GABA: the main inhibitory amino acid (γ- aminobutyric acid or 4-aminobutyric acid) neurotransmitter found throughout the CNS (it inhibits the effects of glutaminergic excitation). It mainly occurs in brain tissue in mammals and is found in very high concentrations in the nigrostriatal system but is also present in grey matter, microorganisms, higher plants and other animal tissue, eg liver in trace amounts. GABA is formed from glutamate by glutamate decarboxylase and its synthesis only occurs in GABAergic tissues.
GABA receptors: receptors for GABA which fall into two groups, ionotropic GABAA and GABAC receptors (which are ligand-gated channel) and GABAB receptors (which are G protein-coupled receptor linked to the activation of K+ and/or Ca2+ channels).
GABAA receptors are located postsynaptically and mediate fast synaptic inhibition (they are also known as fast receptors). These receptors are pentamers comprised of three different subunits (α, β and γ;) forming α-helices around a central ion channel. These receptors are the targets of the actions of benzodiazepines, barbiturates and neurosteroids and mediate sedation, excitation and consciousness.
GABAB receptors are located pre- and postsynaptically and inhibit voltage-gated calcium channels (and decrease neurotransmitter release) and open potassium channels (and decrease postsynaptic membrane excitation). These receptors mediate spasticity and motor function.
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GABA receptor agonists: compounds which agonize GABA receptors. Examples include muscimol, THIP and isoguvacine at GABAA sites, baclofen at GABAB sites and imidazole-4-acetic acid, muscimol and TACA (trans-4-aminocrotonic acid) at GABAC receptors. Some of these compounds are used clinically to treat spasticity such as baclofen.
GABA receptor antagonist: compounds which antagonize GABA receptors. Examples include bicuculline and picrotoxin at GABAA sites, phaclofen, saclofen and CGP35348 at GABAB sites and TPMPA ((1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid), THIP and ZAPA at GABAC receptors.
GABA transaminase (GABA-T): officially known as 4-hydroxyglutamate transaminase (EC 2.6.1.23) the main enzyme in the metabolism of GABA which catalyzes the formation of L-glutamate from 4-aminobutanoate and 2-oxoglutarate in GABAergic tissues to decreasing the levels of GABA.
GABA transaminase inhibitor: inhibitors of GABA transaminase and so compounds which enhance the levels of GABA. Examples include phenylethylidenehydrazine, ethanolamine O-sulphate, γ-aminobutyric acid (irreversible inhibitor) and vigabatrin (an enzyme-activated, irreversible inhibitor of GABA-T) which is currently used clinically to treat partial epilepsy with or without secondary generalization usually in combination with other antiepileptic drugs. GABA transporters (GATs): energy-dependent membrane transporters which move GABA from the synaptic cleft back into the presynaptic nerve and surrounding glial cells (transmitter sequestration). There are four types presently known, GAT-1, GAT-2, GAT-3 (also known as GAT-B) and BGT-1, they have varying affinities for GABA and depend on sodium and chloride electrochemical gradients.
GAT-1 is the most abundant and is found in neurons and specialized glial cells. GAT-2 is found in the pia mater and arachnoid tissues, GAT-3 is found in neurons and glial cells and BGT-1 is also present in neurons.
These transporters are important as some anticonvulsants exert the majority of their effects on these transporter mechanisms. Selective inhibitors or potentiators of these transporters may be of use in the development of drugs to treat GABA disorders.
Schousboe A et al. GABA transporters as targets for modulation of GABAergic activity. Biochem Pharmacol (2004) 68(8); 1557-63
GABA transport inhibitors: inhibitors of GABA transport and compounds which potentiate the effects of GABA at its receptor sites by inhibiting its uptake by presynaptic neurons and glial cells. They are of use as anticonvulsants. Examples include tiagabine, a GAT-1 inhibitor.
GABAergic: relating to the synthesis, storage and release of GABA.
GABAmimetics: compounds which mimic the effects of GABA. Examples include clomethiazole, AR-A008055, phenobarbitone, nipecotic acid and isonipecotic acid. GABAmimetics decrease seizure activity and are used clinically to treat many forms of epilepsy.
Gabapentin: an anticonvulsant and analgesic compound used to treat epilepsy. It is a cyclic GABA analogue but is not GABAmimetic and has no direct action on GABA receptors. Gabapentin enhances the brain synthesis of GABA leading to increased GABA release during seizures. Gabapentin was originally synthesised as a GABAA agonist but was found to have little or no effects on GABA receptors. It binds to a site associated with voltage-sensitive Ca2+ channels, prevents neuronal death and has nociceptive and anxiolytic actions.
GAD: glutamic acid decarboxylase
GAD mouse (gracile axonal dystrophy): a mouse model which shows a spontaneous neurological mutation with axonal dystrophy in the gracile tract of the medulla oblongata and spinal cord. This animal is used in the development of drugs affecting tremor, ataxia and poor coordination of the limbs.
Mukoyama M, Yamazaki K, Kikuchi T, Tomita T. Neuropathology of gracile axonal dystrophy (GAD) mouse. An animal model of central distal axonopathy in primary sensory neurons. Acta Neuropathol. (1989) 79 (3); 294-9
Gaddum equation: also known as the Gaddum-Schild equation.
Gaddum, Sir John Henry (1900-1965): British pharmacologist born on 31st March 1900 and an influential scientist and academic. In 1927 he worked for Sir Henry Dale at the National Institute for Medical Research in London then took up the Chair of Pharmacology at the University of Cairo in 1934. In 1935 he became Professor of Pharmacology at University College London and in 1938 he took the Chair of Pharmacology at the College of the Pharmaceutical Society, London. Gaddum largely worked on methods for estimating the concentration of active substance by measurement of a biological response caused by it. Together with Euler discovered substance P.
Gaddum-Schild equation: also referred to as the Gaddum equation, an equation used to calculate the proportion of binding sites occupied by a ligand when two ligands (A and B) are in equilibrium with a common binding site. The Gaddum-Schild equation is:
pAR is the proportion of binding sites occupied by ligand A,
[A] is the concentration of ligand A,
[B] is the concentration of ligand B,
KA is the dissociation equilibrium constant for ligand A, and
KB is the dissociation equilibrium constant for ligand B.
Gaddum-Schild test: a sensitive method for the detection of adrenaline in tissue based on the fluorescence of noradrenaline exposed to ultraviolet light in the presence of alkali and oxygen. The sensitivity of this test ranges from 1 part in 50 to 1 in 100 million.
GAERS: genetic absence epilepsy rat from Strasbourg, an animal model of human generalized absence epilepsy.
D-Galactosamine (D-GalN): a compound used to induce experimental liver damage. Typically, a rat is treated ip at a dose of 0.5g/kg and within 24 hours liver damage occurs as measured by blood levels of GOT and GPT. Other liver toxic compounds include carbon tetrachloride, chloroform and thioacetamide.
Galanin: a 29 amino acid neuropeptide neurotransmitter widely distributed in mammals which elicits a diverse range of physiological actions. Its actions are mediated via Gi-protein-coupled galanin receptors and ion channels which usually produces inhibition of secretion of transmitters or hormones in the nervous and endocrine system. It inhibits glutamate release in the hippocampus and suppresses insulin secretion. Galanin appears to be a potent inhibitor of seizures.
Schmidt WE et al. Isolation and primary structure of pituitary human galanin, a 30-residue non-amidated neuropeptide. Proc Natl Acad Sci USA (1991) 80; 11435
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Galanin receptors: G-protein coupled receptors for the neuropeptide galanin. There are three cloned receptor subtypes, GalR1, GalR2 and GalR3. They are targets for the development of drugs to treat epilepsy, depression and pain.
Galanin receptor agonists: compounds which agonize galanin receptors and inhibitor seizures. Examples include the tripeptidomimetic galnon and the non-peptide galmic.
Galanin receptor antagonists: compound blocking galanin receptors. Examples include M40, galantide (also known as M15) and M38.
Galantamine: also known as galanthamine, a phenylisoquinoline alkaloid and reversible anticholinesterase obtained from the bulbs of the Caucasian snowdrop (Galanthus woronowii). It has been used as an anticurare agent and is used clinically in the treatment of mild to moderate dementia in Alzheimer's disease as it acts as a cognition enhancer.
Galectins: a family of cytosolic protein lectins which are thought to act by cross-linking β-galactoside-containing glycoconjugates leading to a modulation of cell adhesion and signaling. They are thought to play important roles in cancer, immunity and inflammation.
Gallamine: a noncompetitive and selective M2 muscarinic receptor antagonist. Gallamine also nonselectively blocks nicotinic channels. It has vagolytic and sympathomimetic properties and is used clinically as a muscle relaxant. Gallamine triethiodide is used to immobilize some animals in preparation for surgery.
Ganciclovir: a synthetic guanosine derivative and antiviral related to acyclovir active against cytomegalovirus and used clinically to treat cytomegaloviral retinitis in AIDS patients. It is converted to its triphosphate which then competes with guanosine triphosphate for incorporation into DNA. Its toxicity limits its clinical use. The structural similarity between guanine, guanosine, acyclovir and ganciclovir is shown in the figure below in blue.
Ganglion (the plural is ganglia): discrete collections of neurological tissue present outside the CNS mainly in autonomic tissue largely comprising nerve cell bodies, dendrites and synapses. They receive and relay impulses to the viscera.
Ganglion blocker: compounds which inhibit cholinergic transmission in peripheral autonomic ganglia by either ion channel blockade or by antagonism of (nicotinic) receptors within the ganglia. They can decrease ganglionic transmission by inhibiting ACh release (botulinum toxin and hemicholinium), prolong depolarization (nicotine) and interfere with the postsynaptic action of Ach (nicotinic antagonists). Some ganglion blockers have been used in the treatment of hypertension.
Ganglion stimulant: compounds which enhance synaptic transmission in autonomic ganglia. These compounds have been used as pharmacological tools to study ganglionic transmission. Examples include lobeline and 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP).
Ganglionectomy: the surgical removal of an autonomic or sensory ganglion to study the effects of such removal or to surgically treat some forms of neuralgia.
Ganglioplegics: also known as ganglion blockers, compounds which interrupt neural transmission at nicotinic receptors on postganglionic autonomic neurons. Examples include tetrabutyl ammoniumbromide.
Garry and Gillespie preparation: a preparation of rabbit colon devised to demonstrate the response of the longitudinal muscle of the colon to both parasympathetic and sympathetic nerve stimulation. The Garry and Gillespie doubly-innervated rabbit colon preparation has been modified since it was first proposed in 1954.
Garry RC, Gillespie JC. An in vitro preparation of the distal colon of the rabbit with orthosympathetic and parasympathetic innervation. J Physiol (London). (1954) 123; 60
Gastric inhibitory peptide (GIP): originally called enterogastone and also known as glucose-dependent insulinotropic peptide, a member of the secretin family of hormones and a 42 amino acid peptide found in extracts of intestine which inhibit gastric motility and secretion of acid. It is secreted from mucosal epithelial cells in the upper part of the small intestine and it can enhance the release of insulin in response to high levels of glucose and can inhibits the absorption of water and electrolytes in the small intestine.
Gastric inhibitory peptide inhibitors: compounds which inhibit the actions of gastric inhibitory peptide and which being developed for the treatment of obesity.
Gastrin: a family of two endocrine regulatory gastric peptides (G17 and G34 named according to their number of amino acids and referred to as little gastrin and big gastrin, respectively) of which the main member is a 17 amino acid peptide with a similar structure to cholecystokinin (their carboxyl termini, their biologically active parts, are almost identical) which is produced and secreted by the G cells in the gastric antrum and is released into the blood in response to cholinergic stimulation caused by the presence of food in the stomach. Gastrin promotes the secretion of acid and pepsin, increases the flow of pancreatic fluid into the stomach and promotes cell growth. Gastrin is a cholecystokinin receptor agonist. It was isolated in 1962 from pig stomach and was originally confused with histamine which has similar gastric effects. Gastrin is also known to promote the growth of colon and gastric carcinomas and gastric carcinoids.
Gastrin receptors: see cholecystokinin receptors.
Gastrin releasing peptide (GRP): a neuropeptide released by the post-ganglionic fibres of the vagus nerve which innervate the G cells of the stomach and stimulates them to release gastrin. GRP is the mammalian equivalent of the amphibian tetradecapeptide bombesin. Bombesin/GRP is widely distributed in the human brain and in peripheral nerves especially in the gut.
Gastrin releasing peptide receptor: a receptor which mediates the effects of gastrin releasing peptide and causes the proliferation of many cells in which it is expressed. GRP receptor is not normally expressed by epithelial cells within the gastrointestinal tract but is expressed by many gastrointestinal tumours. See also bombesin receptor.
Gastrin receptor antagonists: compounds which antagonize the effects of gastrin at gastrin receptor sites. They decrease gastric acid secretion and are being developed to treat gastrointestinal ulcers. They may also inhibit the growth of colon cancers. Examples include proglumide and L-365,260 (a non-peptide antagonist of gastrin/CCKB receptors).
Gastrocnemius muscle: a large posterior voluntary muscle of the calf of the leg. It originates at the back of the femur and is attached to the Achilles tendon at the heel. The gastrocnemius muscle pulls the heel up and provides a propelling force in running and jumping. The gastrocnemius muscle preparation typically from the frog is easy to remove and is used in many classical pharmacology studies to demonstrate nerve conduction and skeletal muscle contraction. It is often removed from the frog with the sciatic nerve attached to study the effects that electrical stimulation of the nerve has on muscle contraction.
Gastroprokinetic: also referred to as gastrokinetic, substances which promote peristalsis and secretion of gastrointestinal enzymes and acid. They are used to treat delayed emptying of the stomach due to gastric hypomotility and gastric discomfort. Examples include dopamine antagonists, acetylcholine potentiators, κ-opioid agonists and 5-HT4 agonists.
Gastroprotectants: compounds which protect the gastric mucosa from irritation or damage (including gastric and duodenal ulcers) such as that caused by gastric acid. Examples include sucralfate (a sucrose sulphate-aluminium hydroxide complex). This complex polymerizes to form a viscous gel at a pH of less than 4. The sulfate groups bind to proteins present in ulcerated tissue and protects ulcers from gastrin and acid.
Gating mechanism: a mechanisms in a cell membrane which controls the flow of ions or other substances across the membrane comprising a protein or proteins which changes conformation to allow the passage of substances, i.e. the protein undergoes a transition from closed to open or open to closed in response to a particular stimulus.
Gaussian distribution: the same as normal distribution.
GBH: slang term for γ-hydroxybutyrate, a recreational drug. Originally developed as a general anesthetic, its was abandoned due to toxicity but has found popularity as a 'dance drug' which have been used in nightclubs in the UK to enhance the mood and enjoyment of an individual. GBH is also known as Liquid E.
GCP: good clinical practice.
GCResP: good clinical research practice.
GDEPT: gene-directed enzyme prodrug therapy
Geller-Seifter conflict test: a method of predicting clinical efficacy of anxiolytics. In this test hungry rats, for example, are trained to press a bar for a reward of food. After training they are intermittently shocked via electrical foot shock when they press the bar. A flashing light can indicate when food becomes available and the animal is rewarded by pressing the bar when the light flashes but the conflict comes when the light flashes, they want food but know they'll get a shock if they press the lever. Anxiolytics decrease their fear of shocks.
Geller I and Seifter J. The effects of meprobromate, barbiturates, d-amphetamine and promazine on experimentally induced conflict in the rat. Psychopharmacologia (1960) 1; 482-492
Gemfibrozil: a fibrate which is used clinically to treat various types of hyperlipidemia in patients who have not responded to conventional therapy and for the primary prevention of coronary heart disease. It acts by decreasing serum very low density lipoprotein and triglyceride levels.
Geminal isomer: an isomer in which the substituents in a disubstituted compound are on the same carbon atom.
Generic drugs: an identical drug preparation to one already marketed but one for which the active component is no longer protected by a patent right. Generic drugs are usually cheaper than their patent-protected equivalents and have identical clinical application and efficacy and can be manufactured by any pharmaceutical company. In 2004 in the UK, about 80% of all prescribed drugs were generics and accounted for about 20% of all drug sales.
Generic name: a nonproprietary name for a drug, ie an official and approved name (approved by The World Health Organization) sometimes referred to as an INN (International nonproprietary name). Examples include, atenolol, furosemide and gemfibrozil. Strictly speaking, generic names are things like barbiturates, sulphonamides and benzodiazepines but these terms are not usually taken as being generic.
Gene therapy: the introduction of genes into the tissues and cells of an individual for the purpose of treating diseases particularly hereditary diseases.
Genetically epilepsy-prone rats (GEPR): an animal model of broad-based seizures which is based partly on widespread CNS deficits in noradrenergic and serotoninergic functions. These animals are used as models of human generalized tonic clonic seizures and partial seizures.
Jobe PC, Dailey JW. Genetically epilepsy-prone rats (GEPRs) in drug research. CNS Drug reviews (2000) 6 (3); 241-260
Gene-directed enzyme prodrug therapy (GDEPT): also known as suicide gene therapy, a two-step method aimed at treating cancers particularly solid cancers. In the first step a gene encoding a foreign enzyme is delivered to tumour tissue by a vector. The enzyme is expressed by the tissue then a prodrug is administered in the second step which is activated by the enzyme being expressed by the tumor tissue.
Niculescu-Duvaz I, Springer CJ. Introduction to the background, principles, and state of the art in suicide gene therapy. Mol Biotechnol (2005) May 30(1); 71-88
Genomics: the study of all the genes in an individual (its genome) and how they can be used. Genomics is the systematic use of genetic data in pharmacology, medicine and industry.
Genotoxic: compounds which can cause genetic mutations and so contribute to the development of tumours and genetic diseases.
General anesthesia: a form of anaesthesia.
Gentamicin: an aminoglycoside bactericide widely used clinically in septicemia, neonatal sepsis, meningitis and other CNS infections, biliary tract infection, acute pyelonephritis, endocarditis and pneumonia. It is active against mainly gram-negative and some gram-positive bacteria. Gentamicin inhibits bacterial wall synthesis.
GEPR: genetically epilepsy-prone rats
Gestagens: also known as progestagens, a class of female sex hormones similar to progesterone, which is the only naturally occurring gestagen. Gestagens have anti-oestrogenic and anti-gonadotropic (they inhibit the production of sex hormones in the gonads). They are mainly used in oral contraceptives. Synthetic gestagens are referred to as progestins. Examples of which include medroxyprogesterone, dydrogesterone and norethisterone.
Ghosh and Schild method: a method for measuring the secretion of acid into the stomach and for investigating the effects of drugs on the stimulation and inhibition of gastric acid flow.
Ghosh MN, Schild HO. Continuous recording of gastric secretion in the rat. Br J Pharmacol (1958) 13;54-61
Ghrelin: a 28 amino acid growth-hormone-releasing peptide isolated from the stomach and an endogenous ligand for the growth-hormone secretagogue receptor. It induces food intake and increases fat. Ghrelin has a number of cardiovascular properties including a decrease in systemic vascular resistance and an increases cardiac output in cases of heart failure. Ghrelin may be of use in the treatment of chronic heart failure.
Ghigo E et al. Ghrelin: more than a new frontier in neuroendocrinology. J Endocrinol Invest (2004) 27 (6 Suppl); 101-4
Ghrelin receptors: formerly known as growth hormone secretagogue receptors, receptors which mediate the effects of ghrelin. These receptors are present in the pituitary, hypothalamus, heart and adipose tissues and mediate the secretion of growth factor and regulate energy balance.
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GI: growth inhibition (sometimes shown as GIR-growth inhibition rate) and used as a measure of the cytotoxicity of anticancer agents.
GID: growth inhibiting dose
Gilman, Alfred G (1941-): an American who shared 1994 Nobel Prize for Physiology or Medicine with Rodbell for "G-proteins and the role of these proteins in signal transduction in cells".
http://nobelprize.org/nobel_prizes/medicine/laureates/1994/gilman-autobio.html
GIP: gastric inhibitory peptide
GIRK: gated inward rectifying K+ channel, a type of potassium channel.
GK rat: Goto-Kakizaki rat
Glibenclamide: an oral antidiabetic drug and long-acting sulphonylurea used clinically to treat type 2 diabetes mellitus.
Glitazones: also known as thaizolidinediones, a group of insulin sensitizing compounds which improve glucose utilization in the presence of some insulin but without stimulating the pancreas. They act as peroxisome proliferator activated receptor (PPAR) γ agonists and examples include ciglitazone, pioglitazone, rosiglitazone and troglitazone. The thaizolidinedione moiety is shown in blue in the figure below.
Glomerular filtration rate (GFR): the rate at which fluid is filtered by the glomerulus in the kidney.
GLP: good laboratory practice
Glucagon: a linear 29 amino acid peptide synthesized (together with glucagon-like peptides 1 and 2) as prepro-glucagon and released from the α cells of the islets of Langerhans (then it is cleaved in the small intestines to form glucagon and glucagon-like paptides). Glucagon regulates the breakdown of glycogen in the liver and activates hepatic gluconeogenesis to increase glucose levels in the blood. Glucagon is insulinotropic, its secretion is stimulated by low levels of glucose in the blood and its effects are the opposite of that of insulin which decreases blood glucose levels by forming glycogen and stimulating the entry of glucose into muscle and adipose tissue. See http://www.glucagon.com
Glucagon agonist: compounds which stimulate or mimic the role of glucagon, ie they increase blood glucose levels by stimulation hepatic gluconeogenesis and the breakdown of glucagon. Examples of glucagon agonists include Lys17,18,Glu21-glucagon which is being investigated for its effects on the development of myopia.
Glucagon antagonist: compounds which antagonize the effects of glucagon, ie they inhibit the breakdown of glycogen in the liver and so inhibit a rise in blood sugar levels. Examples include skyrin.
Glucagon receptors: G protein-coupled receptors for the hyperglycaemic hormone glucagon of which one is known (Glu-R). They are present in the liver, kidneys, intestinal smooth muscle, brain and adipose tissue. Glucagon stimulates these receptors present on β cells in the pancreas where they stimulate insulin secretion.
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Glucagon receptor antagonists: block the effects of glucagon at these receptors and so decrease the blood glucose increase associated with the actions of glucagon. They are being developed for the treatment of type 2 diabetes.
Glucagon-like peptides (GLP): a group of two intestinal peptides (GLP-1 and GLP-2). GLP-1 exists in two forms, GLP-1(7-36)amide and GLP-1(7-37) of which GLP-1(7-36)amide is the more common. GLP-1 stimulates glucose-dependent insulin secretion and insulin biosynthesis, inhibit glucagon secretion and gastric emptying, and inhibit food intake.
Glucan: the major carbohydrate polymer component of fungal cell walls. It is a branched, cross-linked polymer which gives cells rigidity and structural strength. It is an essential component of normal fungal growth and is produced by the action of (1,3)β-D-glucan synthase. As this enzyme is absent from mammalian cells it has become the target for the development of antifungal compounds.
Glucan synthase: a fungal enzyme (EC 2.4.1.34) officially known as 1,3-β-glucan synthase which is necessary for the synthesis of glucan in fungal wall synthesis. It catalyzes the polymerization of glucose to (1,3)-β-D-glucan.
Glucan synthase inhibitors: a class of antifungal compound which inhibit the production of fungal wall glucan. Examples include echonocandins and pneumocandins.
Glucose transporter: an energy-dependent cellular transporter system which carries glucose across cell membranes and which is important for cellular uptake of glucose. There are about 14 glucose transporter isoforms known, GLUT1-GLUT14 and they differ in their tissue expression, substrate specificity and kinetic characteristics. Four sodium-glucose transporters, SGLT1-4 are also known and are Na+-dependent. For example, the human Na+-dependent glucose transporter, SGLT1, is abundant in red blood cells, the blood-brain barrier and in epithelial cells and is the most common glucose transporter in humans.
Glucose transporter inhibitors: compounds which inhibit GLUTs and so the transport of glucose across cell membranes. Examples include the GLUT-1 inhibitor cytochalasin B.
Glucosidases: enzymes such as glucoamylase and sucrase which are responsible for the digestion of complex carbohydrates in the gut. They are located in the gut and breakdown complex carbohydrates which can be absorbed by the gut wall.
Glucosidase inhibitors: inhibitors of intestinal a-glucosidases. These inhibitors include the naturally occurring glycomimetic acarabose (an oral hypoglycaemic) which competitively inhibits α-glucosidases and delays the digestion of sucrose resulting in a reduction in postprandial hyperglycemia and hyperinsulinaemia. It is a potential antidiabetic agent.
Azasugar glucosidase inhibitors include nojirimycin, swainsonine and castanospermine are of therapeutic interest as anticancer and anti-HIV agents. a-glucosidase is inhibited by the oral hypoglycaemic acarbose
Glucuronidation: a process in drug metabolim between a drug and glucuronic acid in which a glucuronide is formed and thereby fully or partially inactivating the parent drug molecule.The glucuronide formed also tends to be less lipid soluble than the parent drug so it is more easily eliminated from the body. Examples of drugs undergoing glucuronidation during their metabolism include fluoroquinolone antibiotics, oestrogens, mineralocorticoids and glucocorticiods.
L- Glutamate: an excitatory transmitter in the CNS. It is synthesized throughout the brain and, like other neurotransmitters, is stored in vesicles and released by calcium-dependent exocytosis. The effects of glutamate are terminated by carrier-mediated reuptake and reuptake by glial cells nearby.
Glutamate carboxypeptidase II (NAALADase): a membrane-bound metalloenzyme (EC 3.4.17.21) which catalyzes the hydrolysis of the neurotransmitter N-acetyl-L-aspartyl-L-glutamate (NAAG) to form N-acetyl-L-aspartate and L-glutamate.
Glutamate carboxypeptidase II inhibitors: compounds which inhibit glutamate carboxypeptidase II and thereby decrease brain levels of glutamate (a potent excitatory amino acid neurotransmitter in the brain). They are being investigated as neuroprotectants in the treatment of stroke, amyotrophic lateral sclerosis and neuropathic pain. Examples include 2-phosphonomethyl pentanedioic acid (2-PMPA).
Glutamate decarboxylase (GAD): an enzyme (EC 4.1.1.15) which synthesizes the formation of 4-aminobutanoate from L-glutamate.
Glutathione (GSH): a tripeptide (γ-glutamylcysteinylglycine) comprising glycine, cysteine and glutamic acid present in animal, plant and bacterial cells and which acts as a biological redox agent, a coenzyme and cofactor. It is often a substrate for reactions catalyzed by glutathione S transferase. Glutathione is important because in maintains the sulphhydryl (SH) groups in proteins in the reduced state, it acts as a carrier for reduced glutaredoxin which is a hydrogen donor for nucleotide reductase and the reduction of activated sulphate to sulphate and in maintaining the iron in haemoglobin in the ferrous state. Glutathione is conjugated with xenobiotics by the action of glutathione transferases and this conjugation is important in the detoxification of xenobiotics because mono-oxygenation of xenobiotics leads to an increase in highly reactive electrophilic intermediates.
Glutathione transferases (GST): a group of enzymes (EC 2.5.1.18) which catalyze the conjugation of xenobiotics having electrophilic substituents with glutathione. GST are important in toxicology as they protects nucleophilic groups in proteins and nucleic acids by removing reactive electrophiles.
Glutethimide: a drug introduced in 1954 as a safe barbiturate substitute once used as a sedative and hypnotic to treat insomnia but withdrawn due to side effects of addiction liability.
Glycomimetic: a synthetic or natural product which can modify the biological effects of a complex carbohydrate-containing molecule. Substitution-based glycomimetics are those in which the sugar ring or glycosidic oxygen atom have been replaced with carbon or heteroatom, or where a core hydroxyl group has been replaced with a hydrogen donor/acceptor such as an amine or a thiol or an electronegative group such as a halogen. Examples of glycomimetics include carbasugars (which contains a carbon in place of the anomeric oxygen) and azasugars (which contains a nitrogen in place of the anomeric oxygen). In some glycomimetics, simplification has taken place such as in the elimination of anomeric centers or the removal of non-essential substituents including acetyls, sulfates and phosphates. Simplification can eliminate chiral carbon atoms and lower the molecular weight of the molecule.
The synthesis of glycomimetics has been carried our in the search for new generations of drugs such as antibiotics where modification may lead to decreased bacterial resistance and improved therapeutic index and antiviral drugs. Example of the latter are AZT (a synthetic substitution-based glycomimetic containing an azide group) and acyclovir (a simplified synthetic glycomimetic in which a ring carbon is missing).
Glycopeptide antibiotics: a class of antibiotic which includes vancomycin and teicoplanin. They inhibit cell wall synthesis and inhibit polymer release from the cell membrane. They are used clinically in the treatment of aerobic and anaerobic gram-positive bacterial infections such as in antibiotic-associated colitis (vancomycin which is bactericidal) and against potentially serious gram-positive infections including endocarditis, dialysis-associated peritonitis and serious infections caused by Staphylococcus aureus (teicoplanin). Antibiotic resistance to vancomycin limits its use (vancomycin-resistant enterococci).
Glycopeptide antibiotic resistance: a type of antibiotic resistance.
Glycoproteins: proteins which are covalently linked to oligosaccharides. Almost all proteins found in mammals are glycoproteins, eg antibodies, hormones, heat shock proteins, acute phase proteins, enzymes, coagulation factors, membrane receptors and mucins (one exception being albumin) These should not be confused with peptidoglycans in which the carbohydrate backbone predominates.
Glycoprotein hormones: a group of pituitary gonadotrophins (lutenizing and follicle-stimulating hormones), choriogonadotropin and thyrotropin which all comprise 2 peptide subunits and all of which are glycosylated. These should not be confused with glycosylated protein hormones such as erythropoietin.
Glycosides: a group of compounds in which one or more saccharide groups are linked by acetal bonds with hydroxy groups of alcohols or phenols They are often alkaloids and examples include saponins (plant substance which form soap-like solutions with water) and cardiac glycosides.
Gnotobiotic: a term used to describe an animal about which the microflora and microfauna are completely known. Gnotobiology (also known as gnotobiotics) usually refers to the science of rearing animals which are free of other forms of life such as bacteria and fungi.
Good laboratory practice (GLP): guidelines laid down by regulatory bodies to ensure that laboratory standards are of an acceptable level. This means that animals used in experiments are appropriately cared for and preclinical tests of drugs are properly recorded.
Goitrogens: also known as antithyroid agents.
Goldblatt one-kidney, one clip (Goldblatt I) and two-kidney, one clip (Goldblatt II ) model: animal models of renovascular hypertension caused by renal artery clamping and subsequent renal ischaemia.
Goldblatt H et al. Studies on experimental hypertension. I. The production of persistent elevation of systolic blood pressure by means of renal ischemia. J Exp Med (1934) 59:347-381
Gonadal hormones: also known as sex hormones, these are steroid hormones produced in the testes and ovaries and which determine the male or female characteristics of humans. They are responsible for the development and function of the primary sex characteristics.
Gonadorelin: a synthetic gonadotrophin-releasing hormone (GnRH) used in the assessment of pituitary function. Like GnRH, it controls the secretion of follicle stimulating hormone and leutenizing hormone from the anterior pituitary and injection of gonadorelin caused a rapid rise in both FSH and LH levels.
Gossypol: an aromatic triterpene compound obtained from cotton seeds (Gossypum hirsutum) and tested for its chemical contraceptive effects in men.
Goto-Kakizaki (GK) rat: an animal model of non-insulin-dependent diabetes mellitus which exhibits early hyperglycaemia, hyperinsulinaemia and insulin resistance. It is used as an animal model of diabetes as it exhibits similar metabolic, hormonal and vascular disorders seen in human diabetes.
Gougerotin: a nucleoside (pyrimidine) antibiotic which inhibits bacterial replication in both eukaryotes and prokaryotes by binding to ribosomes and inhibiting protein synthesis by inhibiting peptide bond formation.
G proteins: proteins which are involved in intracellular signaling.
GR113808: a potent and selective 5-HT4 serotonin receptor antagonist.
GR135531: an indole analogue and melatonin receptor ligand which binds with high affinity to MT3 melatonin receptors but shows low affinity and no efficacy at MT1 and MT2 receptor sites.
GR79236: N-([1S,trans]-2-hydroxycyclopentyl)adenosine, a selective A1 adenosine receptor agonist.
Gramicidins: a family of naturally occurring linear or cyclic peptide antibiotics which form cation-specific ion channels. Gramicidins A, B, C, D and S are known. They have been used to study the organization, dynamics and functions of membrane-spanning channels. They are produced by Bacillus brevis and have been used clinically to treat gram-positive organisms particularly gramicidin S.
GRASE: a regulatory term meaning generally recognized as safe and effective.
Green pharmacy: the use of natural plant substances in the treatment of disease in preference to synthetic compounds because they are considered to be less toxic.
Griseofulvin: a cyclohexane benzofuran antifungal compound obtained from strains of Penicillium griseofulvum. It is used as a fungistatic (which is why it is slow acting) in humans. It is used clinically to treat dermatophyte infections of Tinea capitis of the skin, scalp, hair and nails. It is used in veterinary pharmacology to treat infections of Microsporum species and Trichophyton species particularly in dogs, cats and horses.
It is known to be carcinogenic and teratogenic as acts by binding to microtubules to inhibit spindle formation and mitosis.
GRK: G protein-coupled receptor kinase.
Growth inhibiting dose (GID): the amount of substance needed to inhibit the growth of tumor cells in vitro. GID is usually presented as GID50 or GID75 and means the dose of compound required to inhibit 50 or 75% of the growth of the cells in which the compound is being tested. In vivo the units are often mg/m2.
GRP: good review practice.
GSH: glutathion
G-stropanthin: also known as ouabain.
Guanethidine: an adrenergic neurone blocking drug which is taken up by adrenergic neurones by uptake 1, binds to storage granules and prevents release of noradrenaline. It is used clinically in hypertensive crisis as it rapidly lowers blood pressure.
Guanfacine: a centrally-acting and selective agonist of α2A-adrenoceptors of use in the treatment of hypertension.
Guanine nucleotide binding proteins (G proteins): a large class of over 20 membrane-bound, heterotrimeric proteins (they are made up of 3 different subunits, ie α, β and γ subunits) which 'couple' cell surface receptors with an intracellular second messenger (so they mediate transmembrane signaling). G protein-coupled receptors comprise 7 α helical units which are located within the cell membrane itself and are linked by 3 intracellular and 3 extracellular loops. The 3rd intracellular loop is linked to the G protein.
Many G proteins have been cloned and characterized and have been grouped according to the second messenger to which they are coupled although this grouping is not absolute as some G proteins do not couple to the same second messenger in different cell types and some G proteins couple to more than one second messenger in the same cells type.
Gs proteins often link to and activate adenylyl cyclase, Gi proteins are linked to and inhibit adenylyl cyclase and Gq proteins mediate the stimulation of phospholipase C and thus their stimulation causes an increase in cellular phosphoinositide turnover.
Gunn rat: an animal model of bilirubin encephalopathy because the genetic lesions present in these rats closely parallel those observed in Crigler-Najjar syndrome Type I. The Gunn rat model is being used to develop methods for gene therapy for inherited bilirubin-UGT deficiency and severe non-hemolytic un-conjugated hyperbilirubinaemia.
Gut hormones: a group of 20 or so hormones which regulate the function of the gut and allow food intake to regulate appetite and satiety.
Hameed S et al. Gut hormones and appetite control. Oral Dis (2009) Jan; 15(1): 18-26
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