Studies of Benzodiazepine Receptors Using In Vivo Autoradiography
Edythe D. London in Imaging Drug Action in the Brain, 2017
Therefore, benzodiazepines appear to produce their therapeutic effects by increasing the efficiency of submaximal GABAergic neuronal transmission (Richards et al., 1986b) by binding to pharmacological receptors localized in neuronal membranes as part of an oligomeric complex with GABAA receptors and their associated chloride ion channels (Haefely et al., 1985). Benzodiazepine receptors are involved in the coupling mechanism between GABA receptors and the associated chloride ion channels so that benzodiazepines modulate the GABA receptor-effector system (Richards et al., 1986b). Benzodiazepine drugs have no effect when the GABA receptor-effector system is either at rest or maximally activated since these drugs function to modulate the efficiency of the stimulus provided by GABA rather than to produce a direct effect on chloride ion conductance. Benzodiazepine receptors contain recognition sites for three distinct types of high affinity exognous ligands (Polc et al., 1982), each with different functional consequences (Richards et al., 1986b). Agonists bind to the receptor to produce anxiolytic, sedative, anticonvulsant, and muscle relaxant effects and to enhance the chloride ion conductance effect of GABA. On the other hand, inverse agonists have opposite effects. These drugs reduce the effects of GABA, are anxiogenic (anxiety-producing), and are proconvulsant. Finally, competitive antagonists have no intrinsic activity but prevent or abolish the receptor-mediated effects of agonists and inverse agonists.
The Relaxation System Theoretical Construct
Len Wisneski in The Scientific Basis of Integrative Health, 2017
As mentioned, when scientists know that there is a receptor, they are curious to discover which endogenous ligand also fits into the receptor. In 1983, ligands for both peripheral as well as central benzodiazepine receptors were located. The major ligand for the peripheral receptor is called diazepam-binding inhibitor (DBI) because it displaces drugs that have a high affinity for the receptor (for a review of DBI, see Guidotti et al., 1983; Papadopoulos, 1993). There are numerous ligands that have been shown to bind to the central benzodiazepine receptor. Some of the candidates that we will review include β-carboline, nicotinamide, inosine, hypoxanthine, melatonin, and cannabinoids—all potential relaxation hormones. Curiously, in addition to finding agonists and antagonists, researchers also found ligands that acted like inverse agonists, producing anxiety and convulsions, effects opposite to the benzodiazepines (Braestrup et al., 1983; Prado de Carvalho et al., 1983). Researchers continue to unravel the multifaceted relationship of various ligands to the benzodiazepine receptor and GABA complex, including receptor subunits, and seem to be endlessly discovering new ligands (Haefely et al., 1993; Rothstein et al., 1992; Teuber et al., 1999).
H3 Receptor Target: Past, Present, and Future Perspectives from Worldwide H3 Experts
Divya Vohora in The Third Histamine Receptor, 2008
Preclinical data are promising and suggest a tremendous potential of H3R-related drugs in various diseases. However, we must remember that data on chronic studies are meager, and many of the therapeutic conditions in which H3Rs play a role are chronic diseases requiring long-term treatment. The therapeutic applications for agonists/antagonists/inverse agonists of these receptors, thus, require further validation and clinical evaluation. Nevertheless, clinical trials are underway in a number of conditions including ADHD, Alzheimer’s disease, narcolepsy, neuropathic pain, and schizophrenia and the results being awaited with much interest. Hopefully, we may see a novel class of drugs for disorders of the CNS that have so far been largely refractory to pharmacotherapy.
Investigational drugs in early stage clinical trials for thyrotoxicosis with hyperthyroidism
Published in Expert Opinion on Investigational Drugs, 2018
José-Manuel Gómez-Sáez
There are many molecules that biochemically are low molecular weight compounds that bind to cell surface receptors modifying their signaling responses. These responses could be activation of receptor (agonistic), or suppression of the natural activity (antagonistic), or even suppression of the constitutive activity (inverse agonistic). Inverse agonists exert the opposite biological effect of a receptor agonist [17]. These molecules are used in clinic very frequently as amiodarone and its metabolite desethylamiodarone; they are benzofuranic compounds, which, on the other hand, are able to induce thyrotoxicosis with hyperthyroidism and hypothyroidism as side effects as a consequence of their similar structure with T4 and T3 and they high iodine content (about 37% by weight), being the daily dose 200mg [18]. Other drugs that should be considered such as beraprost, a prostacyclin receptor agonist, celecoxib, and diclofenac, two no steroidal anti-inflammatory drugs and dronedarone similar to amiodarone but without iodine content [19,20].
Differential expression and signaling of the human histamine H3 receptor isoforms of 445 and 365 amino acids expressed in human neuroblastoma SH-SY5Y cells
Published in Journal of Receptors and Signal Transduction, 2018
Gustavo Nieto-Alamilla, Juan Escamilla-Sánchez, María-Cristina López-Méndez, Anayansi Molina-Hernández, Agustín Guerrero-Hernández, José-Antonio Arias-Montaño
In the extended ternary cubic model, receptor constitutive activity is explained by the presence of subpopulations of active and inactive receptors. Agonists enhance the active state, whereas inverse agonists increase the fraction of inactive receptors at the expense of the active conformation. Constitutively active receptors will thus have increased affinity for agonists and decreased affinity for inverse agonists. In the study by Bongers et al. [9], the higher potencies and affinities for agonists and lower potencies and affinities for inverse agonists for the hH3R365 isoform over the hH3R445 were modeled and found to be consistent with the increased constitutive activity of the shorter isoform. In contrast, in our study, no constitutive activity was detected for either isoform, in accord with the lack of differences in affinity or potency (Tables 1 and 2). Constitutive activity depends on the receptor expression levels, but also on the expression of partner proteins [21], for example Homer 3, that by interacting with the carboxyl terminus of the metabotropic glutamate receptors mGluR1 and mGluR5 prevents their spontaneous activation [22]. The differences in constitutive activity of the hH3R isoforms may thus depend on the cell lines in which the receptors are expressed.
Pimavanserin: novel pharmacotherapy for Parkinson’s disease psychosis
Published in Expert Opinion on Drug Discovery, 2018
Zeyad T. Sahli, Frank I. Tarazi
Pimavanserin (NuplazidTM, Acadia Pharmaceuticals, San Diego, CA) is a novel compound that displays high nanomolar affinity at 5-HT2A (Ki = 0.4 nM) and 5-HT2C (Ki = 16 nM) receptors [29]. High-throughput screening and chemical lead optimization were utilized to discover this compound from a library of G-protein-coupled receptors (GPCRs). Functionally, pimavanserin is a potent inverse agonist, which acts like an agonist in that it binds to the same receptor as an agonist but produces the opposite effect. While traditional antagonists block the effects of binding agonists, inverse agonists inhibit the basal activity of the receptor [53]. Pimavanserin displays higher selectivity for 5-HT2A over 5-HT2C receptors and no functional activity at a wide range of GPCRs including dopaminergic, muscarinic, adrenergic, and histaminergic receptors [29].
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