1,2,3-Triazole framework: a strategic structure for C-H⋯X hydrogen bonding and practical design of an effective Pd-catalyst for carbonylation and carbon-carbon bond formation.

1,2,3-Triazole is an interesting N-heterocyclic framework which can act as both a hydrogen bond donor and metal chelator. In the present study, C-H hydrogen bonding of the 1,2,3-triazole ring was surveyed theoretically and the results showed a good agreement with the experimental observations. The click-modified magnetic nanocatalyst Pd@click-FeO/chitosan was successfully prepared, in which the triazole moiety plays a dual role as both a strong linker and an excellent ligand and immobilizes the palladium species in the catalyst matrix.

Noncompetitive inhibition of indolethylamine-N-methyltransferase by N,N-dimethyltryptamine and N,N-dimethylaminopropyltryptamine.

Indolethylamine-N-methyltransferase (INMT) is a Class 1 transmethylation enzyme known for its production of N,N-dimethyltryptamine (DMT), a hallucinogen with affinity for various serotonergic, adrenergic, histaminergic, dopaminergic, and sigma-1 receptors. DMT is produced via the action of INMT on the endogenous substrates tryptamine and S-adenosyl-l-methionine (SAM). The biological, biochemical, and selective small molecule regulation of INMT enzyme activity remain largely unknown.

Photoaffinity labeling of the sigma-1 receptor with N-[3-(4-nitrophenyl)propyl]-N-dodecylamine: evidence of receptor dimers.

The sigma-1 receptor is a ligand-regulated endoplasmic reticulum (ER) resident chaperone involved in the maintenance of cellular homeostasis. Coupling of the sigma-1 receptor with various ER and/or plasma membrane ion channels is associated with its ability to regulate the locomotor activity and cellular proliferation produced in response to sigma-1 receptor ligands. A number of endogenous small molecules bind to the sigma-1 receptor and have been shown to regulate its activity; these include progesterone, N,N-dimethyltryptamine, d-erythro-sphingosine, and/or other endogenous lipids.

Development of benzophenone-alkyne bifunctional sigma receptor ligands.

Sigma (σ) receptors are unique non-opioid binding sites that are associated with a broad range of disease states. Sigma-2 receptors provide a promising target for diagnostic imaging and pharmacological interventions to curb tumor progression. Most recently, the progesterone receptor (PGRMC1, 25 kDa) has been shown to have σ2 receptor-like binding properties, thus highlighting the need to understand the biological function of an 18 kDa protein that exhibits σ2-like photoaffinity labeling (denoted here as σ2-18k) but the amino acid sequence of which is not known.

The ligand binding region of the sigma-1 receptor: studies utilizing photoaffinity probes, sphingosine and N-alkylamines.

The sigma-1 receptor is a 26 kDa endoplasmic reticulum resident membrane protein that has been shown to have chaperone activity in addition to its promiscuous binding to pharmacological agents. Ligand binding domain(s) of the sigma-1 receptor have been identified using the E. coli expressed and purified receptor protein and novel radioiodinated azido photoaffinity probes followed by proteolytic and chemical cleavage strategies.

Electron-donating para-methoxy converts a benzamide-isoquinoline derivative into a highly Sigma-2 receptor selective ligand.

The sigma-2 (σ2) receptor has been suggested to be a promising target for pharmacological interventions to curb tumor progression. Development of σ2-specific ligands, however, has been hindered by lack of understanding of molecular determinants that underlie selective ligand-σ2 interactions. Here we have explored effects of electron donating and withdrawing groups on ligand selectivity for the σ2 versus σ1 receptor using new benzamide-isoquinoline derivatives.

Characterization of interactions of 4-nitrophenylpropyl-N-alkylamine with ς receptors.

Sigma receptors are small membrane proteins implicated in a number of pathophysiological conditions, including drug addiction, psychosis, and cancer; thus, small molecule inhibitors of sigma receptors have been proposed as potential pharmacotherapeutics for these diseases. We previously discovered that endogenous monochain N-alkyl sphingolipids, including d-erythro-sphingosine, sphinganine, and N,N-dimethylsphingosine, bind to the sigma-1 receptor at physiologically relevant concentrations [Ramachandran, S., et al.

Synthesis and characterization of N,N-dialkyl and N-alkyl-N-aralkyl fenpropimorph-derived compounds as high affinity ligands for sigma receptors.

The sigma-1 receptor is a unique non-opioid, non-PCP binding site that has been implicated in many different pathophysiological conditions including psychosis, drug addiction, retinal degeneration and cancer. Based on the structure of fenpropimorph, a high affinity (K(i)=0.005 nM)(1) sigma-1 receptor ligand and strong inhibitor of the yeast sterol isomerase (ERG2), we previously deduced a basic sigma-1 receptor pharmacophore or chemical backbone composed of a phenyl ring attached to a di-substituted nitrogen atom via an alkyl chain.

Complementary interactions of the rod PDE6 inhibitory subunit with the catalytic subunits and transducin.

Activation of the cyclic GMP phosphodiesterase (PDE6) by transducin is the central event of visual signal transduction. How the PDE6 inhibitory gamma-subunit (Pgamma) interacts with the catalytic subunits (Palphabeta) and the transducin alpha-subunit (alpha(t)) in this process is not entirely clear. Here we have investigated this issue, taking advantage of site-specific label transfer from throughout the full-length Pgamma molecule to both alpha(t) and Palphabeta.

Microwave-assisted synthesis and characterization of optically active poly (ester-imide)s incorporating L-alanine.

Pyromellitic dianhydride (1) was reacted with L-alanine (2) to result [N,N'-(pyromellitoyl)-bis-L-alanine diacid] (3). This compound (3) was converted to N,N'-(pyromellitoyl)-bis-L-alanine diacyl chloride (4) by reaction with thionyl chloride. The microwave-assisted polycondensation of this diacyl chloride (4) with polyethyleneglycol-diol (PEG-200) and/or three synthetic aromatic diols furnish a series of new PEIs and Co-PEIs in a laboratory microwave oven (Milestone).

OXIDATION OF THIOLS USING K(2)S(2)O(8) IN IONIC LIQUID.

A green, straightforward and novel method for oxidation of thiols to the corresponding disulfides is reported using K(2)S(2)O(8) in the ionic liquid 1-butyl-3-methylimidazolium bromide [(bmim)Br] at 65-70 °C. The corresponding disulfides were obtained in excellent yield and short reaction time.

Synthesis and characterization of new Pd(II) complexes of L-ethylphenylalanate.

Complex (S,S)-[Pd{C(6)H(4)(CH(2)CHNH(2)CO(2)CH(2)CH(3))}(mu-Br)](2) (3) was prepared following the method by Vicente and Saura-Llamas (Organometallics 26:2768-2776, 2007), by the reaction of L: -ethylphenylalanate and Pd(OAc)(2) in 1:1 molar ratio under acetonitrile heating conditions and subsequently treating with NaBr. In addition, the cleavage of halogeno-bridge of the complex 3 via nucleophilic attack of some neutral ligands such as triphenylphosphine, pyridine, 2,4,6-trimethylpyridine and piperidine were investigated and the corresponding complexes (S)-[Pd{C(6)H(4)(CH(2)CHNH(2)CO(2)CH(2)CH(3))(Y)(Br)}] (4a-f) were obtained in moderate yields. The six-member orthopalladated complexes were characterized by (1)H-NMR, (31)P-NMR, FT-IR and elemental analysis techniques.

The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator.

The sigma-1 receptor is widely distributed in the central nervous system and periphery. Originally mischaracterized as an opioid receptor, the sigma-1 receptor binds a vast number of synthetic compounds but does not bind opioid peptides; it is currently considered an orphan receptor. The sigma-1 receptor pharmacophore includes an alkylamine core, also found in the endogenous compound N,N-dimethyltryptamine (DMT).

Synthesis and characterization of new optically active poly(azo-ester-imide)s via interfacial polycondensation.

N,N'-Pyromelliticdiimido-di-L-amino acids (1a-1d) were prepared from the reaction of pyromellitic dianhydride with the corresponding L-amino acids in a solution of glacial acetic acid/pyridine (3:2) at refluxing temperature. 4,4'-sulfonyl bis(4,1-phenylene) bis(diazene-2,1-diyl) diphenol, 4,4'-oxy bis(4,1-phenylene) bis(diazene-2,1-diyl) diphenol and 4,4'-methylene bis(4,1-phenylene) bis(diazene-2,1-diyl) diphenol, were prepared from 4,4'-diamino diphenyl sulfone, 4,4'-diamino diphenyl ether, 4,4'-diamino diphenyl methane, sodium nitrite and phenol following the general procedure of diazo coupling. Interfacial polycondensation method was used to prepare the corresponding poly(azo-ester-imid)s (PAEI(1-12)) in biphasic solution of water/dichloromethane.

Probing the steroid binding domain-like I (SBDLI) of the sigma-1 receptor binding site using N-substituted photoaffinity labels.

Radioiodinated photoactivatable photoprobes can provide valuable insights regarding protein structure. Previous work in our laboratory showed that the cocaine derivative and photoprobe 3-[ (125)I]iodo-4-azidococaine ([ (125)I]IACoc) binds to the sigma-1 receptor with 2-3 orders of magnitude higher affinity than cocaine [Kahoun, J. R.

Juxtaposition of the steroid binding domain-like I and II regions constitutes a ligand binding site in the sigma-1 receptor.

sigma-1 receptors represent unique binding sites that are capable of interacting with a wide range of compounds to mediate different cellular events. The composition of the ligand binding site of this receptor is unclear, since no NMR or crystal structures are available. Recent studies in our laboratory using radiolabeled photoreactive ligands suggested that the steroid binding domain-like I (SBDLI) (amino acids 91-109) and the steroid binding domain-like II (SBDLII) (amino acids 176-194) regions are involved in forming the ligand binding site(s) ( Chen, Y.

Identification of regions of the sigma-1 receptor ligand binding site using a novel photoprobe.

sigma Receptors, once considered a class of opioid receptors, are now regarded as a unique class of receptors that contain binding sites for a wide range of ligands, including the drug 1-N(2',6'-dimethylmorpholino)3-(4-t-butylpropylamine) (fenpropimorph), a yeast sterol isomerase inhibitor. Because fenpropimorph has high-binding affinity to the sigma-1 receptor, we have synthesized a series of fenpropimorph-like derivatives with varying phenyl ring substituents and have characterized their binding affinities to the sigma-1 receptor. In addition, we have synthesized a carrier-free, radioiodinated fenpropimorph-like photoaffinity label, 1-N-(2',6'-dimethyl-morpholino)-3-(4-azido-3-[(125)I]iodo-phenyl)propane ([(125)I]IAF), which covalently derivatized the sigma-1 receptor (25.

Specific derivatization of the vesicle monoamine transporter with novel carrier-free radioiodinated reserpine and tetrabenazine photoaffinity labels.

Two iodophenylazide derivatives of reserpine and one iodophenylazide derivative of tetrabenazine have been synthesized and characterized as photoaffinity labels of the vesicle monoamine transporter (VMAT2). These compounds are 18-O-[3-(3'-iodo-4'-azidophenyl)-propionyl]methyl reserpate (AIPPMER), 18-O-[N-(3'-iodo-4'-azidophenethyl)glycyl]methyl reserpate (IAPEGlyMER), and 2-N-[(3'-iodo-4'-azidophenyl)-propionyl]tetrabenazine (TBZ-AIPP). Inhibition of [3H]dopamine uptake into purified chromaffin granule ghosts showed IC50 values of approximately 37 nM for reserpine, 83 nM for AIPPMER, 200 nM for IAPEGlyMER, and 2.

Characterization of the cocaine binding site on the sigma-1 receptor.

The cocaine photoaffinity label 3-iodo-4-azidococaine ([125I]IACoc) binds to the sigma-1 receptor with an affinity that is 2-3 orders of magnitude higher than the parent compound cocaine [Kahoun, J. R., and Ruoho, A.

A convenient and efficient protocol for oxidative aromatization of Hantzsch 1,4-dihydropyridines using benzyltriphenylphosphonium peroxymonosulfate under almost neutral reaction conditions.

Oxidative aromatization of 4-alkyl or aryl and heterocyclic-substituted derivatives of Hantzsch 1,4-dihydropyridines to the corresponding pyridine derivatives has been studied using benzyltriphenylphosphonium peroxymonosulfate as an oxidant in the presence of BiCl(3) under nearly neutral reaction conditions at ambient temperature.

The inhibitory gamma subunit of the rod cGMP phosphodiesterase binds the catalytic subunits in an extended linear structure.

The unique feature of rod photoreceptor cGMP phosphodiesterase (PDE6) is the presence of inhibitory subunits (Pgamma), which interact with the catalytic heterodimer (Palphabeta) to regulate its activity. This uniqueness results in an extremely high sensitivity and sophisticated modulations of rod visual signaling where the Pgamma/Palphabeta interactions play a critical role. The quaternary organization of the alphabetagammagamma heterotetramer is poorly understood and contradictory patterns of interaction have been previously suggested.

Sulfhydryl-reactive, cleavable, and radioiodinatable benzophenone photoprobes for study of protein-protein interaction.

The major task in proteomics is to understand how proteins interact with their partners. The photo-cross-linking technique enables direct probing of protein-protein interaction. Here we report the development of three novel sulfhydryl-reactive benzophenone photoprobes of short "arm" length, each with a substitution of either amino, iodo, or nitro at the para-position, rendering the benzophenone moiety directly radioiodinatable.

Asymmetric interaction between rod cyclic GMP phosphodiesterase gamma subunits and alphabeta subunits.

Rod phosphodiesterase (PDE6) is the central effector enzyme in vertebrate visual transduction. Holo-PDE6 consists of two similar catalytic subunits (Palphabeta) and two identical inhibitory subunits (Pgamma). Palphabeta is the only heterodimer in the PDE superfamily, yet its significance for the function of PDE6 is poorly understood.

Wet silica-supported permanganate for the cleavage of semicarbazones and phenylhydrazones under solvent-free conditions.

Wet silica-supported potassium permanganate was used as an inexpensive and efficient reagent for conversion of semicarbazones and phenylhydrazones to the corresponding carbonyl compounds under solid-state conditions.

Selective and efficient oxidation of sulfides and thiols with benzyltriphenylphosphonium peroxymonosulfate in aprotic solvent.

Benzyltriphenylphosphonium peroxymonosulfate could be used for selective oxidation of aromatic and aliphatic sulfides and thiols to their corresponding sulfoxides and disulfides under nonaqueous and aprotic conditions without catalyst.