Synthesis of a series of γ-amino alcohols comprising an N-methyl isoindoline moiety and their evaluation as NMDA receptor antagonists

We report a series of new stereoisomeric γ-amino alcohols comprising an N-methyl isoindoline moiety as ligands for the ifenprodil binding site of the NMDA receptor. Among the four series of stereoisomers, 8a-c, 9a-c, 10a-c, and 11a-c, synthesised, the highest potencies and NMDA-NR2B subtype selectivity was found for the methyl derivative 11a and the chloro derivative 11c, both possessing the [1S,1'S] configuration. However, additional moderate potency of 11a and 11c at the hERG channel with values of 2.6 ± 2.4% and 1.6 ± 2.0%, respectively, rendered them unsuitable for medical use.     

Essential role of NMDA receptor channel ε4 subunit (GluN2D) in the effects of phencyclidine, but not methamphetamine

Phencyclidine (PCP), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, increases locomotor activity in rodents and causes schizophrenia-like symptoms in humans. Although activation of the dopamine (DA) pathway is hypothesized to mediate these effects of PCP, the precise mechanisms by which PCP induces its effects remain to be elucidated. The present study investigated the effect of PCP on extracellular levels of DA (DA(ex)) in the striatum and prefrontal cortex (PFC) using in vivo microdialysis in mice lacking the NMDA receptor channel ε1 or ε4 subunit (GluRε1 [GluN2A] or GluRε4 [GluN2D]) and locomotor activity. PCP significantly increased DA(ex) in wildtype and GluRε1 knockout mice, but not in GluRε4 knockout mice, in the striatum and PFC. Acute and repeated administration of PCP did not increase locomotor activity in GluRε4 knockout mice. The present results suggest that PCP enhances dopaminergic transmission and increases locomotor activity by acting at GluRε4.     

Synthesis and evaluation of 4-substituted piperidines and piperazines as balanced affinity μ opioid receptor (MOR) agonist/δ opioid receptor (DOR) antagonist ligands

In this letter, we describe a series of 4-substituted piperidine and piperazine compounds based on tetrahydroquinoline 1, a compound that shows balanced, low nanomolar binding affinity for the mu opioid receptor (MOR) and the delta opioid receptor (DOR). We have shown that by changing the length and flexibility profile of the side chain in this position, binding affinity is improved at both receptors by a significant degree. Furthermore, several of the compounds described herein display good efficacy at MOR, while simultaneously displaying DOR antagonism. The MOR agonist/DOR antagonist has shown promise in the reduction of negative side effects displayed by selective MOR agonists, namely the development of dependence and tolerance.     

Isolation and Identification of ( – ) - Quinic Acid as an Unidentified Major Tea-component

A new enzyme, N-acetyl- d-hexosamine dehydrogenase (N-acety 1-α-d-hexosamine: NAD⁺ 1-oxidoreductase), was purified to homogeneity on polyacrylamide gel electrophoresis from a strain of Pseudomonas sp. about 900-fold with a yield of 12 %. The molecular weight of the enzyme was about 124,000 on gel filtration and 30,000 on SD S-polyacrylamide gel electrophoresis, respectively. Its isoelectric point was 4.7. The optimum pH was about 10.0. The enzyme was most stable between pH 8.0 and pH 10.5. The highest enzyme activity was observed with N-acetyl-d-glucosamine (Km = 5.3mm) and N-acetyl-d-galactosamine (Km = 0.8mm) as the sugar substrate. But it was not so active on N-acetyl-d-mannosamine. NAD⁺ was used specifically as the hydrogen acceptor. The anomeric requirement of the enzyme for N-acetyl-d-glucosamine was the α-pyranose form, and the reaction product was N-acetyl-d-glucosaminic acid. The enzyme activity was inhibited by Hg and SDS, but many divalent cations, metal-chelating reagents, and sulfhydryl reagents had no effect.     

(−)-Menthylamine derivatives as potent and selective antagonists of transient receptor potential melastatin type-8 (TRPM8) channels

A series of twenty-two (?)-menthylamine derivatives was synthesized and tested on TRPM8, TRPV1, and TRPA1 channels. Five of the novel compounds, that is, 1d, 1f, 2b, 2c, and 2e behaved as potent TRPM8 antagonists with IC₅₀ values versus icilin and (?)-menthol between 20 nM and 0.7 μM, and were between 4- and ～150-fold selective versus TRPV1 and TRPA1 activation. Compound 1d also induced caspase 3/7 release in TRPM8-expressing LNCaP prostate carcinoma cells, but not in non-TRPM8 expressing DU-145 cells. Five other derivatives, that is, 1a, 1g, 1h, 2f, and 2h were slightly less potent than previous compounds but still relatively selective versus TRPV1 and TRPA1.     

Synthesis and structure–activity relationships of N3-pyridylpyrazinones as corticotropin-releasing factor-1 (CRF1) receptor antagonists

A series of N³-pyridylpyrazinones was investigated as corticotropin-releasing factor-1 receptor antagonists. It was observed that the binding affinity of analogues containing a pyridyl group was influenced not only by the substitution pattern on the pyridyl group, but also by the pK_a of the pyridyl nitrogen. Analogues containing a novel 6-(difluoromethoxy)-2,5-dimethylpyridin-3-amine group were among the most potent N³-pyridylpyrazinones synthesized. The synthesis and SAR of N³-pyridylpyrazinones is described herein.     

Development of ligands at γ-aminobutyrric acid type A (GABAA) receptor subtype as new agents for pain relief

The identification of compounds with selective anxiolytic-like effects, exerted through the benzodiazepine site on γ-aminobutyric acid type A (GABA_A) receptors, and that show pronounced antihyperalgesia in several pain models, has oriented research towards the development of new agents for the relief of pain. Starting from our previously reported ligands at the benzodiazepine site on GABA_A receptors showing selective anxiolytic-like effects, we have designed new compounds with the aim of identifying those devoid of the typical side effects of the classical benzodiazepines. Our preliminary results indicate that compounds 4, 10(±) and 11 have a very promising antihyperalgesic profile in different animal pain models (peripheral mono-neuropathy, STZ-induced hyperalgesia). In particular 11 exhibits high potency since it exerted its protective effect starting from the dose of 3 mg/kg po, after single injection.     

Selective inhibition of MBNL1�CCCUG interaction by small molecules toward potential therapeutic agents for myotonic dystrophy type 2 (DM2)

Myotonic dystrophy type 2 (DM2) is an incurable neuromuscular disease caused by expanded CCUG repeats that may exhibit toxicity by sequestering the splicing regulator MBNL1. A series of triaminotriazine- and triaminopyrimidine-based small molecules (ligands 1–3) were designed, synthesized and tested as inhibitors of the MBNL1–CCUG interaction. Despite the structural similarities of the triaminotriazine and triaminopyrimidine units, the triaminopyrimidine-based ligands bind with low micromolar affinity to CCUG repeats (K_d ∼ 0.1–3.6 µM) whereas the triaminotriazine ligands do not bind CCUG repeats. Importantly, these simple and small triaminopyrimidine ligands exhibit both strong inhibition (K_i ∼ 2 µM) of the MBNL1–CCUG interaction and high selectivity for CCUG repeats over other RNA targets. These experiments suggest these compounds are potential lead agents for the treatment of DM2.     

A study of structure–activity relationship and anion-controlled quinolinyl Ag(I) complexes as antimicrobial and antioxidant agents as well as their interaction with macromolecules

BioMetals - In this communication, we feature the synthesis and in-depth characterization of a series of silver(I) complexes obtained from the complexation of quinolin-4-yl Schiff base ligands...     

Identification and characterization of lipopolysaccharide binding protein (LBP) as an estrogen receptor α specific serum biomarker

Estrogen Receptor α (ERα) and Estrogen Receptor β (ERβ) are steroid nuclear receptors that transduce estrogen signaling to control diverse physiological processes linked to reproduction, bone remodeling, behavior, immune response and endocrine-related diseases. In order to differentiate between ERα and ERβ mediated effects in vivo, ER subtype selective biomarkers are essential. We utilized ERα knockout (AERKO) and ERβ knockout (BERKO) mouse liver RNA and genome wide profiling to identify novel ERα selective serum biomarker candidates. Results from the gene array experiments were validated using real-time RT-PCR and subsequent ELISA's to demonstrate changes in serum proteins. Here we present data that Lipopolysacharide Binding Protein (LBP) is a novel liver-derived ERα selective biomarker that can be measured in serum.     

Sulfonamide phenylalanine (SPA) series of analogues as an antibacterial,antifungal, anticancer agents along with p53 tumor suppressor-DNA complex inhibitor – part 1

Abstract

A series of N-[1-benzyl-2-oxo-2-substituted(ethyl)] benzene/p-toluene sulfonamide (K1–K12) are synthesized. Structure of the synthesized analogues has been confirmed by FT-IR, ¹H & ¹³C NMR and ESI-MS spectroscopic techniques. All the synthesized analogues (K1–K12) have also been examined for their in-vitro antibacterial and antifungal activities. Compounds showed good antibacterial and antifungal activity against standard drug. Anticancer study has been carried out on three cancer cell lines PC-3, MCF-7 and A549 on two different concentrations (mg/mL and μg/mL). The K4 sulfonamide analogue showed better anticancer activity amongst all analogues against PC-3 and A549 cell lines. K4 inhibit G0/G1 phase in cell-cycle analysis experiment. All synthesized molecules (K1–K12) dock at junction p53-DNA and make hydrogen bonded with residues of p53 protein as per docking study. ADMET predictions of synthesized phenylalanine sulfonamide analogues (K1–K12) has been done using ‘Lipinski rule’ and it has been observed that all synthesized analogues did not violate the rule. Electronic, chemical properties and mulliken atomic charges of analogues were calculated using density functional theory (DFT).

Communicated by Ramaswamy H. Sarma     

Synthesis and structure–activity relationships of 2-(1,4′-bipiperidin-1′-yl)thiazolopyridine as H3 receptor antagonists

A series of 2-(1,4′-bipiperidine-1′-yl)thiazolopyridines was synthesized and evaluated as a new lead of non-imidazole histamine H₃ receptor antagonists. Introduction of diversity at the 6-position of the pyridine ring was designed to enhance in vitro potency and decrease hERG activity. The structure–activity relationships for these new thiazolopyridine antagonists are discussed.     

Identification of N-acyl 4-(3-pyridonyl)phenylalanine derivatives and their orally active prodrug esters as dual acting α4β1 and α4β7 receptor antagonists

From a series of N-acyl 4-(3-pyridonyl)phenylalanine derivatives of 4, the trifluoromethyl derivative 28 was identified as a potent, dual acting alpha4 integrin antagonist with activity in primate models of allergic asthma. Investigation of a series of prodrug esters led to the discovery of the morpholinopropyl derivative 48 that demonstrated good intestinal fluid stability, solubility and permeability. Compound 48 gave high blood levels of 28 when dosed orally in cynomolgus monkeys. Surprisingly, hydrolysis of 48 was rapid in liver microsomes from the pharmacological species, mouse, rat and monkey, but slow in dog and human; in vivo studies also indicated there was prolonged exposure to unchanged prodrug in dogs.     

Novel 7α-alkoxy-17α-(4'-halophenylethynyl)estradiols as potential SPECT/PET imaging agents for estrogen receptor expressing tumours: Synthesis and binding affinity evaluation

In order to develop potential radiolabelled probes for imaging estrogen receptor (ER) positive tumours, we have synthesized and characterized a series of novel 7α-alkoxy-17α-(4'-iodophenylethynyl)estra-1,3,5(10)-triene-3,17β-diols and 7α-alkoxy-17α-(4'-fluorophenylethynyl)estra-1,3,5(10)-triene-3,17β-diols. The fluoro-substituted compounds showed a higher ER binding affinity than the corresponding iodo-derivatives, where 7α-methoxy- and 17α-(4'-fluorophenylethynyl)estra-1,3,5(10)-triene-3,17β-diol showed the highest ER binding affinities (RBA=80.9% and 78.9%, respectively), among the halophenylethynyl compounds studied and should be further explored as potential PET biomarkers for imaging of ER expressing tumours.     

Identification of biaryl sulfone derivatives as antagonists of the histamine H₃ receptor: discovery of (R)-1-(2-(4'-(3-methoxypropylsulfonyl)biphenyl-4-yl)ethyl)-2-methylpyrrolidine (APD916)

The design of a new clinical candidate histamine-H(3) receptor antagonist for the potential treatment of excessive daytime sleepiness (EDS) is described. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were modified by replacement of the sulfonamide linkage with a sulfone. One compound from this series, 2j (APD916) increased wakefulness in rodents as measured by polysomnography with a duration of effect consistent with its pharmacokinetic properties. The identification of a suitable salt form of 2j allowed it to be selected for further development.     

Fighting antimicrobial resistance (AMR): Chinese herbal medicine as a source of novel antimicrobials – an update

Antimicrobial resistance (AMR) has now emerged as a global public health crisis, requiring the discovery of new and novel antimicrobial compounds, that may be precursors of future therapeutic antibiotics. Chinese Herbal Medicine (CHM) comes with a rich pedigree of holistic and empirical usage in Asia for the last 5000 years. Extracts of Anemarrhena asphodeloides Bunge, Angelica sinensis (Oliv.) Diels, Dianthus superbus L. Forsythiae fructus (Lian Qiao), Lonicerae flos (Jin Yin Hua), Naemorhedi cornu, Platycladus orientalis Franco, Polygonum aviculare, Polygonum cuspidatum, Poria cocos (Schw.), Rehmannia glutinosa (Gaertn.) DC, Rheum palmatum, Salvia miltiorrhiza Bunge, Scutellaria barbata, Scutellariae radix (Huang Qin) and Ursi fel (Xiong Dan) have shown to have antimicrobial properties against clinically significant Gram-negative and Gram-positive bacterial pathogens, as well as the mycobacteria (TB and non-tuberculous mycobacteria). Evidence is now beginning to emerge through systematic reviews of the outcomes of clinical studies employing CHM to treat infections. Of the 106 Cochrane systematic reviews on CHM, 16 (ca 15%) reviews examine CHM in the context of treating a specific infection disease or state. This update examines direct antimicrobial effect of CHM on bacterial pathogens, as well as synergistic effects of combining CHM with conventional antibiotics.     

β-Lactotensin derived from bovine β-lactoglobulin exhibits anxiolytic-like activity as an agonist for neurotensin NTS(2) receptor via activation of dopamine D(1) receptor in mice

β-Lactotensin (His-Ile-Arg-Leu) is a bioactive peptide derived from bovine milk β-lactoglobulin, acting as a natural agonist for neurotensin receptors. We found that β-lactotensin exhibited anxiolytic-like activity in an elevated plus-maze test after its intraperitoneal (i.p.) administration in mice. β-Lactotensin was also orally active. The anxiolytic-like activity of β-lactotensin after i.p. administration was blocked by levocabastine, an antagonist for the neurotensin NTS(2) receptor. β-Lactotensin had anxiolytic-like activity in wild-type but not Ntsr2-knockout mice. β-Lactotensin increased intracellular Ca(2+) flux in glial cells derived from wild-type mice but not Ntsr2 knockout mice. These results suggest that β-lactotensin acts as an NTS(2) receptor agonist having anxiolytic-like activity. The anxiolytic-like activity of β-lactotensin was also blocked by SCH23390 and SKF83566, antagonists for dopamine D(1) receptor, but not by raclopride, an antagonist for D(2) receptor. Taken together, β-lactotensin may exhibit anxiolytic-like activity via NTS(2) receptor followed by D(1) receptor.     

Identification of N-acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives and their orally active prodrug esters as dual-acting alpha4–beta1 and alpha4–beta7 receptor antagonists

N-Acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives of type 4 were designed to replace the 2,6-dichlorobenzoylamine portion of compound 1 in order to identify novel compounds with improved potency against α4-integrins. Several derivatives were identified as very potent dual-acting α4-integrin, α4β1 and α4β7 antagonists. Investigation of a limited number of prodrug esters led to the discovery of the ethyl ester prodrug 42, which demonstrated good intestinal fluid stability and good permeability. Despite low solubility, 42 gave acceptable blood levels of 30 when dosed orally in non-human primates. Additionally, 42 had an overall excellent profile and was selected for clinical trials. Investigation of N-acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives led to the discovery of several very potent dual-acting α4-integrin antagonists. Ethyl ester prodrug 42 advanced to human clinical trials based on the excellent intestinal fluid stability, good permeability and superior efficacy in non-human primates.     

Gold nanoparticles inhibited the receptor activator of nuclear factor-κb ligand (RANKL)-induced osteoclast formation by acting as an antioxidant

Gold nanoparticles inhibited osteoclast (OC) formation induced by the receptor activator of nuclear factor-κB ligand (RANKL) in bone marrow-derived macrophages (BMMs). This was accompanied by a decreased level of tartrate-resistant alkaline phosphatase (TRAP) and less activation of nuclear factor (NF)-κB. The nanoparticles also reduced the production of reactive oxygen species (ROS) in response to RANKL and upregulated RANKL-induced glutathione peroxidase-1 (Gpx-1), suggesting a role as an antioxidant in the BMM. The inhibitory effects on OC formation might have been due to elevated defense against oxidative stress.