Doctors, Patients, and Interpreters' Views on the Co-Construction of Empathic Communication in Interpreter-Mediated Consultations: A Qualitative Content Analysis of Video Stimulated Recall Interviews.

Doctors and patients rely on verbal and nonverbal resources to co-construct clinical empathy. In language-discordant consultations, interpreters' communicative actions might compromise this process. We aim to explore doctors, patients, and professional interpreters' perspectives on their own and others' actions during their empathic interaction in interpreter-mediated consultations (IMCs).

Emotion work in interpreter-mediated consultations: A systematic literature review.

Objective: To identify the ways in which physicians, patients and interpreters express emotions, react to emotional expressions and/or coordinate the emotional interaction in interpreter-mediated consultations (IMCs).

Methods: We systematically searched four databases and screened 10 307 articles. The following inclusion criteria were applied: 1) participants are patients with limited proficiency in the host language, physicians and professional interpreters, 2) analysis of patient-physician-interpreter interaction, 3) focus on emotions, 4) in vivo spoken language interpretation, and 5) authentic primary data.

Use of a fluorescent polarization based high throughput assay to identify new calmodulin ligands.

In order to develop a fluorescence polarization (FP) assay for calcium binding proteins, a fluorescent peptides based library of 1328 compounds has been synthesized. The use of this library has been validated by setting up a FP-high-throughput screening (FP-HTS) assay for calmodulin using the synthetic gene product (synCaM). With this assay, a set of 880 FDA approved compounds was screened.

Similarity in drugs: reflections on analogue design.

A survey of novel small-molecule therapeutics reveals that the majority of them result from analogue design and that their market value represents two-thirds of all small-molecule sales. In natural science, the term analogue, derived from the Latin and Greek analogia, has always been used to describe structural and functional similarity. Extended to drugs, this definition implies that the analogue of an existing drug molecule shares structural and pharmacological similarities with the original compound.

Selective optimization of side activities: the SOSA approach.

Selective optimization of side activities of drug molecules (the SOSA approach) is an intelligent and potentially more efficient strategy than HTS for the generation of new biological activities. Only a limited number of highly diverse drug molecules are screened, for which bioavailability and toxicity studies have already been performed and efficacy in humans has been confirmed. Once the screening has generated a hit it will be used as the starting point for a drug discovery program.

Development of novel 1,2,3,4-tetrahydroisoquinoline derivatives and closely related compounds as potent and selective dopamine D3 receptor ligands.

Based on N-alkylated 1,2,3,4-tetrahydroisoquinoline derivatives, which are structurally related to the partial agonist BP 897, a series of novel, selective dopamine D3 receptor antagonists has been synthesised. Derivatisation included changes in the arylamide moiety and the tetrahydroisoquinoline substructure leading to compounds with markedly improved selectivities and affinities in the low nanomolar concentration range. From the 55 structures presented here, (E)-3-(4-iodophenyl)-N-(4-(1,2,3,4-tetrahydroisoquinolin-2-yl)butyl)acrylamide (51) has high affinity (Ki(hD3)=12 nM) and a 123-fold preference for the D3 receptor relative to the D2 receptor subtype.

Prednisone reduces muscle degeneration in dystrophin-deficient Caenorhabditis elegans.

Duchenne muscular dystrophy is a degenerative muscular disease caused by mutations in the dystrophin gene. There is no curative treatment against Duchenne muscular dystrophy. In several countries, the steroid prednisone (or analogs) is prescribed as a palliative treatment.

N-(omega-(4-(2-methoxyphenyl)piperazin-1-yl)alkyl)carboxamides as dopamine D2 and D3 receptor ligands.

The dopamine D(3) receptor is recognized as a potential therapeutic target for the treatment of various neurological and psychiatric disorders. Targetting high affinity and D(3) versus D(2) receptor-preferring ligands, the partial agonist BP 897 was taken as a lead structure. Variations in the spacer and the aryl moiety led to N-alkylated 1-(2-methyoxyphenyl)piperazines with markedly improved affinity and selectivity.

A convenient 3-step synthesis of 3-acetamido-6-arylpyridazines directed to novel Y5 receptor antagonist.

A 3-step synthesis of 3-acetamido-6-arylpyridazines as potential NPY5 antagonists.

Design, synthesis, and structure-activity relationships of a series of 3-[2-(1-benzylpiperidin-4-yl)ethylamino]pyridazine derivatives as acetylcholinesterase inhibitors.

Starting from the 3-[2-(1-benzylpiperidin-4-yl)ethylamino]-6-phenylpyridazine 1, we performed the design, the synthesis, and the structure-activity relationships of a series of pyridazine analogues acting as AChE inhibitors. Structural modifications were achieved on four different parts of compound 1 and led to the following observations: (i) introduction of a lipophilic environment in the C-5 position of the pyridazine ring is favorable for the AChE-inhibitory activity and the AChE/BuChE selectivity; (ii) substitution and various replacements of the C-6 phenyl group are possible and led to equivalent or slightly more active derivatives; (iii) isosteric replacements or modifications of the benzylpiperidine moiety are detrimental to the activity. Among all derivatives prepared, the indenopyridazine derivative 4g was found to be the more potent inhibitor with an IC(50) of 10 nM on electric eel AChE.

Structure-based 3D QSAR and design of novel acetylcholinesterase inhibitors.

The paper describes the construction, validation and application of a structure-based 3D QSAR model of novel acetylcholinesterase (AChE) inhibitors. Initial use was made of four X-ray structures of AChE complexed with small, non-specific inhibitors to create a model of the binding of recently developed aminopyridazine derivatives. Combined automated and manual docking methods were applied to dock the co-crystallized inhibitors into the binding pocket.

Medicinal chemistry in the development of societies. Biodiversity and natural products.

This document has been elaborated by the IUPAC Medicinal Chemistry section and is backed by a large number of scientists, many of whom have had direct involvement and whose names appear at the end of the article. This work discusses the role that the discovery of new medicinal agents has in the development of societies as well as in the conservation of biodiversity in terms of work carried out on natural products. Also included are several recommendations for countries which are presently in search of their own scientific and technological development in medicinal agents.

Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist.

Environmental stimuli that are reliably associated with the effects of many abused drugs, especially stimulants such as cocaine, can produce craving and relapse in abstinent human substance abusers. In animals, such cues can induce and maintain drug-seeking behaviour and also reinstate drug-seeking after extinction. Reducing the motivational effects of drug-related cues might therefore be useful in the treatment of addiction.

Aminopyridazines as acetylcholinesterase inhibitors.

Following the discovery of the weak, competitive and reversible acetylcholinesterase (AChE)-inhibiting activity of minaprine (3c) (IC50 = 85 microM on homogenized rat striatum AChE), a series of 3-amino-6-phenylpyridazines was synthesized and tested for inhibition of AChE. A classical structure-activity relationship exploration suggested that, in comparison to minaprine, the critical elements for high AChE inhibition are as follows: (i) presence of a central pyridazine ring, (ii) necessity of a lipophilic cationic head, (iii) change from a 2- to a 4-5-carbon units distance between the pyridazine ring and the cationic head. Among all the derivatives investigated, 3-[2-(1-benzylpiperidin-4-yl)ethylamino]-6-phenylpyridazine (3y), which shows an IC50 of 0.

5-HT3 antagonists derived from aminopyridazine-type muscarinic M1 agonists.

A conformational analysis, performed on muscarinic M1 agonists, identified four structural features characteristic of the muscarinic M1 pharmacophore: (i) a protonable basic or quaternary nitrogen acting as a cationic head; (ii) an electronegative dipole usually part of a planar mesomeric ester, amide, or amidine function which can be replaced by an ether (muscarine) or a dioxolane (AF 30); (iii) an intercharge distance of 5 +/- 0.5 A between the cationic head and the electronegative atom of the dipole; (iv) an elevation of 0.5 +/- 0.

Modelling of the binding site of the human m1 muscarinic receptor: experimental validation and refinement.

Our model of the human m1 muscarinic receptor has been refined on the basis of the recently published projection map of bovine rhodopsin. The refined model has a slightly different helix arrangement, which reveals the presence of an extra hydrophobic pocket located between helices 3, 4 and 5. The interaction of series of agonists and antagonists with the m1 muscarinic receptor has been studied experimentally by site-directed mutagenesis.

Lectin activities of cytokines and growth factors: function and implications for pathology.

The discovery that certain cytokines have carbohydrate-binding (lectin) properties opens new concepts in the understanding of their mechanism of action. The carbohydrate-recognition domain, which is localized opposite to the receptor-binding domain, makes these molecules bi-functional. The expression of the biological activity of the cytokine relies on its carbohydrate-binding activity which allows the association of the cytokine receptor with molecular complexes comprising the specific kinase involved in receptor phosphorylation and in specific signal transduction.

Novel arylaminopyridazine-GABA receptor antagonists examined electrophysiologically in Ascaris suum.

The structure-activity relationships of 35 novel derivatives of 2-(carboxypropyl)-3-amino-4-methyl-6-phenyl pyridazine (SR 95103) were examined as gamma-aminobutyric acid (GABA) antagonists in the flap preparation of the parasitic nematode, Ascaris suum, using a two-microelectrode current-clamp technique. All but one of the potent antagonists displaced GABA dose-response curves to the right without reduction in the maximum response. The dissociation constants of the more potent competitive antagonists were described using a model which assumed that two molecules of GABA were required to open the ion channel but that only one molecule of antagonist acted on each ion channel.

Inhibitors of prolyl endopeptidase: characterization of the pharmacophoric pattern using conformational analysis and 3D-QSAR.

A structure-activity study has been carried out on several compounds known as inhibitors of the serine protease prolyl endopeptidase. Conformational analysis has been done using different molecular mechanics methods such as molecular dynamics, or a randomized conformational search method. The conformers obtained were classified using geometric and energetic criteria.

Aminopyridazines--an alternative route to potent muscarinic agonists with no cholinergic syndrome.

In the search for central cholinergic agents which do not derive from already well-known agonists such as arecoline, pilocarpine or oxotremorine, we selected minaprine [3-(beta-morpholinoethylamino)-4-methyl-6-phenyl-pyridazine dihydrochloride] as a lead structure. Effectively, beside its antidepressive properties, minaprine shows a weak but highly selective affinity for hippocampic M1 receptors (IC50 = 17.10(-6) [3H]-pirenzepine).