"Do you smoke?" - content and linguistic analysis of students' substance histories in simulated patient interviews.

Background: The use of tobacco, alcohol and other drugs has considerable health consequences. Substance histories are often only incompletely taken in everyday clinical practice. When learning to take a medical history in medical school, one of the learning objectives is to inquire about consumption behavior.

Abolishing Dopamine D/D Receptor Affinity of Subtype-Selective Carbamoylguanidine-Type Histamine H Receptor Agonists.

3-(2-Amino-4-methylthiazol-5-yl)propyl-substituted carbamoylguanidines are potent, subtype-selective histamine H receptor (HR) agonists, but their applicability as pharmacological tools to elucidate the largely unknown HR functions in the central nervous system (CNS) is compromised by their concomitant high affinity toward dopamine D-like receptors (especially to the DR). To improve the selectivity, a series of novel carbamoylguanidine-type ligands containing various heterocycles, spacers, and side residues were rationally designed, synthesized, and tested in binding and/or functional assays at H and D receptors. This study revealed a couple of selective candidates (among others and ), and the most promising ones were screened at several off-target receptors, showing good selectivities.

Structure-Activity Relationships and Computational Investigations into the Development of Potent and Balanced Dual-Acting Butyrylcholinesterase Inhibitors and Human Cannabinoid Receptor 2 Ligands with Pro-Cognitive in Vivo Profiles.

The enzyme butyrylcholinesterase (BChE) and the human cannabinoid receptor 2 (hCBR) represent promising targets for pharmacotherapy in the later stages of Alzheimer's disease. We merged pharmacophores for both targets into small benzimidazole-based molecules, investigated SARs, and identified several dual-acting ligands with a balanced affinity/inhibitory activity and an excellent selectivity over both hCBR and hAChE. A homology model for the hCBR was developed based on the hCBR crystal structure and used for molecular dynamics studies to investigate binding modes.

Binding Kinetics and Pathways of Ligands to GPCRs.

Previously, drugs were developed focusing on target affinity and selectivity. However, it is becoming evident that the drug-target residence time, related to the off-rate, is an important parameter for successful drug development. The residence time influences both the on-rate and overall effectiveness of drugs.

Competitive association binding kinetic assays: a new tool to detect two different binding orientations of a ligand to its target protein under distinct conditions?

Within the last years, for several ligands, binding to G protein-coupled receptors or other target proteins, a binding of the ligand in two different orientations is described. One appropriate experimental technique to detect two different binding orientations is the crystallization of the ligand-protein-complex, but crystallization and subsequent X-ray analysis do not belong to the routine methods. By traditional competitive radioligand equilibrium binding assays, it is not possible to detect or to distinguish between two different binding orientations, but there is a possibility to identify two different binding orientations by performing kinetic competitive radioligand-binding assays.