The Concise Guide to PHARMACOLOGY 2017/18 provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links ...to an open access knowledgebase of drug targets and their ligands (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.13881/full. Other ion channels are one of the eight major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ligand‐gated ion channels, voltage‐gated 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‐2017, and supersedes data presented in the 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature Committee of the Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug ...targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full.
Nuclear hormone receptors are one of the seven major pharmacological targets into which the Guide is divided, with the others being G protein‐coupled receptors, ligand‐gated ion channels, ion channels, catalytic receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets.
It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors and Channels. It is produced in conjunction with NC‐IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR‐DB and the Guide to Receptors and Channels, providing a permanent, citable, point‐in‐time record that will survive database updates.
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Background and Purpose
The enzyme α/β‐hydrolase domain containing 6 (ABHD6), a new member of the endocannabinoid system, is a promising therapeutic target against neuronal‐related diseases. However, ...how ABHD6 activity is regulated is not known. ABHD6 coexists in protein complexes with the brain‐specific carnitine palmitoyltransferase 1C (CPT1C). CPT1C is involved in neuro‐metabolic functions, depending on brain malonyl–CoA levels. Our aim was to study CPT1C–ABHD6 interaction and determine whether CPT1C is a key regulator of ABHD6 activity depending on nutritional status.
Experimental Approach
Co‐immunoprecipitation and FRET assays were used to explore ABHD6 interaction with CPT1C or modified malonyl–CoA‐insensitive or C‐terminal truncated CPT1C forms. Cannabinoid CB1 receptor‐mediated signalling was investigated by determining cAMP levels. A novel highly sensitive fluorescent method was optimized to measure ABHD6 activity in non‐neuronal and neuronal cells and in brain tissues from wild‐type (WT) and CPT1C–KO mice.
Key Results
CPT1C interacted with ABHD6 and negatively regulated its hydrolase activity, thereby regulating 2‐AG downstream signalling. Accordingly, brain tissues of CPT1C–KO mice showed increased ABHD6 activity. CPT1C malonyl–CoA sensing was key to the regulatory role on ABHD6 activity and CB1 receptor signalling. Fasting, which attenuates brain malonyl–CoA, significantly increased ABHD6 activity in hypothalamus from WT, but not CPT1C–KO, mice.
Conclusions and Implications
Our finding that negative regulation of ABHD6 activity, particularly in the hypothalamus, is sensitive to nutritional status throws new light on the characterization and the importance of the proteins involved as potential targets against diseases affecting the CNS.
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
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 (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.15539. Ion channels are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, 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.
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Plasma levels of the major endocannabinoids 2-arachidonoylgycerol (2AG) and anandamide (N-arachidonoylethanolamine, AEA) have been identified to vary independently with particular pathological ...conditions. The levels of these endocannabinoids are tightly regulated by two hydrolytic enzymes, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), respectively.
In this study, we have quantified these enzyme activities in the major blood fractions.
In blood fractions from human volunteers, radiometric assays were used to quantify monoacylglycerol lipase and fatty acid amide hydrolase. Tagging with fluorophosphonate-rhodamine allowed quantification of platelet serine hydrolase activities.
Fatty acid amide hydrolase activity was highest in platelets, while MAGL activity was most abundant in erythrocytes. Sampling the blood of donors on two further occasions 15 days apart showed no significant change in platelet FAAH or erythrocyte MAGL activities. Activities were not different when comparing female donors with males. Storage of these blood fractions at − 80 °C was associated with a rapid loss in enzyme activities, which could largely by avoided by storage in liquid nitrogen. Incubation of platelets and erythrocytes in the presence of thrombin lead to release of measurable FAAH, but not MAGL, activity. Tagging of serine hydrolase activities with fluorophosphonate-rhodamine allowed confirmation of MAGL activity in platelet preparations, as well as multiple other enzymes.
These investigations suggest a potential role for FAAH in regulation of coagulation, while the role of MAGL in blood requires further investigation.
•Endocannabinoid levels, but not their associated hydrolases, have previously been quantified in blood fractions.•Monoacylglycerol lipase and fatty acid amide hydrolase activities were identified in washed platelets and erythrocytes.•These activities were similar for men and women and were well maintained on repeated visits, but not on storage at -80 °C.•Fatty acid amide hydrolase release from platelets and erythrocytes was prompted by co-incubation with thrombin.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cannabinoids are reported to have actions through peroxisome proliferator‐activated receptors (PPARs), which led us to investigate PPAR agonists for activity at the cannabinoid receptors. ...Radio‐ligand binding and functional assays were conducted using human recombinant cannabinoid type 1 (CB1) or cannabinoid type 2 (CB2) receptors, as well as the guinea pig isolated ileum, using the full agonist CP55940 as a positive control. The PPAR‐α agonist fenofibrate exhibited submicromolar affinity for both receptors (pKi CB1, 6.3 ± 0.1; CB2, 7.7 ± 0.1). Functionally, fenofibrate acted as an agonist at the CB2 receptor (pEC50, 7.7 ± 0.1) and a partial agonist at the CB1 receptor, although with a decrease in functional response at higher concentrations, producing bell‐shaped concentration‐response curves. High concentrations of fenofibrate were able to increase the dissociation rate constant for 3H‐CP55940 at the CB1 receptor, (kfast without: 1.2 ± 0.2/min; with: 3.8 ± 0.1 × 10‐2/min) and decrease the maximal response to CP55940 (Rmax, 86 ± 2%), which is consistent with a negative allosteric modulator. Fenofibrate also reduced electrically induced contractions in isolated guinea pig ileum via CB1 receptors (pEC50, 6.0 ± 0.4). Fenofibrate is thus identified as an example of a new class of cannabinoid receptor ligand and allosteric modulator, with the potential to interact therapeutically with cannabinoid receptors in addition to its primary PPAR target.—Priestley, R. S., Nickolls, S. A., Alexander, S. P. H., Kendall, D. A. A potential role for cannabinoid receptors in the therapeutic action of fenofibrate. FASEB J. 29, 1446‐1455 (2015). www.fasebj.org
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The use of Cannabis-based preparations for medicinal use has waxed and waned in the multi-millennial history of human co-existence with the plant and its cultivation. Recorded use of preparations ...from Cannabis is effectively as old as recorded history with examples from China, India and Ancient Egypt. Prohibition and restriction of availability allowed a number of alternatives to take the place of Cannabis preparations. However, there has been a worldwide resurgence in medicinal Cannabis advocacy from the public. Media interest has been piqued by particular evocative cases. Altogether, therefore, there is pressure on healthcare professionals to prescribe and dispense Cannabis-based preparations. This review enunciates some of the barriers which are slowing the wider adoption of medicinal Cannabis.
Full text
Available for:
NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
BACKGROUND AND PURPOSE Elevating levels of endocannabinoids with inhibitors of fatty acid amide hydrolase (FAAH) is a major focus of pain research, purported to be a safer approach devoid of ...cannabinoid receptor‐mediated side effects. Here, we have determined the effects of sustained pharmacological inhibition of FAAH on inflammatory pain behaviour and if pharmacological inhibition of FAAH was as effective as genetic deletion of FAAH on pain behaviour.
EXPERIMENTAL APPROACH Effects of pre‐treatment with a single dose, versus 4 day repeated dosing with the selective FAAH inhibitor, URB597 (i.p. 0.3 mg·kg−1), on carrageenan‐induced inflammatory pain behaviour and spinal pro‐inflammatory gene induction were determined in rats. Effects of pain induction and of the drug treatments on levels of arachidonoyl ethanolamide (AEA), palmitoyl ethanolamide (PEA) and oleolyl ethanolamide (OEA) in the spinal cord were determined.
KEY RESULTS Single, but not repeated, URB597 treatment significantly attenuated the development of inflammatory hyperalgesia (P < 0.001, vs. vehicle‐treated animals). Neither mode of URB597 treatment altered levels of AEA, PEA and OEA in the hind paw, or carrageenan‐induced paw oedema. Single URB597 treatment produced larger increases in AEA, PEA and OEA in the spinal cord, compared with those after repeated administration. Single and repeated URB597 treatment decreased levels of immunoreactive N‐acylphosphatidylethanolamine phospholipase D (NAPE‐PLD) in the spinal cord and attenuated carrageenan‐induced spinal pro‐inflammatory gene induction.
CONCLUSION AND IMPLICATIONS Changes in the endocannabinoid system may contribute to the loss of analgesic effects following repeated administration of low dose URB597 in this model of inflammatory pain.
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
To investigate the impact of an experimental model of osteoarthritis (OA) on spinal nociceptive processing and the role of the inhibitory endocannabinoid system in regulating sensory ...processing at the spinal level.
Methods
Experimental OA was induced in rats by intraarticular injection of sodium mono‐iodoacetate (MIA), and the development of pain behavior was assessed. Extracellular single‐unit recordings of wide dynamic range (WDR) neurons in the dorsal horn were obtained in MIA‐treated rats and saline‐treated rats. The levels of endocannabinoids and the protein and messenger RNA levels of the main synthetic enzymes for the endocannabinoids (N‐acyl phosphatidylethanolamine phospholipase D NAPE‐PLD and diacylglycerol lipase α DAGLα) in the spinal cord were measured.
Results
Low‐weight (10 gm) mechanically evoked responses of WDR neurons were significantly (P < 0.05) facilitated 28 days after MIA injection compared with the responses in saline‐treated rats, and spinal cord levels of anandamide and 2‐arachidonoyl glycerol (2‐AG) were increased in MIA‐treated rats. Protein levels of NAPE‐PLD and DAGLα, which synthesize anandamide and 2‐AG, respectively, were elevated in the spinal cords of MIA‐treated rats. The functional role of endocannabinoids in the spinal cords of MIA‐treated rats was increased via activation of cannabinoid 1 (CB1) and CB2 receptors, and blockade of the catabolism of anandamide had significantly greater inhibitory effects in MIA‐treated rats compared with control rats.
Conclusion
Our findings provide new evidence for altered spinal nociceptive processing indicative of central sensitization and for adaptive changes in the spinal cord endocannabinoid system in an experimental model of OA. The novel control of spinal cord neuronal responses by spinal cord CB2 receptors suggests that this receptor system may be an important target for the modulation of pain in OA.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
PDF
