The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (http://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14748. G protein‐coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Members of the Opioid Receptor (OR) family of G protein-coupled receptors (GPCRs) are found throughout the peripheral and central nervous system where they play key roles in nociception and analgesia. Unlike the classical ORs, δ–OR, κ–OR,1 and μ-OR,2 which were delineated by pharmacological criteria in the 1970’s and 1980’s, the nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP, aka ORL-1) was discovered relatively recently via molecular cloning and characterization of an orphan GPCR3. Despite its high sequence similarity (~60%) with ORs, NOP has a strikingly distinct pharmacology4,5. Despite high sequence similarity with classical opioid G protein-coupled receptor subtypes, the nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP) has a distinct biological and pharmacological role, featuring activation by the endogenous peptide N/OFQ, and unique selectivity for exogenous ligands. This study reports the crystal structure of human NOP solved in complex with the peptide mimetic antagonist Banyu Compound-24 (C-24), revealing atomic details of ligand-receptor recognition and selectivity. C-24 mimics the first four N-terminal residues of the NOP-selective peptide antagonist UFP-101, a close derivative of N/OFQ, and provides important clues to binding of these peptides. The X-ray structure also reveals substantial conformational differences in the pocket regions between NOP and the “classical” opioid receptors κ (Ref. 1) and μ (Ref. 2), which are likely due to a small number of residues that vary between the two receptors. The NOP/C-24 structure explains the divergent selectivity profile of NOP and provides a new structural template for the design of NOP ligands.

Nociceptin (NC), alias Orphanin FQ, has been recently identi®ed as the endogenous ligand of the opioid receptor-like 1 receptor (OP 4 ). This new NC/OP 4 receptor system belongs to the opioid family and has been characterized pharmacologically with functional and binding assays on native (mouse, rat, guinea-pig) and recombinant (human) receptors, by using speci®c and selective agonists (NC, NC(1 ± 13)NH 2 ) and a pure and competitive antagonist, [Nphe 1 ]NC(1 ± 13)NH 2 . The similar order of potency of agonists and a nity values of the antagonist indicate that the same receptor is present in the four species. OP 4 is expressed in neurons, where it reduces activation of adenylyl cyclase and Ca 2+ channels while activating K + channels in a manner similar to opioids. In this way, OP 4 mediates inhibitory e ects in the autonomic nervous system, but its activities in the central nervous system can be either similar or opposite to those of opioids. In vivo experiments have demonstrated that NC modulates a variety of biological functions ranging from nociception to food intake, from memory processes to cardiovascular and renal functions, from spontaneous locomotor activity to gastrointestinal motility, from anxiety to the control of neurotransmitter release at peripheral and central sites. These actions have been demonstrated using NC and various pharmacological tools, as antisense oligonucleotides targeting OP 4 or the peptide precursor genes, antibodies against NC, an OP 4 receptor selective antagonist and with data obtained from animals in which the receptor or the peptide precursor genes were knocked out. These new advances have contributed to better understanding of the pathophysiological role of the NC/OP 4 system, and ultimately will help to identify the therapeutic potential of new OP 4 receptor ligands.

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein‐coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

The NOP receptor (nociceptin/orphanin FQ opioid peptide receptor) is the most recently discovered member of the opioid receptor family and, together with its endogenous ligand, N/OFQ, make up the fourth members of the opioid receptor and opioid peptide family. Because of its more recent discovery, an understanding of the cellular and behavioral actions induced by NOP receptor activation are less well developed than for the other members of the opioid receptor family. All of these factors are important because NOP receptor activation has a clear modulatory role on mu opioid receptor-mediated actions and thereby affects opioid analgesia, tolerance development, and reward. In addition to opioid modulatory actions, NOP receptor activation has important effects on motor function and other physiologic processes. This review discusses how NOP pharmacology intersects, contrasts, and interacts with the mu opioid receptor in terms of tertiary structure and mechanism of receptor activation; location of receptors in the central nervous system; mechanisms of desensitization and downregulation; cellular actions; intracellular signal transduction pathways; and behavioral actions with respect to analgesia, tolerance, dependence, and reward. This is followed by a discussion of the agonists and antagonists that have most contributed to our current knowledge. Because NOP receptors are highly expressed in brain and spinal cord and NOP receptor activation sometimes synergizes with mu receptor-mediated actions and sometimes opposes them, an understanding of NOP receptor pharmacology in the context of these interactions with the opioid receptors will be crucial to the development of novel therapeutics that engage the NOP receptor

Nociceptin (NC) and some of its fragments as well as nociceptin-(1-13)-peptide amide [NC- (1-13)-NH2] and a series of its analogues were prepared and tested in the mouse vas deferens in an attempt to identify the sequences involved in the activation (message) and in the binding (address) of nociceptin to its receptor. The NC receptor that inhibits the electrically evoked twitches of the mouse vas deferens was demonstrated to be distinct from the delta opioid receptor, since naloxone and Dmt-Tic-OH (a selective delta opioid receptor antagonist) block the delta opioid receptor but have no effect on the nociceptin receptor. Results from structure-activity experiments suggest that (a) the entire sequence of NC may not be required for full biological activities, since NC(1-13)-NH2 is as active as NC; (b) fragments of NC have however to be amidated as in NC(1-13)-NH2 in order to be protected from degradation by proteases; (c) cationic residues (as Arg8,12, Lys9,13) appear to play a functional role, since their replacement with Ala in the sequence of NC(1-13)-NH2 leads to inactivity; (d) the N-terminal tetrapeptide Phe-Gly-Gly-Phe is essential for activity: its full length and flexibility appear to be required for NC receptor activation and/or occupation; (e) Phe4 and not Phe1 appears to be the residue involved in receptor activation, since the replacement of Phe1 with Leu has no effect, while that of Phe4 leads to inactivity. Results summarized in this paper indicate that the structural requirements of NC for occupation and activation of its receptor are different from that of opioids, particularly delta agonists.

Background and purpose: Neuropeptide S (NPS) was recently identified as the endogenous ligand of an orphan receptor, now referred to as the NPS receptor. In vivo, NPS produces a unique behavioural profile by increasing wakefulness and exerting anxiolytic-like effects. In the present study, we further evaluated the effects of in vivo supraspinal NPS in mice. Experimental approach: Effects of NPS, injected intracerebroventricularly (i.c.v.), on locomotor activity (LA), righting reflex (RR) recovery and on anxiety states (measured with the elevated plus maze (EPM) and stress-induced hyperthermia (SIH) tests) were assessed in Swiss mice. Key results: NPS (0.01-1 nmol per mouse) caused a significant increase in LA in naive mice, in mice habituated to the test cages and in animals sedated with diazepam (5 mg kg À1 ). In the RR assay, NPS dose dependently reduced the proportion of animals losing the RR in response to diazepam (15 mg kg À1 ) and their sleeping time. In the EPM and SIH test, NPS dose dependently evoked anxiolytic-like effects by increasing the time spent by animals in the open arms and reducing the SIH response, respectively. Conclusions and implications:We provide further evidence that NPS acts as a novel modulator of arousal and anxiety-related behaviours by promoting a unique pattern of effects: stimulation associated with anxiolysis. Therefore, NPS receptor ligands may represent innovative drugs for the treatment of sleep and anxiety disorders.

[Phe 1 C(CH 2 -NH)Gly 2 ]NC(1-13)NH 2 has been tested in the electrically stimulated guinea pig ileum and mouse vas deferens, two nociceptin sensitive preparations. The new compound showed per se little or no eect in the two tissues, but it displaced to the right the concentration-response curves of nociceptin in a concentration-dependent manner. Reinscheid et al., 1995) to be the endogenous ligand of the opioid-like orphan receptor (ORL-1). Despite the structural homology of NC and its receptor with the peptides and receptors of the opioid family this peptide/receptor system appears to be pharmacologically distinct from the opioids. During the last two years several papers have described new biological eects mediated by NC both in the periphery and in the central nervous system. Such eects were not modi®ed by naloxone or other more selective opioid receptor antagonists and were considered to be mediated by the activation of a speci®c NC receptor (the ORL-1). Lack of selective NC receptor antagonists prevented a de®nitive pharmacological characterization of ORL-1. In 1997, Kobayashi et al. showed that carbetapentane and rimcazole act as antagonists at the NC receptor. However these compounds showed little anity (IC 50 about 10 mM) and, more importantly, they were found to interact also with other functional sites such as s-, m-, and k-opioid receptors and M 1 -muscarinic receptors. Being non selective, they were therefore considered of little utility for receptor characterization.In the present study, we describe the chemical structure and the in vitro pharmacological eects of [Phe