Receptor Binding Assays and Drug Discovery.

Although Solomon Snyder authored hundreds of research reports and several books covering a broad range of topics in the neurosciences, he is best known by many as the person who developed neurotransmitter receptor radioligand binding assays. By demonstrating the utility of this approach for studying transmitter receptors in brain, Dr. Snyder provided the scientific community with a powerful new tool for identifying and characterizing these sites, for defining their relationship to neurological and psychiatric disorders, and their involvement in mediating the actions of psychotherapeutics. Although it was hoped the receptor binding technique could also be used as a primary screen to speed and simplify the identification of novel drug candidates, experience has taught that ligand binding is most useful for drug discovery when it is used in conjunction with functional, phenotypic assays. The incorporation of ligand binding assays into the drug discovery process played a significant role in altering the search for new therapeutics from solely an empirical undertaking to a mechanistic and hypothesis-driven enterprise. This illustrates the impact of Dr. Snyder's work, not only on neuroscience research but on the discovery, development, and characterization of drugs for treating a variety of medical conditions.

Guidelines for manuscript submission in the peer-reviewed pharmacological literature.

Recent reports have highlighted studies in biomedical research that cannot be reproduced, tending to undermine the credibility, relevance and sustainability of the research process. To address this issue, a number of factors can be monitored to improve the overall probability of reproducibility. These include: (i) shortcomings in experimental design and execution that involve hypothesis conceptualization, statistical analysis, and data reporting; (ii) investigator bias and error; (iii) validation of reagents including cells and antibodies; and (iv) fraud. Historically, research data that have undergone peer review and are subsequently published are then subject to independent replication via the process of self-correction. This often leads to refutation of the original findings and retraction of the paper by which time considerable resources have been wasted in follow-on studies. New NIH guidelines focused on experimental conduct and manuscript submission are being widely adopted in the peer-reviewed literature. These, in their various iterations, are intended to improve the transparency and accuracy of data reporting via the use of checklists that are often accompanied by "best practice" guidelines that aid in validating the methodologies and reagents used in data generation. The present Editorial provides background and context to a newly developed checklist for submissions to Biochemical Pharmacology that is intended to be clear, logical, useful and unambiguous in assisting authors in preparing manuscripts and in facilitating the peer review process. While currently optional, development of this checklist based on user feedback will result in it being mandatory within the next 12 months.

GABA pharmacology: the search for analgesics.

Decades of research have been devoted to defining the role of GABAergic transmission in nociceptive processing. Much of this work was performed using rigid, orthosteric GABA analogs created by Povl Krogsgaard-Larsen and his associates. A relationship between GABA and pain is suggested by the anatomical distribution of GABA receptors and the ability of some GABA agonists to alter nociceptive responsiveness. Outlined in this report are data supporting this proposition, with particular emphasis on the anatomical localization and function of GABA-containing neurons and the molecular and pharmacological properties of GABAA and GABAB receptor subtypes. Reference is made to changes in overall GABAergic tone, GABA receptor expression and activity as a function of the duration and intensity of a painful stimulus or exposure to GABAergic agents. Evidence is presented that the plasticity of this receptor system may be responsible for the variability in the antinociceptive effectiveness of compounds that influence GABA transmission. These findings demonstrate that at least some types of persistent pain are associated with a regionally selective decline in GABAergic tone, highlighting the need for agents that enhance GABA activity in the affected regions without compromising GABA function over the long-term. As subtype selective positive allosteric modulators may accomplish these goals, such compounds might represent a new class of analgesic drugs.

Characterization of GABA receptors.

Described in this unit are ligand-binding assays for GABAA , GABAB , and the homomeric ρ GABAA (formerly GABAC ) receptor recognition sites in brain tissue. Although GABA binding sites are present in peripheral organs, most research is directed toward examining these receptors in the CNS. These assays may also be used to determine the affinity of an unlabeled compound for the GABA binding sites. Excluded from the unit are ligand-binding assays for other components of the GABAA receptor complex, such as the benzodiazepine or ion-channel binding sites.

A legacy of discovery: from monoamines to GABA.

Seldom does a single individual have such a profound effect on the development of a scientific discipline as Erminio Costa had on neuropharmacology. During nearly sixty years of research, Costa and his collaborators helped established many of the basic principles of the pharmacodynamic actions of psychotherapeutics. His contributions range from defining basic neurochemical, physiological and behavioral properties of neurotransmitters and their receptors, to the development of novel theories for drug discovery. Outlined in this report is a portion of his work relating to the involvement of monoamines and GABA in mediating the symptoms of neuropsychiatric disorders and as targets for drug therapies. These studies were selected for review because of their influence on my own work and as an illustration of his logical and insightful approach to research and his clever use of techniques and technologies. Given the significance of his work, the legions of scientist who collaborated with him, and those inspired by his reports, his research will continue to have an impact as long as there is a search for new therapeutics to alleviate the pain and suffering associated with neurological and psychiatric disorders. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.

Prospects for neurodegenerative and psychiatric disorder drug discovery.

The discovery of CNS-active drugs has, to a major extent, resulted from clinical serendipity. Once targets for such compounds were identified, conventional mechanism-based approaches were used to identify new chemical entities for the treatment of neurological and psychiatric disorders. Most of these have, however, failed to display any greater efficacy than existing psychotherapeutics and may, in fact, be less efficacious because of side effect liabilities. Among the reasons for this lack of success in drug discovery include a lack of fundamental knowledge regarding the causes of CNS disorders, the absence of biomarkers for diagnosing and monitoring these conditions, a paucity of animal models that are congruent with the human disease state and the increasing likelihood that CNS conditions are multifactorial in their etiology. These challenges force the inclusion of a Phase IIa proof of concept trial as a component of the drug discovery program. Unlike other therapeutic areas, serendipity is a major factor in the CNS translational medicine interface requiring a close collaboration between preclinical and clinical scientists trained to appreciate unusual behavioral phenotypes. When combined with conventional target-based drug discovery technologies, this increases the likelihood of identifying truly novel drugs for the treatment of CNS disorders.