Effects of hempseed and flaxseed oils on the profile of serum lipids, serum total and lipoprotein lipid concentrations and haemostatic factors.

Background: Both hempseed oil (HO) and flaxseed oil (FO) contain high amounts of essential fatty acids (FAs); i.e. linoleic acid (LA, 18:2n-6) and alpha-linolenic acid (ALA, 18:3n-3), but almost in opposite ratios.

3D-QSAR studies on cannabinoid CB1 receptor agonists: G-protein activation as biological data.

G-protein activation via the CB1 receptor was determined for a group of various CB1 ligands and utilized as biological activity data in subsequent CoMFA and CoMSIA studies. Both manual techniques and automated docking at CB1 receptor models were used to obtain a common alignment of endocannabinoid and classical cannabinoid derivatives. In the final alignment models, the endocannabinoid headgroup occupies a unique region distinct from the classical cannabinoid structures, supporting the hypothesis that these structurally diverse molecules overlap only partially within the receptor binding site.

Binding kinetics and duration of in vivo action of novel prolyl oligopeptidase inhibitors.

Prolyl oligopeptidase (POP) is a serine protease that specifically hydrolyses small peptides at the carboxyl end of the proline residue. POP has gained pharmaceutical interest, since its inhibitors have been shown to have antiamnesic properties in rat. We examined the effect of the 2(S)-substituents CN and COCH(2)OH at the P1 site of the parent inhibitors isophthalic acid 2(S)-(cyclopentanecarbonyl)pyrrolidine-l-prolyl-pyrrolidine amide and 4-phenylbutanoyl-l-prolyl-pyrrolidine and bulky 5-t-butyl group at the P2 site l-prolyl residue of the parent inhibitor 4-phenylbutanoyl-l-prolyl-pyrrolidine on the binding kinetics to the enzyme.

Dicarboxylic acid azacycle l-prolyl-pyrrolidine amides as prolyl oligopeptidase inhibitors and three-dimensional quantitative structure-activity relationship of the enzyme-inhibitor interactions.

A series of dicarboxylic acid azacycle l-prolyl-pyrrolidine amides was synthesized, and their inhibitory activity against prolyl oligopeptidase (POP) from porcine brain was tested. Three different azacycles were tested at the position beyond P3 and six different dicarboxylic acids at the P3 position. l-Prolyl-pyrrolidine and l-prolyl-2(S)-cyanopyrrolidine were used at the P2-P1 positions.

Prediction of contact angle for pharmaceutical solids from their molecular structure.

Three methods for modeling and predicting water contact angle for a heterogeneous series of pharmaceuticals using computed molecular descriptors and statistical analysis were developed. A number of theoretical molecular descriptors that were related to the structure and physicochemical properties were computed for compounds (n=34) whose experimental water contact angle was known. Thereafter, the descriptors were subjected to partial least squares projections to latent structures analysis.

A cyclopent-2-enecarbonyl group mimics proline at the P2 position of prolyl oligopeptidase inhibitors.

With the aim to replace the natural amino acid proline by a proline mimetic structure, a cyclopent-2-enecarbonyl moiety was studied at the P2 position of prolyl oligopeptidase (POP) inhibitors. The cyclopent-2-enecarbonyl moiety proved to be an excellent proline mimetic at the P2 position of POP inhibitors. The replacement is particularly useful when increased lipophilicity is needed.

Slow-binding inhibitors of prolyl oligopeptidase with different functional groups at the P1 site.

POP (prolyl oligopeptidase) specifically hydrolyses a number of small proline-containing peptides at the carboxy end of the proline residue and POP inhibitors have been shown to have cognition-enhancing properties. It has been noted that certain functional groups at the P1 site of the inhibitor, which correspond to the substrate residue on the N-terminal side of the bond to be cleaved, increase the inhibitory potency. However, detailed mechanistic and kinetic analysis of the inhibition has not been studied.

Development of a 3D model for the human cannabinoid CB1 receptor.

A novel comparison model of the human cannabinoid CB1 receptor has been constructed using the bovine rhodopsin X-ray structure as a template. The model was subjected to a 500-ps molecular dynamics simulation, and thereafter new conformers of the receptor model were produced in a simulated annealing procedure. Using an automated docking procedure, well-known cannabimimetic ligands were docked into six different model conformers, of which one was chosen for a detailed study of receptor-ligand interactions.

Synthesis and CB1 receptor activities of novel arachidonyl alcohol derivatives.

Novel derivatives of arachidonyl alcohol were synthesized and evaluated for their CB1 receptor activity by [(35)S]GTP(gamma)S assay using rat cerebellar membranes.

Molecular determinants of steroid inhibition for the mouse constitutive androstane receptor.

The constitutive androstane receptor (CAR) regulates drug and steroid metabolism through binding to cytochrome P450 2B, 2C, and 3A gene enhancers. Uniquely among nuclear receptors, mouse CAR (mCAR) can be suppressed by androstenol and activated by structurally diverse drugs, pesticides, and environmental pollutants. To gain insight into presently ill-defined structural requirements of mCAR ligands, we employed a mCAR inhibition assay in mammalian HEK293 cells to create a QSAR model that could well predict the inhibition by three unknown steroids.

New prolyl oligopeptidase inhibitors developed from dicarboxylic acid bis(l-prolyl-pyrrolidine) amides.

Isophthalic acid bis(l-prolyl-pyrrolidine) amide is a very potent prolyl oligopeptidase inhibitor, but it has a log P value of -0.2, which is very low for a compound targeted to the brain. Therefore, these types of compounds were further modified to improve the structure-activity relationships, with the focus on increasing the log P value.

Conformationally rigid N-acyl-5-alkyl-L-prolyl-pyrrolidines as prolyl oligopeptidase inhibitors.

In the N-acyl-L-prolyl-pyrrolidine type of prolyl oligopeptidase inhibitors the L-prolyl group was replaced by different 5-alkyl-L-prolyl groups, resulting in a series of N-acyl-5-alkyl-L-prolyl-pyrrolidines. Since N-amides of 5-alkyl-L-prolines are conformationally more rigid than those of L-proline, the main objective was to make more rigid prolyl oligopeptidase inhibitors. In the series of compounds where the N-acyl group was a Boc group, the 5(R)-tert-butyl group increased the potency strongly.

Pharmacodynamic response of entacapone in rats after administration of entacapone formulations and prodrugs with varying bioavailabilities.

The aim of this in vivo study was to assess the effect of improved oral bioavailability of entacapone on its actual pharmacodynamic response, COMT inhibition in erythrocytes. Rats were administered entacapone orally as a suspension, as a plain solution, an entacapone/HP-beta-CD solution, two N-alkyl-carbamate ester prodrugs and intravenously as a solution. Also the relationship between pharmacodynamic and pharmacokinetic responses of entacapone was investigated.

Dicarboxylic acid bis(L-prolyl-pyrrolidine) amides as prolyl oligopeptidase inhibitors.

New dicarboxylic acid bis(L-prolyl-pyrrolidine) amides were synthesized, and their inhibitory activity against prolyl oligopeptidase from pig brain was tested in vitro. As compared with earlier described prolyl oligopeptidase inhibitors, these new compounds have in common an L-prolyl-pyrrolidine moiety, but the typical lipophilic acyl end group is replaced by another L-prolyl-pyrrolidine moiety connected symmetrically with a short dicarboxylic acid linker. These compounds are a new type of peptidomimetic prolyl oligopeptidase inhibitor.

Substrate-dependent, non-hyperbolic kinetics of pig brain prolyl oligopeptidase and its tight binding inhibition by JTP-4819.

Prolyl oligopeptidase (POP) is a cytosolic serine protease that hydrolyses small peptides at the carboxyl end of the proline residue. It has raised pharmaceutical interest, since its inhibitors have been shown to have antiamnesic properties. We studied prolyl oligopeptidase kinetics with two 7-amino-4-methylcoumarin derivatives: Z-Gly-Pro-AMC and Suc-Gly-Pro-AMC.

Modulation of mouse and human phenobarbital-responsive enhancer module by nuclear receptors.

The constitutive androstane receptor (CAR) regulates mouse and human CYP2B genes through binding to the direct repeat-4 (DR4) motifs present in the phenobarbital-responsive enhancer module (PBREM). The preference of PBREM elements for nuclear receptors and the extent of cross-talk between CAR and other nuclear receptors are currently unknown. Our transient transfection and DNA binding experiments indicate that binding to DR4 motifs does not correlate with the activation response and that mouse and human PBREM are efficiently 'insulated' from the effects of other nuclear receptors despite their substantial affinity for DR4 motifs.

4-Phenylbutanoyl-2(S)-acylpyrrolidines and 4-phenylbutanoyl-L-prolyl-2(S)-acylpyrrolidines as prolyl oligopeptidase inhibitors.

New 4-phenylbutanoyl-2(S)-acylpyrrolidines and 4-phenylbutanoyl-L-prolyl-2(S)-acylpyrrolidines were synthesized. Their inhibitory activity against prolyl oligopeptidase from pig brain was tested in vitro. In the series of 4-phenylbutanoyl-2(S)-acylpyrrolidines, the cyclopentanecarbonyl and benzoyl derivatives were the best inhibitors having IC(50) values of 30 and 23 nM, respectively.

Design and synthesis of a novel L-dopa-entacapone codrug.

A novel codrug, in which L-Dopa and entacapone are linked via a biodegradable carbamate spacer to form a single chemical entity, was synthesized and studied kinetically. This carbamate codrug provides adequate stability [t(1/2) = 12.1 h (pH 1.