4–(CH2CH2)2N–) were prepared and characterized by elemental analysis, NMR, IR, HSMS and X-ray crystallography. All complexes exhibit fac-{Re(CO)3N3} coordination geometry in the cationic molecular unit. Crystal data for C13H17BrN3O3Re (4): orthorhombic, Pbca, a = 13.4510(8) A, b = 10.5728(6) A, c = 22.5378(13) A, V = 3205.2(3) A3, Z = 8; C17H23BrN3O5Re (5): orthorhombic, Pcca, a = 16.5907(7) A,b = 14.8387(6) A, c = 16.7075(7) A, V = 4113.1(3) A3, Z = 8; C13H25BrN3O7Re (7 · 4H2O): monoclinic, P21/n, a = 14.0698(17) A, b = 9.6760(12) A, c = 15.6099 (19) A, β = 114.930(2)°, V = 1927.1(4) A3, Z = 4; C17H23BrN3O5Re (8): monoclinic, P21/n, a = 7.5312(5) A, b = 16.0366(10) A, c = 16.8741(10) A, β = 98.9990(10)°, V = 2012.9(2) A3, Z = 4.

The In vitro metabolism of the alpha-1A-adrenergic antagonist, RWJ-69597, an analog of pyridine-phenylpiperazines, was conducted after incubation with rat, dog and human hepatic S9 fractions in the presence of an NADPH-generating system. Unchanged RWJ-69597 (or =43% of the sample in all species) plus 9 metabolites were profiled, quantified, and tentatively identified on the basis of API-MS and MS/MS data. The four metabolic pathways for the formation of RWJ-69597 metabolites are: 1. methyl/phenyl/piperazinylhydroxylation, 2. N/Odealkylation, 3. N-dephenylation, and 4. dehydration. Pathway 1 formed 1 major (8-36%) and 3 minor (1-3%) hydroxylated metabolites. Pathway 2 produced 2 moderate/minor N/O-dealkylated metabolites (1-or =11%), and in conjunction with pathway 1, formed 1 minor diol metabolites (or =2%). Pathways 3 and 4 generated 2 minor metabolites, N-desphenyl RWJ-69597 (or =4%) and dehydrated RWJ-69597 (or =2%), respectively. RWJ-69597 is more extensively metabolized in the rat than the dog or the human in this hepatic system.

Starting from FAUC 365, a series of iodine substituted heteroaryl carboxamides has been synthesized revealing high affinity and selectivity for the dopamine D3 receptor. Binding data showed a 15-560-fold selectivity for the dopamine D3 over D2. A 2,3-dichloro substitution pattern on the phenylpiperazine moiety led to the highest subtype selectivity, whereas the 2-methoxy substituted compounds showed superior D3 affinity. Suitable precursors were radioiodinated with high radiochemical yields (53-85%) leading to potential imaging agents for the D3 receptor by SPET.

Arylpiperazines, XC6H4N(CH2CH2)2NH, are readily alkylated to give the N-alkylpiperazines of the type XC6H4N(CH2CH2)2N(CH2)nNH2. The amine functions of these derivatives are in turn easily subjected to mono- or dialkylation to provide potentially tridentate ligands of the types XC6H4N(CH2CH2)2N(CH2)nN(H)(CH2Y) and XC6H4N(CH2CH2)2N(CH2)nN(CH2Y)(CH2Z), respectively. The latter class of dialkylated derivatives may be symmetrically (Y=Z) or unsymmetrically (Y ≠ Z) substituted. The donor groups Y and Z of this study include pyridine, imidazole, methyl-imidazole, thiazole, carboxylate and thiolate. The reactions of these ligands with [NEt4]2[Re(CO)3Br3] yield complexes of the type [Re(CO)3{(YCH2)N(H)(CH2)n(H)xN(CH2CH2)2N(H)yC6H4X}]n and [Re(CO)3{(ZCH2)(YCH2)N(CH2)n(H)xN(CH2CH2)2N(H)yC6H4X}]n where the molecular charge n (0, +1, or +2) depends on the nature of the donor groups Y and Z (whether neutral or anionic or a combination of neutral and anionic) and on the degree of protonation of the piperazine unit (x=0 or 1; y=0 or 1). This variety of tridentate chelators provides complexes with fac-{Re(CO)3N3}, {Re(CO)3N2O}, {Re(CO)3NO2}, {Re(CO)3N2S} and {Re(CO)3NS2} coordination geometries. The structures of the model compound [Re(CO)3{(CH3N2C3H2CH2)N(H)CH2CH2-piperidine}]Br · H2O, [Re(CO)3{(CH3N2C3H2CH2)N(H)CH2CH2-Fphenpip}]Br, [Re(CO)3{(NC5H4CH2)N(H)CH2CH2-Fphenpip}]Br, [Re(CO)3{(O2CCH2)2NCH2CH2CH2-CH3OphenpipH}] · xCH3OH (x≈0.875), [Re(CO)3{(NC5H4CH2)2NCH2CH2CH2-CH3OphenpipH}]Br2 · 2CH2Cl2 · H2O and [Re(CO)3{(CH3N2C3H2CH2)(O2CCH2)NCH2CH2CH2-CH3OphenpipH2}]BrCl · 1.5CH3OH · H2O are discussed (phenpip: phenylpiperazine, –C6H4N(CH2CH2)2N–).

The previously unknown antiplasmodial activity of the plant derived natural product totarol is reported. Novel β-amino alcohol derivatives based on this natural product were designed, synthesised and evaluated for in vitro antiplasmodial activity and cytotoxicity. These derivatives showed antiplasmodial IC 50 values in the range of 0.6–3.0 μM and were equally active against a chloroquine-sensitive and resistant strain of Plasmodium falciparum , while showing little cytotoxicity against a mammalian cell line (CHO). In terms of lead development, two of the compounds based on substituted phenylpiperazine warrant further investigation as potential antiplasmodial leads. In addition to their selective antiplasmodial activity and lack of chloroquine cross-resistance, these compounds are structurally different to any of the available antimalarial drugs.

The P2X(7) receptor is involved in several processes relevant to inflammation (cytokine release, NO generation, killing of intracellular pathogens, cytotoxicity); thus, it may be an appealing target for pharmacological intervention. The characterization of native and recombinant P2X(7) receptor continues to be hindered by the lack of specific and subtype-selective antagonists. However, a tyrosine derivative named KN-62 exhibits selective P2X(7) receptor-blocking properties. The present study was designed to evaluate the functional antagonistic properties of a novel series of KN-62-related compounds characterized by the presence of different phenyl-substituted piperazine moieties. Antagonistic activity of KN-62 derivatives was tested on HEK293 cells transduced with the human P2X(7) receptor and monocyte-derived human macrophages, a cell type well-known for the high level of expression of this receptor. The biological responses investigated were ATP-dependent Ca(2+) influx across the plasma membrane, ethidium bromide uptake, and secretion of the cytokine interleukin-1beta. KN-62 was characterized by the presence of a phenylpiperazine moiety, and the presence of a one-carbon linker between the piperazine nitrogen and the phenyl ring (compound 61) increases the activity, while a two-carbon linker (compound 62) decreases biological activity 10-fold. Also, the nature and the position of substituents on the phenyl ring tethered to the piperazine seemed to exert a fundamental influence on the biological activity. In the series of synthesized compounds, the presence of a fluorine in the para position gives the most potent compound (63), while the same atom in the ortho position reduces potency by 3-fold. When the p-fluorine was replaced in the same position with other halogens, such as chlorine (compound 64) or iodine (compound 65), the activity decreased dramatically. We then tested the activity of the four most potent KN-62 derivatives on ATP-stimulated secretion of IL-1beta from monocyte-derived human macrophages, a key cell type in inflammation and innate immunity. Interestingly, compound 68 and 71 caused a complete inhibition of IL-1beta release, while with KN-62, 63, and 85, there was a small residual cytokine secretion even at concentrations exceeding 100 nM. None of the compounds tested on IL-1beta release had any effect on isolated CaMII kinase activity up to 20 microM (not shown).

Yilmaz, Veysel/0000-0002-2849-3332; Ozkanca, Resit/0000-0003-2756-0633; CESUR, HASAN/0000-0001-9494-4085 WOS: 000183158900006 Potassium salts of phenylpiperazine (Phpzdtc), fluorophenylpiperazine (F-Phpzdtc) and nitrophenylpiperazine (N-Phpzdtc) dithiocarbamates and their manganese(II), iron(II), cobalt(II), nickel(II), copper(II) and zinc(II) complexes have been synthesized and characterized by elemental analyses, IR, UV-VIS, magnetic moment measurements and thermal analysis techniques. On the basis of experimental data, the dithiocarbamates (dtcs) have been observed to coordinate to the metal ions via both sulphur atoms of the -NCS2 group forming metal complexes with a metal to ligand ratio of 1:2. The thermal reactivity and antimicrobial activity of the ligands and their metal complexes were also studied. The decomposition of the metal complexes resulted in the formation of the corresponding metal thiocyanates or cyanates as stable intermediates. Phpzdtc was found to be microbiologically more active than its nitro and fluoro derivatives and biological activity of the dtc ligands either remained unaltered or decreased on complexation with metal ions.

A series of N , N -disubstituted 4-aminophenylazobenzaldehydes (azo dyes) were synthesized by the reaction of phenylpiperazine derivatives with 4-formylbenzenediazonium tetrafluoroborate. The salt was easily prepared by reacting poly(aminobenzaldehyde) with sodium nitrite in the presence of tetrafluoroboric acid. A representative sample was studied by crystallography, and the charge distribution of the molecule was calculated with the aim of understanding the form of molecular stacking on the basis of crystal data. The mesogenic behaviour of the azo dyes was also studied.

The Suzuki–Miyaura cross-coupling reaction between 1-{3-bromo-4-chloro-5-[1-( R )-fluoropropyl]}phenylpiperazine (( R )- 1b ) and thermally unstable ( o -cyanophenyl)boronic ester 6b in the presence of dichlorobis(triphenylphosphine)palladium and potassium phosphate hydrate in boiling toluene was found to afford 1-{3-(2-cyanophenyl)-4-chloro-5-[1-( R )-fluoropropyl]}phenylpiperazine (( R )- 5 ), an intermediate for the synthesis of E2040, in excellent yields. The reaction conditions for the cross-coupling were optimized by the design of experiments (DOE) approach and found to be applicable to electron-rich and/or sterically hindered aryl bromides. Safety evaluation for the production of ( R )- 5 is also described.

Although several tritiated agonists have been used for radiolabelling serotonin (5-hydroxytryptamine, 5-HT)1B receptors in rats, data with a selective, radiolabelled antagonist have not been presented. Inasmuch as [3H]GR125,743 specifically labels cloned, human and native guinea pig 5-HT1B receptors and has been employed for characterization of cerebral 5-HT1B receptor in the latter species [Eur. J. Pharmacol. 327 (1997) 247.], the present study evaluated its utility for characterization of native, cerebral 5-HT1B sites in the rat. In homogenates of frontal cortex, [3H]GR125,743 (0.8 nM) showed rapid association (t1/2=3.4 min), >90% specific binding and high affinity (Kd=0.6 nM) for a homogeneous population of receptors with a density (Bmax) of 160 fmol/mg protein. In competition binding studies, affinities were determined for 15 chemically diverse 5-HT1B agonists, including 2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl]-1H-indole-3-yl]ethylamine (L694,247; pKi, 10.4), 5-carboxamidotryptamine (5-CT; 9.7), 3-[3-(2-dimethylamino-ethyl)-1H-indol-6-yl]-N-(4-methoxybenzyl)acrylamide (GR46,611; 9.6), 5-methoxy-3-(1,2,5,6-tetrahydro-4-pyridinyl)-1H-indole (RU24,969; 9.5), dihydroergotamine (DHE; 8.6), 5-H-pyrrolo[3,2-b]pyridin-5-one,1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl (CP93,129; 8.4), anpirtoline (7.9), sumatriptan (7.4), 1-[2-(3-fluorophenyl)ethyl]-4-[3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl]piperazine (L775,606; 6.4) and (−)-1(S)-[2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl]-N-methyl-3,4-dihydro-1H-2-benzopyran-6-carboxamide (PNU109,291

A series of novel 3-substituted-1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-1-trans-propenes in order to improve the in vitro and in vivo activity of our prototype 3-[4-(3-chlorophenyl)-1-piperazinyl]-1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-1-trans-propene (2) were synthesized and evaluated by assays of growth inhibition against several tumor cell lines in vitro and antitumor activity against some tumor models when dosed both intraperitoneally and orally in vivo. Compounds 7a and 7e, the 3,5-difluorophenyl and 3,5-dichlorophenyl analogues of 2, respectively, showed significantly more potent cytotoxicity than 2 in vitro and potent antitumor activities without causing decrease of body temperature related to side effects.

An N,N-disubstituted 4-[(4-aminophenyl)diazenyl]benzaldehyde (‘azo dye') with nematic phase was synthesized by reaction of the phenylpiperazine derivative with the formylbenzenediazonium salt. The salt was prepared by a simplified reaction of poly(aminobenzaldehyde) with NaNO2 in the presence of HBF4. The azo dye was further studied by crystallography. On the basis of molecular stacking identified from crystallography, the molecular modeling was carried out to explore the molecular interactions, and it was found that the attraction of two coplanar molecules with side-to-side contact is favored, and a nematic phase is thus formed during the thermal process.

Thermotropic liquid crystals are of great technological importance. Much research is devoted to the development of stable compounds with transition temperatures close to room temperature. The interest of this work is the synthesis of thermotropic liquid crystal precursor units containing phenylpiperazine and/or phenylacetylenic units. Homologues of a Schiff base series and an enyne series have been synthesized, allowing comparisons of their mesomorphic and thermodynamic properties. The Schiff bases showed smectogenic behavior and the enynes a smectic dimorphism and/or a nematic phase. The synthetic methodology was efficient for the synthesis of the desired precursor, 4-[4′-(prop-1-yn-3-al)phenyl]-piperazine-1-carboxylic acid ethyl ester.

Human epidermal growth factor receptor (EGFR) is an important drug target that plays a fundamental role in signal transduction pathways in oncology. We report herein the discovery of a novel class of phenylpiperazine derivatives with improved potency toward EGFR. The biological activity of compound 3p as inhibitor of EGFR was further investigated both in vitro and in vivo. Notably, compound 3p exhibited an IC50 in the nanomolar range in A549 cell cultures and induced a cessation of tumor growth with no toxicity, as determined by loss of body weight and death of treated mice. Compoutational docking studies also showed that compound 3p has interaction with EGFR key residues in the active site.

The phenylpiperazine derivative naftopidil is an α1-adrenoceptor (AR) antagonist that has been used clinically to treat benign prostatic hyperplasia. In our drug repositioning research, naftopidil shows the unique growth-inhibitory effects. Naftopidil inhibits cell cycle progression not only in cancer cells, but also in fibroblasts and vascular endothelial cells. Naftopidil-inhibited cell cycle progression is independent of α1-AR expression in cells. Therefore, the antiproliferative effects of naftopidil may be due to the off-target effects of the drug. In this study, we attempted to identify the off-target molecules of naftopidil using the magnetic nanobeads, ferrite glycidyl metharcrylate (FG) beads. Similar to naftopidil, its derivatives TG09-01 and TG09-02, which were introduced with amino groups for immobilizing to FG beads, inhibited cell growth in human HT29 colon adenocarcinoma cells. Both derivatives were associated with inhibition of cell cycle progression in HT29 cells. This observation is consistent with that seen with naftopidil. Using TG09-02-immobilized FG beads, α- and β-tubulins were identified as the specific binding proteins of naftopidil. The tubulin polymerization assay clearly indicated that naftopidil bound directly to tubulin and inhibited the polymerization of tubulin. Other phenylpiperazine derivatives, such as RS100329, BMY7378, and KN-62, also inhibited the polymerization of tubulin. These results suggest that phenylpiperazine derivatives including naftopidil may have broad spectrum of cellular cytotoxicity in various types of cells. In addition, the tubulin polymerization-inhibiting activity of phenylpiperazine derivatives may be a specific feature of the phenylpiperazine-based structure. These findings can allow us to design and synthesize new tubulin-binding drugs derived from naftopidil as a lead compound.

The current study is focused on newly developed phenylpiperazine derivatives of aromatic methylhydantoin differing in mutual positions of methyl and phenyl moieties. The new compounds were synthesized using Bucherer–Bergs reaction, two-phase alkylation, Mitsunobu reaction and/or an alkylation under microwave irradiation. The compounds developed were assessed on their affinity for serotoninergic receptors 5-HT1A, 5-HT6, 5-HT7 and α1-ARs in radioligand binding assays. Selected compounds were tested on their inhibitory effect at human 5-HT3A expressed in Xenopus Oocytes as well as on their activity at α1-adrenoceptor subtypes in functional and electrophysiological bioassays, respectively. Most of investigated compounds exhibited affinities for α1-ARs, 5-HT1A, 5-HT7 (Ki ∼ 0.8–353 nM) significantly higher than those for 5-HT6 receptors. Very weak inhibitory effect at 5-HT3A accompanied with high activity at α1D-AR subtypes were observed for selected representative compounds. Among the current series, particularly 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione hydrochloride (25a) displayed the highest 5-HT7 affinity with Ki = 3 nM and selectivity with 40–3600 fold towards 5-HT1A, 5-HT6, and α1-ARs.

A series of alkyl N,N-disubstituted aminophenylazo-4-benzoates were prepared from the reactions of an acyl phenylpiperazine with a series of the diazonium salts. The mesogenic behaviours of the resulting dyes were studied by polarizing optical microscopy and differential scanning calorimetry. Single crystal structure determination, powder XRD, and molecular modelling of a representative compound were also undertaken to understand the relative structural conformation.

As a continuation of previous research on anticholinergic drugs derived from 2,2-diphenyl-2-ethylthioacetic acid, several 5,5-diphenyl-5-ethylthio-2-pentynamines ( 2 – 11 ) were synthetised and their antimuscarinic activity on M 1–4 receptor subtypes was evaluated by functional tests and binding experiments. One of the compounds obtained showed unexpected agonistic activity in functional experiments on M 2 receptors. Since the compound carried a phenylpiperazine moiety, other similar compounds ( 12 – 17 ) were prepared and found to be endowed with similar behaviour. These ligands, although possessing the bulky structure characterising muscarinic antagonists, display agonistic activity at M 2 subtypes while, as expected, behaving as antagonists on M 3 and M 4 subtypes. On M 1 subtypes, they show agonistic activity which, however, is not blocked by atropine. The peculiar pharmacological profile of these compounds is of interest for studying muscarinic receptor subtypes.

Traceless linking of diethoxymethyl (DEM)-protected 5- and 6-cyanoindoles and subsequent incorporation of phenylpiperazine derivatives led to the 2- and 3-piperazinylmethyl-substituted cyanoindoles 3a-m. Dopamine receptor binding studies on the final products 3a-m clearly indicated strong and selective recognition of the D(4) subtype which is known as a promising target for the treatment of neuropsychiatric disorders. The most interesting binding properties were observed for the 2-aminomethyl-5-cyanoindoles FAUC 299 (3f) and FAUC 316 (3j) (K(i) = 0.52 and 1.0 nM, respectively) when the fluoro derivative 3j proved extraordinary selectivity over D(1), D(2long), D(2short), and D(3) (8600). To determine ligand efficacy, mitogenesis experiments were performed indicating partial agonist effects for the test compounds 3f,j (35% and 30%, when compared to the full agonist quinpirole).

Phenylpiperazine derivatives were synthesized as dual cytokine regulators with TNF-α suppressing and IL-10 augmenting activity. Lead optimization led to compound 5k Scheme 2. Reagents and conditions: (a) Ac2O, NaOH, H2O, rt (87%); (b) cH2SO4, MeOH, reflux (72%); (c) LiAlH4, THF, 0 °C–rt (98%); (d) SOCl2, CHCl3, reflux (91%); (e) arylpiperazines, K2CO3, DMF, 80 °C (49–58%). Figure options Download full-size image Download high-quality image (32 K) Download as PowerPoint slide having the potent regulatory activity and demonstrating remarkable protective effects against the lethal challenge of LPS in mice, suggesting that 5k would be a promising drug candidate for the treatment of TNF-α associated diseases including septic shock.

WAY100635 (2), N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xanecarboxamide, is a silent serotonin 5-HT(1A) antagonist, which is now widely used to study the 5-HT(1A) receptor both in vivo and in vitro. In this paper, we describe the synthesis and in vitro (5-HT(1A) affinity and pA(2) values at guinea pig ileum strips) and in vivo (hypothermia and ultrasonic vocalization) pharmacology at the serotonin 5-HT(1A) receptor of several closely related analogues of 2. Test compounds 12 and 14, in which the arylpiperazine moiety of 2 has been replaced by an arylaminopiperidine moiety, showed no affinity or antagonistic activity at the 5-HT(1A) receptor. Substitution of the o-methoxy group of 2 by larger fluoroalkoxy or sulfonyloxy substituents did not alter the in vitro or in vivo pharmacology to any great extent; in vivo both the fluoropropyl analogue 5 and the triflate analogue 7 are equipotent to WAY100635 itself. The O-desmethyl analogue 3 proved to be the most potent antagonist at the serotonin 5-HT(1A) postsynaptic receptor sites in this series.

Dihydropyrimidinones, such as 1, represent a novel class of α1a adrenoceptor antagonists with potential for the treatment of benign prostatic hyperplasia (BPH) (see part 1 of this series). Analysis of the metabolites of 1 revealed that 4-methoxycarbonyl-4-phenylpiperidine is formed as the major metabolite and is an agonist at the μ-opioid receptor. To circumvent any potential liability resulting from the metabolite, we decided to identify alternate templates devoid of agonist activity at the μ-opioid receptor to replace the 4-methoxycarbonyl-4-phenylpiperidine moiety. The present study describes the synthesis and SAR of dihydropyrimidinones linked to substituted 4-phenylpiperazine containing side chains. Compound (+)-38 was identified as a lead compound with a binding and functional profile comparable to that of 1. The putative metabolite 2-carboxamidophenylpiperazine has negligible affinity for the μ-opioid receptor.

A novel series of antiferroelectric liquid crystalline compounds having a phenylpiperazine unit and a biphenyl or a phenyl moiety in the core structure was synthesized using the optically active alcohols 2-methyl octanol and 1,1,1-trifluoromethyl octanol. Most of the compounds exhibited enantiotropic SmC*A, SmC* and SmA mesophases. The phase transition temperatures, response times, sponta A neous polarizations and the field-transmittance hysteresis loops were monitored. These data were compared with those of the MHPOBC compounds, which represent the most conventional core structure of the biphenyl/phenyl combination. The replacement of the biphenyl moiety, with the phenylpiperazine unit, reduced the isotropization temperature as well as the SmC*A-SmC transition point. It was found that some of the new compounds, which consisted ofAan octyl or a nonyl terminal chain with a 2-methyloctyl 2-fluorophenylcaboxylate group in the core structure, could have a potential application in display devices. Some work on...

Four 7-[3-(4-phenyl-1-piperazinyl)propoxy]coumarins were synthesized. The affinities of these compounds for DA (D2A, D3) and 5HT1A receptors were evaluated for their ability to displace [3H]-raclopride and [3H]-8-OH-DPAT respectively from their specific binding sites. The affinities of the target compounds were all in the nanomolar range and followed the order 5-HT1A > D2 > D3.

The synthesis of several bioisosteric analogs based on the 3-OH-N1-phenylpiperazine dopamine D2 agonist template (i.e., 4) is described. The indolone (5) and 2-CF3-benzimidazole (13) were observed to have excellent affinity for the D2 receptor. Several D4 selective compounds were also identified. Molecular modeling studies and a putative bioactive conformation are discussed.

A metabolite of Aripiprazole (1), 7-[4-[4-(2,3-dichloro-4-hydroxyphenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolinone (2), was prepared by the coupling reaction of 1-(4-benzyloxy-2,3-dichlorophenyl)-piperazine (11) with 7-(4-chlorobutoxy)-3,4-dihydro-2(1H)-quinolinone (16). The palladium-catalyzed amination of contiguous tri- and tetra-substituted benzenes with piperazine derivatives was investigated. The key intermediate 11 was efficiently prepared using the palladium-catalyzed amination of phenyl bromide 15 with piperazine.

The present report illustrates the application of dansyl chloride coupled with ion spray tandem mass spectrometry (IS-MS/MS) in identifying polar urinary metabolites. In the course of the metabolism studies of a drug that is currently in development, the urine from rats and dogs was collected following oral administration of radiolabelled compound. Urinary metabolic profiles of the rat and dog indicated the presence of four major peaks and one major peak, respectively, in the radiochromatogram. Since all attempts to identify the peaks by conventional MS/MS techniques failed, the metabolites were isolated by fraction collection and dansylated. Derivatization of the metabolites resulted in the formation of more hydrophobic, readily ionizable species which were more sensitive in IS-MS/MS analysis than the underivatized metabolites. Examination of the molecular ions and the product ion mass spectra of these derivatives revealed the structures of all the urinary metabolites. The metabolites in the rat and the dog were 4-hydroxyphenylpiperazine glucuronide (M1), 1,4-dihydroxyphenyl glucuronide (M2), 1,4-dihydroxyphenyl sulfate (M3) and phenylpiperazine (M4). Thus, derivatization with dansyl chloride in conjunction with tandem mass spectrometry is a useful tool in identifying polar urinary metabolites.

The labeled serotonin agonist 3-[ 18 F]fluoro- N -(α,α,α-trifluoro- m -tolyl)piperazine ( 18 FTFMPP) was prepared rapidly using the labeling procedure for trifluorotoluenes, [ 18 F]fluoro-for-nitro exchange, followed by an alumina-supported bis-alkylation. After normal-phase HPLC purification, the labeled product was obtained in 20–32% ( n = 20) decay-corrected radiochemical yield with a radiochemical purity >98% and a specific activity of 100 GBq/μmol. The synthesis time including purification was 3 h. The receptor binding affinity of FTFMPP to rat brain membranes was found to be similar to that of the nonfluorinated parent compound (TFMPP). Although TFMPP has been proposed by others as an agent for the imaging of serotonin receptors, only minimal receptor-mediated uptake was observed.

Piperazine derivatives are a class of psychoactive substances applied in prescription medicines like antidepressants as well as in drugs of abuse. They are known to increase brain levels of catecholamines, likely via reversal of reuptake transporters. However, other mechanisms could also contribute to increased neurotransmitter levels, e.g., reduced inhibitory inputs on catecholaminergic neurons.Inhibition of the main inhibitory input in the brain, the GABAergic system, by piperazine derivatives could contribute to increased neurotransmitter levels. Our previous studies support this by demonstrating that 1-(3-chlorophenyl)piperazine (3CPP/mCPP) is an antagonist of the human α1β2γ2 GABAA receptor (GABAA-R). We therefore investigated the effect of 12 additional piperazine derivatives on the function of the human α1β2γ2 GABAA-R expressed in Xenopus oocytes, using the two-electrode voltage-clamp technique. Tested derivatives included benzylpiperazine (BZP), methylbenzylpiperazines (2/3MBP), phenylpiperazine (PP), methoxyphenylpiperazines (2/3/4MPP/MeOPP), chlorophenylpiperazines (2/4CPP) and fluorophenylpiperazines (4FPP/TFMPP).All derivatives concentration-dependently inhibited the GABA-evoked ion current. Chlorophenylpiperazines were the most potent GABAA-R antagonists; the IC20 value for 1-(2-chlorophenyl)piperazine (2CPP) was 46μM and 2CPP induced a maximum inhibition of ~90% at 1mM. Derivatives can be ranked as follows from highest to lowest potency based on IC20 values: 2CPP>3MPP>4CPP>4MPP>2MBP>3CPP>PP>4FPP>2MPP>TFMPP>3MBP>BZP.This study demonstrates a novel mode of action of piperazine derivatives, i.e., antagonism of the GABAA-R. This mechanism can result in increased catecholamine levels that indirectly contribute to toxicity, e.g., adverse effects during overdoses. Therefore, this important mode of action is not only relevant for therapeutic psychiatric interventions, but could also proof valuable for therapeutic interventions in intoxications.

In an attempt to increase the affinity of our antipsychotic lead compound LASSBio-579 (1-((1-(4-chlorophenyl)-1H-pyrazol-4-yl)methyl)-4-phenylpiperazine; ( 2 )) for the 5-HT 2A receptor, we synthesized five new N -phenylpiperazine derivatives using a linear synthetic route and the homologation strategy. The binding profile of these compounds was evaluated for a series of dopaminergic, serotonergic and alpha-adrenergic receptors relevant for schizophrenia, using classical competition assays. Increasing the length of the spacer between the functional groups of ( 2 ) proved to be appropriated since the affinity of these compounds increased 3–10-fold for the 5-HT 2A receptor, with no relevant change in the affinity for the D 2 -like and 5-HT 1A receptors. A GTP-shift assay also indicated that the most promising derivative (1-(4-(1-(4-chlorophenyl)-1 H -pyrazol-4-yl) butyl)-4-phenylpiperazine) (LASSBio-1635) ( 6 ) has the expected efficacy at the 5-HT 2A receptors, acting as an antagonist. Intraperitoneal administration of ( 6 ) prevented apomorphine-induced climbing behavior and ketamine-induced hyperlocomotion in mice, in a dose dependent manner. Together, these results show that ( 6 ) could be considered as a new antipsychotic lead compound.

We present an exploration of the chemiluminescence from reactions of benzylpiperazines and phenylpiperazines with tris(2,2′-bipyridine) ruthenium(III). The selectivity of the reagent towards these compounds was found to be highly dependent upon the pH of the solution, and the relative emission intensity was strongly influenced by electron donating or withdrawing substituents on the phenyl or benzyl ring. In spite of previous investigations showing poor responses for aromatic-substituted amines (compared to their aliphatic amine counterparts), intense emissions were observed with phenylpiperazines under acidic conditions, particularly those with halogen or trifluoromethyl substituents on the aromatic ring. Buffered alkaline conditions provided much broader selectivity for the detection of both phenylpiperazine and benzylpiperazine compounds, which we have applied to a rapid HPLC procedure for the determination of piperazines of forensic interest in 'party pill' samples. Refereed/Peer-reviewed

The thermodynamic parameters delta G degree, delta H degree and delta S degree of the binding equilibrium of 15 ligands (eight agonists and seven antagonists) to the 5-HT1A receptor subtype have been determined by affinity measurements carried out on rat cortex membranes (minus striatum) at six different temperatures (0, 10, 20, 25, 30, 35 degrees C), and by van't Hoff plots. Most of the compounds studied are tryptamine, phenylpiperazine and tetralin derivatives. Affinity constants were measured by saturation experiments for the selective 5-HT1A receptor agonist [3H]8-hydroxy-N,N-dipropyl-2-aminotetralin ([3H]8-OH-DPAT) and by inhibition assays of [3H]8-OH-DPAT binding for the other compounds. Scatchard plots were monophasic in the full range of temperatures, indicating a single class of high affinity binding sites. Van't Hoff plots of all ligands were linear in the temperature range investigated (0-30 degrees C or 0-35 degrees C). 5-Hydroxytryptamine (serotonin) and 5-methoxy-tryptamine (mexamine) displayed a positive slope. Experimental data indicate that for 5-HT1A receptor subtype agonists and antagonists are not thermodynamically discriminated. The results are discussed from a quantitative point of view with the aim of obtaining new details on the nature of the forces driving the 5-HT1A binding at a molecular level.

The phenylpiperazine ring which could not be obtained by reacting aniline derivatives with bis(2-bromoethyl)-N-(ethoxycarbonyl)amine (1a) in a wide spectrum of solvents and temperatures was synthesized rapidly on solid support in high yield. By this approach the potent serotonin agonist TFMPP (2) was synthesized in 40 min, in 80% yield. The time scale of this reaction and the simplicity of the work-up match the requirements for short lived neurological radiopharmaceutical production.

s / Parkinsonism and Related Disorders 22 (2016) e149ee192 e178 3. O'Leary TP, Savoie V, Brown RE. Learning, memory and search strategies of inbred mouse strains with different visual abilities in the Barnes maze. Behavioural brain research. 2011;216:531-542. 4. Andrade C. Quantifying the ECT dose: the right unit remains elusive. The journal of ECT 2001;17:75. P 6.009. IMPROVEMENT OF COGNITIVE PERFORMANCE AND CHOLINERGIC TRANSMISSION BY DEVELOPMENT OF NOVEL ACRIDINE-PIPERAZINE HYBRIDS Anuradha Sharma, Poonam Piplani. University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, Chandigarh, India Objective: The objective of the present study was to design and synthesize some novel acridine-piperazine hybrids and evaluation of their ability to improve scopolamine induced cognitive deficit. Further, to elucidate mechanism of action using acetylcholinesterase inhibitory assay. Methods: 1. In-silico studies: Vlife, Phase and QikProp (Maestro) softwares were employed to design novel hybrids. 2. Synthesis: Alkylation of substituted aniline with o-bromobenzoic acid was done to afford substituted phenylamino benzoic acid derivatives. These intermediates were cyclized to form substituted acridone analogues, which were subsequently chlorinated in the presence of phosphorus oxychloride and then refluxed with fluoropiperazines to afford the final compounds (1-5). 3. Pharmacological Evaluation: Behavioral studies were carried out using elevated plus maze and passive avoidance tests on mice. Biochemical studies were carried out to study their acetylcholinesterase inhibitory profile using Ellman method. Results: Four point pharmacophore (ADHR) was developed using Phase to design the hybrids, which were docked at the defined cavity of enzyme to understand the possible interactions as shown in the figure (Vlife). Compounds bearing fluoro halogen substituent at 4th position of phenylpiperazine ring enhances the binding interactions. The calculated ADME properties confirmed the druglikeness using QikProp. Conclusion: The compound 1 was found to be most potent with IC50 0.33 out of all the synthesized hybrids. Rational design of novel series of potent acridine-piperazine hybrids as cognition enhacers, binding to the active site of AChE structure was disclosed which can act as a future lead in this area. References: 1. Ellman GL, Courtney KD, Andres V, Featherstone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochemical pharmacology1961;7: 88-95. 2. Rachna G, Lalit KG, Pramod KM, Swapan KB. Effect of resveratrol on scopolamine-induced cognitive impairment in mice. Pharmacological Reports 2012;64,438-444.