5z These recommendations may be useful for the future to avo

These recommendations may be useful for the future to avoid misleading reports and pairings. However, the existing literature can also hold back current research on some given orphans. Before entering into drug development or further physiological conceptual framework, these pairings should be thoroughly confirmed. While preparing this manuscript, we noticed that a significant number of receptors received no attention for the past 10 years although they have been “paired” to a ligand by a single paper. It is tempting to speculate that investigators and funders are reluctant to perform studies that may lead to “negative” data. However, although it can be quite frustrating to pursue a scientific project with high risk of generating negative data, these experiments and their description in the literature are of paramount importance. Another possible issue is that they might be perceived as more difficult to publish or less rewarding for career advancement. The basic pharmacology journal should promote such negative studies that could correct literature and unblock the quest on some receptors. In addition, inexperienced teams are susceptible to start project based on the assumption that some mediators work through a given receptor, only to realize at later stage that the starting 5z was not robust enough. Therefore, effort in reproducing independently initial pairing could spare a significant amount of valuable time and resources. It should be noted that there seem to be an encouraging trend as several important “negative” reports have been published recently, on GPR18 or GPR17 for instance (Table 2).
Benzodiazepines Past, Present, and Future Ligands of the high-affinity benzodiazepine (see Glossary) binding site have been immensely successful drugs for the past decades. Unlike many other drugs they are nearly free from acute and chronic toxicity [1]. For treatment of sleep disorders they are the drugs of choice, and they are often used in anxiety disorders. Additional popular uses are as sedatives in anesthesia and in psychiatric use, as well as centrally acting muscle relaxants. Why should they still be of scientific interest 57 years after their introduction to the market? Does this type of drug have a future? This review explains why the answer is still yes. Benzodiazepines exert their effects through that respond to the neurotransmitter GABA. Benzodiazepine site-targeting drugs such as diazepam or Z-drugs (Box 1) bind with high affinity to some subtypes of GABAA receptors (2, 3 for review) and with low affinity to different sites in most other receptor subtypes. Understanding these receptor subtypes offers abundant opportunities for the separation of the pleiotropic effects of benzodiazepines that include sedation, hypnosis, anxiolysis, and muscle relaxation. At present, novel applications for benzodiazepines in neuropsychiatry are being investigated, for example in cognitive enhancement, pain relief, and possibly in the treatment of depression 4, 5. Moreover, ligands of high-affinity benzodiazepine binding sites are valuable tracer molecules for ligand-based imaging methods such as positron emission tomography (PET) [6] and single-photon emission computed tomography (SPECT). Recent developments in ligand discovery, binding-site characterization, and mapping of pharmacological effects to specific receptor subtypes are reviewed here. We first discuss the molecular properties of GABAA receptors.
The high-affinity binding site for benzodiazepines was first isolated from bovine brain and was described as a protein complex with two subunits named α and β [7]. This protein complex turned out to be identical to the GABAA receptor. Cloning and expression of these two subunits confirmed the identity of the protein complex [8]. It was rapidly recognized that there are multiple subunit isoforms, and to date subunits named α1–6, β1–3, γ1–3, ρ1–3, δ, ε, θ, and π have been identified in mammalian species (9, 10, 11 for review) (Box 2). One to five out of these subunit isoforms are assembled into a ring-like pentameric complex with a central chloride and bicarbonate ion-selective channel. Binding of the neurotransmitter GABA opens this channel, and benzodiazepines modulate this opening. The major subunit isoform consists of α1, β2, and γ2, arranged α1γ2β2α1β2 counterclockwise as seen from the outside of the cell 12, 13, 14. The two binding sites for the agonist GABA are located at the extracellular subunit interfaces β2/α1, and the high-affinity binding site for benzodiazepines is located at a closely homologous position at the α1/γ2 interface in this receptor. There may be dozens of other GABAA receptor subtypes (Boxes 2,3). Even receptors with the same subunit composition may assemble into different receptor species [15]. It has been shown that different subcellular compartments of neurons, such as postsynaptic densities, perisynaptic dendritic regions, and cell somata, contain distinct receptor subtypes [16].