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The Development of Beta Receptor Agonist Drugs
Published in Richard Beasley, Neil E. Pearce, The Role of Beta Receptor Agonist Therapy in Asthma Mortality, 2020
Attempts to find drugs with increased separation between the bronchodilator and cardiac stimulant doses, i.e., with improved beta2-beta1 selectivity, were continued. The selectivity of the clinically used drugs was not great and, with the development of ligand-binding techniques, it was later shown that although salbutamol and fenoterol showed bronchodilator-cardiac selectivity in vitro and in vivo, there was no difference in their affinities for beta2 and beta1 receptors.78 The functional selectivity of these drugs was attributed to their higher efficacy on beta2 than beta1 receptors. Fenoterol, unlike salbutamol but like isoprenaline, was a full agonist on guinea pig atria (rate) as well as on trachea (relaxation).61 These properties made this drug a useful tool in studies designed to classify beta receptor subtypes in tissues.66However, whether this difference is of relevance in the use of fenoterol in severe asthma has never been thoroughly explored.
Dopamine Receptors, Signaling Pathways, and Drugs
Published in Nira Ben-Jonathan, Dopamine, 2020
Over the last decade, the knowledge of the DAR signaling cascade has greatly expanded [44,45], leading to an extensive reassessment of the mechanism of signaling by the DARs. The classical view stipulated a “linear” response, whereby an agonist-activated receptor is coupled to a specific G protein, resulting in predictable stimulation or inhibition of the intracellular responses. However, recent data revealed much more complex responses by typical agonists, involving not only G proteins but also effectors such as β-arrestins and GRKs. Consequently, new terms have been proposed to define the noncanonical signaling of the DARs as “collateral efficacy,” “functional selectivity,” “inverse agonism” or “biased agonism” [46,47]. Regardless of the terminology being used, G proteins occupy a central, albeit not an exclusive, position, as the regulators of DAR-driven signaling cascade. Although most of activities of the DARs are channeled through the G proteins, some activation occurs through G protein-independent pathways, such as those mediated by β-arrestins.
Voltammetry in Brain Slices
Published in Avital Schurr, Benjamin M. Rigor, BRAIN SLICES in BASIC and CLINICAL RESEARCH, 2020
Two main factors determine the functional selectivity of FCV measurements: the proportions of each amine released in a mixture and the relative sensitivity of the electrodes to each component. As a result of the high voltage scan rates integral to the technique, FCV has limited capacity to resolve DA, NA, and 5-HT in mixtures.49 Consequently, most FCV recordings have been made in areas that contain a predominance of one amine over the others, such as the dopaminergic forebrain. This is not always the case, and Table 2 shows the relative concentrations of the monoamines in a number of rat brain nuclei. This table gives an indication of those areas that are likely to be suitable for investigation assuming (albeit only as a first approximation) that local stimulation evokes monoamine efflux in proportion to the relative tissue levels.
How can we improve the measurement of receptor signaling bias?
Published in Expert Opinion on Drug Discovery, 2023
G protein-coupled receptors (GPCRs) are flexible and dynamic signaling entities that can adopt multiple active conformations upon activation [1,2]. However, each agonist stabilizes a distinct receptor conformation at a definite point of time allowing transmission of a specific conformational information to downstream transducers and effectors. This signaling modality known as biased agonism or functional selectivity has rapidly attracted interest as a means to improve drug discovery by screening for drug candidates that can direct their stimuli toward pathways that are therapeutically beneficial while avoiding those associated with adverse effects. Although appealing as a work plan, screening for biased ligands is a challenging process that needs to be correctly assessed and interpreted. In fact, numerous studies reported identifying compounds with biased signaling properties, but very few of those compounds have progressed to clinical testing, leaving open the question of whether it would be possible to translate a biased drug stimulus into a therapeutically desired response.
A descriptive study of aripiprazole, brexpiprazole, and cariprazine exposures in children ages 0 to 5 years reported to United States poison centers
Published in Clinical Toxicology, 2023
Nicholas Husak, Thomas W. Laudone, James B. Leonard
Aripiprazole, brexpiprazole, and cariprazine, share similar mechanisms of action that differ from traditional (first and second generation) agents [23–25]. This has led to their classification as “third-generation” antipsychotics. The most distinguishing pharmacodynamic feature of third generation agents is partial agonist activity at post-synaptic D2 receptors [26]. As a result, they can either stimulate or antagonize dopamine receptors depending on the conditions of endogenous dopamine neurotransmission [27]. Separately, the concept of “functional selectivity,” has been used to explain the diverse activity these agents exhibit at dopaminergic receptors. This refers to a pharmacological phenomenon in which drugs may illicit a range of responses from a single receptor [28]. Both partial dopamine agonism and functional selectivity may explain the waxing and waning of symptoms that some children exhibited in the published cases [23,24].
Preclinical discovery and development of oliceridine (Olinvyk®) for the treatment of post-operative pain
Published in Expert Opinion on Drug Discovery, 2022
Ammar A.H. Azzam, David G. Lambert
Historical classification of drug efficacy is a full agonist, partial agonist, antagonist, and inverse agonist. The relative influence of different signaling pathways can be used to further describe/classify responsiveness; apparent full agonist at one pathway and partial at another. This, of course, brings in the concept of coupling reserve or more traditional signal amplification. Upstream (closer to the receptor) events are less amplified than downstream (away from receptor; e.g. cAMP in the case of opioids), which can be more amplified. In these examples, when a single end-point is studied/described, a ligand can be returned as a partial agonist upstream and full agonist downstream; effectively misclassifying new ligands. We have discussed this with respect to NOP signaling [8]. Therefore, efficacy can be described as pluridimensional [9]. To reiterate biased agonism (or functional selectivity) is the ability of a particular ligand to drive one signaling pathway over another. There are several examples of biased agonists across pharmacology [10], Table 1 shows some of those acting at the opioid receptor family [11–17]; see also Figure 1. Of particular note are PZM-21, identified using a computational docking strategy of more than 3 million compounds [15] and SR-17018 [16]. We have been working with Anna Janecka and colleagues on peptides with varying degrees of apparent bias who have reported two; F-81 (with apparent G protein bias) and C-33 (with apparent β-arrestin-2 bias) [18].