Showing papers in "British Journal of Pharmacology in 2006"

The role of inflammation in CNS injury and disease.

Abstract: For many years, the central nervous system (CNS) was considered to be 'immune privileged', neither susceptible to nor contributing to inflammation. It is now appreciated that the CNS does exhibit features of inflammation, and in response to injury, infection or disease, resident CNS cells generate inflammatory mediators, including proinflammatory cytokines, prostaglandins, free radicals and complement, which in turn induce chemokines and adhesion molecules, recruit immune cells, and activate glial cells. Much of the key evidence demonstrating that inflammation and inflammatory mediators contribute to acute, chronic and psychiatric CNS disorders is summarised in this review. However, inflammatory mediators may have dual roles, with detrimental acute effects but beneficial effects in long-term repair and recovery, leading to complications in their application as novel therapies. These may be avoided in acute diseases in which treatment administration might be relatively short-term. Targeting interleukin (IL)-1 is a promising novel therapy for stroke and traumatic brain injury, the naturally occurring antagonist (IL-1ra) being well tolerated by rheumatoid arthritis patients. Chronic disorders represent a greater therapeutic challenge, a problem highlighted in Alzheimer's disease (AD); significant data suggested that anti-inflammatory agents might reduce the probability of developing AD, or slow its progression, but prospective clinical trials of nonsteroidal anti-inflammatory drugs or cyclooxygenase inhibitors have been disappointing. The complex interplay between inflammatory mediators, ageing, genetic background, and environmental factors may ultimately regulate the outcome of acute CNS injury and progression of chronic neurodegeneration, and be critical for development of effective therapies for CNS diseases.

The discovery of nitric oxide and its role in vascular biology

Abstract: Nitric oxide (NO) is a relative newcomer to pharmacology, as the paper which initiated the field was published only 25 years ago. Nevertheless its impact is such that to date more than 31,000 papers have been published with NO in the title and more than 65,000 refer to it in some way. The identification of NO with endothelium-derived relaxing factor and the discovery of its synthesis from L-arginine led to the realisation that the L-arginine: NO pathway is widespread and plays a variety of physiological roles. These include the maintenance of vascular tone, neurotransmitter function in both the central and peripheral nervous systems, and mediation of cellular defence. In addition, NO interacts with mitochondrial systems to regulate cell respiration and to augment the generation of reactive oxygen species, thus triggering mechanisms of cell survival or death. This review will focus on the role of NO in the cardiovascular system where, in addition to maintaining a vasodilator tone, it inhibits platelet aggregation and adhesion and modulates smooth muscle cell proliferation. NO has been implicated in a number of cardiovascular diseases and virtually every risk factor for these appears to be associated with a reduction in endothelial generation of NO. Reduced basal NO synthesis or action leads to vasoconstriction, elevated blood pressure and thrombus formation. By contrast, overproduction of NO leads to vasodilatation, hypotension, vascular leakage, and disruption of cell metabolism. Appropriate pharmacological or molecular biological manipulation of the generation of NO will doubtless prove beneficial in such conditions.

How corticosteroids control inflammation: Quintiles Prize Lecture 2005.

Abstract: Corticosteroids are the most effective anti-inflammatory therapy for many chronic inflammatory diseases, such as asthma but are relatively ineffective in other diseases such as chronic obstructive pulmonary disease (COPD). Chronic inflammation is characterised by the increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors, such as nuclear factor-kappaB and activator protein-1, that bind to and activate coactivator molecules, which then acetylate core histones to switch on gene transcription. Corticosteroids suppress the multiple inflammatory genes that are activated in chronic inflammatory diseases, such as asthma, mainly by reversing histone acetylation of activated inflammatory genes through binding of liganded glucocorticoid receptors (GR) to coactivators and recruitment of histone deacetylase-2 (HDAC2) to the activated transcription complex. At higher concentrations of corticosteroids GR homodimers also interact with DNA recognition sites to active transcription of anti-inflammatory genes and to inhibit transcription of several genes linked to corticosteroid side effects. In patients with COPD and severe asthma and in asthmatic patients who smoke HDAC2 is markedly reduced in activity and expression as a result of oxidative/nitrative stress so that inflammation becomes resistant to the anti-inflammatory actions of corticosteroids. Theophylline, by activating HDAC, may reverse this corticosteroid resistance. This research may lead to the development of novel anti-inflammatory approaches to manage severe inflammatory diseases.

Cannabinoid pharmacology: the first 66 years

Abstract: Research into the pharmacology of individual cannabinoids that began in the 1940s, several decades after the presence of a cannabinoid was first detected in cannabis, is concisely reviewed. Also described is how this pharmacological research led to the discovery of cannabinoid CB1 and CB2 receptors and of endogenous ligands for these receptors, to the development of CB1- and CB2-selective agonists and antagonists and to the realization that the endogenous cannabinoid systemhas significant roles in both health and disease, and that drugs which mimic, augment or block the actions of endogenously released cannabinoids must have important therapeutic applications. Some goals for future research are identified. British Journal of Pharmacology (2006) 147, S163–S171. doi:10.1038/sj.bjp.0706406

Monoamine oxidase: isoforms and inhibitors in Parkinson's disease and depressive illness.

Abstract: A few years after the foundation of the British Pharmacological Society, monoamine oxidase (MAO) was recognized as an enzyme of crucial interest to pharmacologists because it catalyzed the major inactivation pathway for the catecholamine neurotransmitters, noradrenaline, adrenaline and dopamine (and, later, 5-hydroxytryptamine, as well). Within the next decade, the therapeutic value of inhibitors of MAO in the treatment of depressive illness was established. Although this first clinical use exposed serious side effects, pharmacological interest in, and investigation of, MAO continued, resulting in the characterization of two isoforms, MAO-A and -B, and isoform-selective inhibitors. Selective inhibitors of MAO-B have found a therapeutic role in the treatment of Parkinson's disease and further developments have provided reversible inhibitors of MAO-A, which offer antidepressant activity without the serious side effects of the earlier inhibitors. Clinical observation and subsequent pharmacological analysis have also generated the concept of neuroprotection, reflecting the possibility of slowing, halting and maybe reversing, neurodegeneration in Parkinson's or Alzheimer's diseases. Increased levels of oxidative stress in the brain may be critical for the initiation and progress of neurodegeneration and selective inhibition of brain MAO could contribute importantly to lowering such stress. There are complex interactions between free iron levels in brain and MAO, which may have practical outcomes for depressive disorders. These aspects of MAO and its inhibition and some indication of how this important area of pharmacology and therapeutics might develop in the future are summarized in this review.

Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder

Abstract: 1 The effectiveness of antimuscarinic agents in the treatment of the overactive bladder (OAB) syndrome is thought to arise through blockade of bladder muscarinic receptors located on detrusor smooth muscle cells, as well as on nondetrusor structures. 2 Muscarinic M-3 receptors are primarily responsible for detrusor contraction. Limited evidence exists to suggest that M-2 receptors may have a role in mediating indirect contractions and/or inhibition of detrusor relaxation. In addition, there is evidence that muscarinic receptors located in the urothelium/suburothelium and on afferent nerves may contribute to the pathophysiology of OAB. Blockade of these receptors may also contribute to the clinical efficacy of antimuscarinic agents. 3 Although the role of muscarinic receptors in the bladder, other than M3 receptors, remains unclear, their role in other body systems is becoming increasingly well established, with emerging evidence supporting a wide range of diverse functions. Blockade of these functions by muscarinic receptor antagonists can lead to similarly diverse adverse effects associated with antimuscarinic treatment, with the range of effects observed varying according to the different receptor subtypes affected. 4 This review explores the evolving understanding of muscarinic receptor functions throughout the body, with particular focus on the bladder, gastrointestinal tract, eye, heart, brain and salivary glands, and the implications for drugs used to treat OAB. The key factors that might determine the ideal antimuscarinic drug for treatment of OAB are also discussed. Further research is needed to show whether the M-3 selective receptor antagonists have any advantage over less selective drugs, in leading to fewer adverse events. (Less)

Histamine and its receptors.

Abstract: This article reviews the development of our knowledge of the actions of histamine which have taken place during the course of the 20th century. Histamine has been shown to have a key physiological role in the control of gastric acid secretion and a pathophysiological role in a range of allergic disorders. The synthesis of, and pharmacological studies on, selective agonists and antagonists has established the existence of four types of histamine receptor and histamine receptor antagonists have found very important therapeutic applications. Thus, in the 1940s, H(1)-receptor antagonists ('the antihistamines') yielded and still provide valuable treatment for allergic conditions such as hay fever and rhinitis. In the late 1970s and 1980s, H(2)-receptor antagonists (in the discovery of which the two authors were personally involved) revolutionised the treatment of peptic ulcer and other gastric acid-related diseases. The H(3)-receptor antagonists, although available since 1987, have been slower to find a therapeutic role. However, the discovery of nonimidazole derivatives such as brain-penetrating H(3) antagonists has provided drugs that are in early-phase clinical trials, possibly for application in obesity, and a variety of central nervous system disorders, such as memory, learning deficits and epilepsy. Finally, the most recently (1999) discovered H(4) receptor promises the potential to provide drugs acting on the immunological system with possible applications in asthma and inflammation.

Heterotrimeric G-proteins: a short history

Abstract: Some 865 genes in man encode G-protein-coupled receptors (GPCRs). The heterotrimeric guanine nucleotide-binding proteins (G-proteins) function to transduce signals from this vast panoply of receptors to effector systems including ion channels and enzymes that alter the rate of production, release or degradation of intracellular second messengers. However, it was not until the 1970s that the existence of such transducing proteins was even seriously suggested. Combinations of bacterial toxins that mediate their effects via covalent modification of the α-subunit of certain G-proteins and mutant cell lines that fail to generate cyclic AMP in response to agonists because they either fail to express or express a malfunctional G-protein allowed their identification and purification. Subsequent to initial cloning efforts, cloning by homology has defined the human G-proteins to derive from 35 genes, 16 encoding α-subunits, five β and 14 γ. All function as guanine nucleotide exchange on–off switches and are mechanistically similar to other proteins that are enzymic GTPases. Although not readily accepted initially, it is now well established that β/γ complexes mediate as least as many functions as the α-subunits. The generation of chimeras between different α-subunits defined the role of different sections of the primary/secondary sequence and crystal structures and cocrystals with interacting proteins have given detailed understanding of their molecular structure and basis of function. Finally, further modifications of such chimeras have generated a range of G-protein α-subunits with greater promiscuity to interact across GPCR classes and initiated the use of such modified G-proteins in drug discovery programmes.

α1‐, α2‐ and β‐adrenoceptors in the urinary bladder, urethra and prostate

Abstract: 1 We have systematically reviewed the presence, functional responses and regulation of alpha(1)-, alpha(2)- and beta-adrenoceptors in the bladder, urethra and prostate, with special emphasis on human tissues and receptor subtypes 2 Alpha(1)-adrenoceptors are only poorly expressed and play a limited functional role in the detrusor Alpha(1)-adrenoceptors, particularly their alpha(1A)-subtype, show a more pronounced expression and promote contraction of the bladder neck, urethra and prostate to enhance bladder outlet resistance, particularly in elderly men with enlarged prostates Alpha(1)-adrenoceptor agonists are important in the treatment of symptoms of benign prostatic hyperplasia, but their beneficial effects may involve receptors within and outside the prostate 3 Alpha(2)-adrenoceptors, mainly their alpha(2A)-subtype, are expressed in bladder, urethra and prostate They mediate pre-junctional inhibition of neurotransmitter release and also a weak contractile effect in the urethra of some species, but not humans Their overall post-junctional function in the lower urinary tract remains largely unclear 4 Beta-adrenoceptors mediate relaxation of smooth muscle in the bladder, urethra and prostate The available tools have limited the unequivocal identification of receptor subtypes at the protein and functional levels, but it appears that the beta(3)- and beta(2)-subtypes are important in the human bladder and urethra, respectively Beta(3)-adrenoceptor agonists are promising drug candidates for the treatment of the overactive bladder 5 We propose that the overall function of adrenoceptors in the lower urinary tract is to promote urinary continence Further elucidation of the functional roles of their subtypes will help a better understanding of voiding dysfunction and its treatment

The orexin system regulates alcohol-seeking in rats.

Abstract: 1. Orexin-containing neurons have been implicated in feeding, sleep-wake cycles and more recently in drug-seeking behaviour. 2. Pretreatment of alcohol-preferring (iP) rats with an orexin1 receptor antagonist (SB-334867, 20 mg kg(-1), intraperitoneally) completely abolished an olfactory cue-induced reinstatement of alcohol-seeking behaviour, and also attenuated alcohol responding under an operant fixed ratio regimen without affecting water responding. 3. The mRNA encoding orexin within the hypothalamus was expressed at a similar density in iP and non-preferring (NP) rats; chronic consumption of ethanol in iP rats did not significantly regulate the density of this expression, but did increase the area of expression within the lateral, but not medial, hypothalamus. 4. These data indicate that while orexin may not be implicated in the development of an alcohol preference, re-exposure of cues previously associated with alcohol availability is sufficient and adequate to activate orexin-containing neurons and drive reinstatement of alcohol-seeking.

Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40: identification of agonist and antagonist small molecules

Abstract: 1. Long chain fatty acids have recently been identified as agonists for the G protein-coupled receptors GPR40 and GPR120. Here, we present the first description of GW9508, a small-molecule agonist of the fatty acid receptors GPR40 and GPR120. In addition, we also describe the pharmacology of GW1100, a selective GPR40 antagonist. These molecules were used to further investigate the role of GPR40 in glucose-stimulated insulin secretion in the MIN6 mouse pancreatic beta-cell line. 2. GW9508 and linoleic acid both stimulated intracellular Ca2+ mobilization in human embryonic kidney (HEK)293 cells expressing GPR40 (pEC50 values of 7.32+/-0.03 and 5.65+/-0.06, respectively) or GPR120 (pEC50 values of 5.46+/-0.09 and 5.89+/-0.04, respectively), but not in the parent HEK-293 cell line. 3. GW1100 dose dependently inhibited GPR40-mediated Ca2+ elevations stimulated by GW9508 and linoleic acid (pIC50 values of 5.99+/-0.03 and 5.99+/-0.06, respectively). GW1100 had no effect on the GPR120-mediated stimulation of intracellular Ca2+ release produced by either GW9508 or linoleic acid. 4. GW9508 dose dependently potentiated glucose-stimulated insulin secretion in MIN6 cells, but not in primary rat or mouse islets. Furthermore, GW9508 was able to potentiate the KCl-mediated increase in insulin secretion in MIN6 cells. The effects of GW9508 on insulin secretion were reversed by GW1100, while linoleic acid-stimulated insulin secretion was partially attenuated by GW1100. 5. These results add further evidence to a link between GPR40 and the ability of fatty acids to acutely potentiate insulin secretion and demonstrate that small-molecule GPR40 agonists are glucose-sensitive insulin secretagogues.

Integrative control of the lower urinary tract: preclinical perspective

Abstract: Storage and periodic expulsion of urine is regulated by a neural control system in the brain and spinal cord that coordinates the reciprocal activity of two functional units in the lower urinary tract (LUT): (a) a reservoir (the urinary bladder) and (b) an outlet (bladder neck, urethra and striated muscles of the urethral sphincter). Control of the bladder and urethral outlet is dependent on three sets of peripheral nerves: parasympathetic, sympathetic and somatic nerves that contain afferent as well as efferent pathways. Afferent neurons innervating the bladder have A-δ or C-fibre axons. Urine storage reflexes are organized in the spinal cord, whereas voiding reflexes are mediated by a spinobulbospinal pathway passing through a coordination centre (the pontine micturition centre) located in the brainstem. Storage and voiding reflexes are activated by mechanosensitive A-δ afferents that respond to bladder distension. Many neurotransmitters including acetylcholine, norepinephrine, dopamine, serotonin, excitatory and inhibitory amino acids, adenosine triphosphate, nitric oxide and neuropeptides are involved in the neural control of the LUT. Injuries or diseases of the nervous system as well as disorders of the peripheral organs can produce LUT dysfunctions including: (1) urinary frequency, urgency and incontinence or (2) inefficient voiding and urinary retention. Neurogenic detrusor overactivity is triggered by C-fibre bladder afferent axons, many of which terminate in the close proximity to the urothelium. The urothelial cells exhibit ‘neuron-like' properties that allow them to respond to mechanical and chemical stimuli and to release transmitters that can modulate the activity of afferent nerves.

Regulation of vascular nitric oxide in vitro and in vivo; a new role for endogenous hydrogen sulphide?

Abstract: Background and Purpose: The aim of these experiments was to evaluate the significance of the chemical reaction between hydrogen sulphide (H2S) and nitric oxide (NO) for the control of vascular tone. Experimental Approach: The effect of sodium hydrosulphide (NaHS; H2S donor) and a range of NO donors, such as sodium nitroprusside (SNP), either alone or together, was determined using phenylephrine (PE)-precontracted rat aortic rings and on the blood pressure of anaesthetised rats. Key Results: Mixing NaHS with NO donors inhibited the vasorelaxant effect of NO both in vitro and in vivo. Low concentrations of NaHS or H2S gas in solution reversed the relaxant effect of acetylcholine (ACh, 400 nM) and histamine (100 μM) but not isoprenaline (400 nM). The effect of NaHS on the ACh response was antagonized by CuSO4 (200 nM) but was unaffected by glibenclamide (10 μM). In contrast, high concentrations of NaHS (200–1600 μM) relaxed aortic rings directly, an effect reduced by glibenclamide but unaffected by CuSO4. Intravenous infusion of a low concentration of NaHS (10 μmol kg-1 min-1) into the anaesthetized rat significantly increased mean arterial blood pressure. L-NAME (25 mg kg-1, i.v.) pretreatment reduced this effect. Conclusions and Implications: These results suggest that H2S and NO react together to form a molecule (possibly a nitrosothiol) which exhibits little or no vasorelaxant activity either in vitro or in vivo. We propose that a crucial, and hitherto unappreciated, role of H2S in the vascular system is the regulation of the availability of NO. British Journal of Pharmacology (2006) 149, 625–634. doi:10.1038/sj.bjp.0706906

Molecular targets underlying general anaesthesia

Abstract: The discovery of general anaesthesia, over 150 years ago, revolutionised medicine. The ability to render a patient unconscious and insensible to pain made modern surgery possible and general anaesthetics have become both indispensible as well as one of the most widely used class of drugs. Their extraordinary chemical diversity, ranging from simple chemically inert gases to complex barbiturates, has baffled pharmacologists, and ideas about how they might work have been equally diverse. Until relatively recently, thinking was dominated by the notion that anaesthetics acted ‘nonspecifically' by dissolving in the lipid bilayer portions of nerve membranes. While this simple idea could account for the chemical diversity of general anaesthetics, it has proven to be false and it is now generally accepted that anaesthetics act by binding directly to sensitive target proteins. For certain intravenous anaesthetics, such as propofol and etomidate, the target has been identified as the GABAA receptor, with particular subunits playing a crucial role. For the less potent inhalational agents, the picture is less clear, although a relatively small number of targets have been identified as being the most likely candidates. In this review, I will describe the work that led up to the identification of the GABAA receptor as the key target for etomidate and propofol and contrast this with current progress that has been made in identifying the relevant targets for other anaesthetics, particularly the inhalational agents.

75 years of opioid research: the exciting but vain quest for the Holy Grail.

Abstract: Over the 75-year lifetime of the British Pharmacological Society there has been an enormous expansion in our understanding of how opioid drugs act on the nervous system, with much of this effort aimed at developing powerful analgesic drugs devoid of the side effects associated with morphine – the Holy Grail of opioid research. At the molecular and cellular level multiple opioid receptors have been cloned and characterised, their potential for oligomerisation determined, a large family of endogenous opioid agonists has been discovered, multiple second messengers identified and our understanding of the adaptive changes to prolonged exposure to opioid drugs (tolerance and physical dependence) enhanced. In addition, we now have greater understanding of the processes by which opioids produce the euphoria that gives rise to the intense craving for these drugs in opioid addicts. In this article, we review the historical pathway of opioid research that has led to our current state of knowledge.

Phosphodiesterase inhibitors: Phosphodiesterase inhibitors

Abstract: Phosphodiesterases are a diverse family of enzymes that hydrolyse cyclic nucleotides and thus play a key role in regulating intracellular levels of the second messengers cAMP and cGMP, and hence cell function. Theophylline and papaverine have historically been used therapeutically and are known to be weak inhibitors of PDE, but to what extent this contributed toward their clinical efficacy was poorly defined. However, the discovery of 11 isoenzyme families and our increased understanding of their function at the cell and molecular level provides an impetus for the development of isoenzyme selective inhibitors for the treatment of various diseases. This review focuses on the development of PDE3 inhibitors for congestive heart failure, PDE4 inhibitors for inflammatory airways disease and most successfully, PDE5 inhibitors for erectile dysfunction

μ opioid and CB1 cannabinoid receptor interactions: reciprocal inhibition of receptor signaling and neuritogenesis

Abstract: Several studies have described functional interactions between opioid and cannabinoid receptors; the underlying mechanism(s) have not been well explored. One possible mechanism is direct receptor-receptor interactions, as has been demonstrated for a number of G-protein-coupled receptors. In order to investigate interactions between opioid and cannabinoid receptors, we epitope tagged mu, delta and kappa opioid receptors with Renilla luciferase and CB1 cannabinoid or CCR5 chemokine receptors with yellow fluorescent protein and examined the extent of substrate hydrolysis induced bioluminescence resonance energy transfer (BRET) signal. We find that coexpression of opioid receptors with cannabinoid receptors, but not with chemokine receptors, leads to a significant increase in the level of BRET signal, suggesting that the opioid-cannabinoid interactions are receptor specific. In order to examine the implications of these interactions to signaling, we used GTPgammaS binding and mitogen-activated protein kinase (MAPK) phosphorylation assays and examined the effect of receptor activation on signaling. We find that the mu receptor-mediated signaling is attenuated by the CB1 receptor agonist; this effect is reciprocal and is seen in heterologous cells and endogenous tissue expressing both receptors. In order to explore the physiological consequences of this interaction, we examined the effect of receptor activation on the extent of Src and STAT3 phosphorylation and neuritogenesis in Neuro-2A cells. We find that the simultaneous activation of mu opioid and CB1 cannabinoid receptors leads to a significant attenuation of the response seen upon activation of individual receptors, implicating a role for receptor-receptor interactions in modulating neuritogenesis.

GABA and glycine as neurotransmitters: a brief history

Abstract: gamma-Aminobutyric acid (GABA) emerged as a potentially important brain chemical just over 50 years ago, but its significance as a neurotransmitter was not fully realized until over 16 years later We now know that at least 40% of inhibitory synaptic processing in the mammalian brain uses GABA Establishing its role as a transmitter was a lengthy process and it seems hard to believe with our current knowledge that there was ever any dispute about its role in the mammalian brain The detailed information that we now have about the receptors for GABA together with the wealth of agents which facilitate or reduce GABA receptor mechanisms make the prospects for further research very exciting The emergence of glycine as a transmitter seems relatively painless by comparison to GABA Perhaps this is appropriate for the simplest of transmitter structures! Its discovery within the spinal cord and brainstem approximately 40 years ago was followed only 2 years later by the proposal that it be conferred with 'neurotransmitter' status It was another 16 years before the receptor was biochemically isolated Now it is readily accepted as a vital spinal and supraspinal inhibitory transmitter and we know many details regarding its molecular structure and trafficking around neurones The pharmacology of these receptors has lagged behind that of GABA There is not the rich variety of allosteric modulators that we have come to readily associate with GABA receptors and which has provided us with a virtual treasure trove of important drugs used in anxiety, insomnia, epilepsy, anaesthesia, and spasticity, all stemming from the actions of the simple neutral amino acid GABA Nevertheless, the realization that glycine receptors are involved in motor reflexes and nociceptive pathways together with the more recent advent of drugs that exhibit some subtype selectivity make the goal of designing selective therapeutic ligands for the glycine receptor that much closer

Antiviral prodrugs – the development of successful prodrug strategies for antiviral chemotherapy

Abstract: Following the discovery of the first effective antiviral compound (idoxuridine) in 1959, nucleoside analogues, especially acyclovir (ACV) for the treatment of herpesvirus infections, have dominated antiviral therapy for several decades. However, ACV and similar acyclic nucleosides suffer from low aqueous solubility and low bioavailability following oral administration. Derivatives of acyclic nucleosides, typically esters, were developed to overcome this problem and valaciclovir, the valine ester of ACV, was among the first of a new series of compounds that were readily metabolized upon oral administration to produce the antiviral nucleoside in vivo, thus increasing the bioavailility by several fold. Concurrently, famciclovir was developed as an oral formulation of penciclovir. These antiviral 'prodrugs' thus established a principle that has led to many successful drugs including both nucleoside and nucleotide analogues for the control of several virus infections, notably those caused by herpes-, retro- and hepatitisviruses. This review will chart the origins and development of the most important of the antiviral prodrugs to date.

Tamoxifen (ICI46,474) as a targeted therapy to treat and prevent breast cancer

Abstract: Antihormonal therapy targeted to the oestrogen receptor (OER) is recognized as a significant advance in the treatment and prevention of breast cancer. However, the research method used to achieve the current successes seen in the clinic was not linear but was based on the changing fashions in research and the application of appropriate testing models. The discovery and investigation of nonsteroidal antioestrogens by the pharmaceutical industry during the 1960s was initially an exciting prospect for clinical development. The drugs were superb antifertility agents in laboratory animals, so the prospect of marketing a 'morning after' pill was a high priority. Unfortunately, the reproductive endocrinology of the rat was found to be completely different from that of the human. Antioestrogens, in fact, improved fertility by inducing ovulation in subfertile women so much of the drug development was discontinued. The successful reinvention of ICI46,474 from its origins as a failed contraceptive to a pioneering breast cancer treatment targeted to the OER presaged the development of the current menu of medicines targeted to a range of different survival mechanisms in cancer cells.

The anti-amnesic and neuroprotective effects of donepezil against amyloid β25-35 peptide-induced toxicity in mice involve an interaction with the σ1 receptor

Abstract: Background and purpose: The acetylcholinesterase inhibitor, donepezil, is also a high affinity σ1 receptor agonist. We examined the involvement of σ1 receptors in its anti-amnesic and neuroprotective properties against amyloid β25-35 peptide-induced toxicity in mice.

Glucocorticoids: exemplars of multi-tasking.

Abstract: Well over 80 years ago Philip Smith described the beneficial clinical effects of adrenocortical extracts in animal models of adrenal insufficiency. In the ensuing years, scientists across the globe have sought to understand the mechanisms by which adrenal hormones and their synthetic analogues produce their complex and varied actions. Particular attention has focused on the glucocorticoids, partly because they have a vital place in the treatment of inflammatory and autoimmune disorders but also because dysregulation of the secretion and/or activity of endogenous glucocorticoids is increasingly implicated in a number of common disorders that pose a growing clinical burden, such as obesity, type II diabetes, the metabolic syndrome, hypertension and depression. This review considers some of the key advances that have been made in our understanding of the physiology, pathology and pharmacology of the glucocorticoids. Emphasis is placed on the molecular mechanisms of glucocorticoid signalling and the complex mechanisms that regulate the access of steroids in the systemic circulation to their receptors in their various target cells and tissues. In addition, consideration is given to the irreversible 'organisational' actions of glucocorticoids in perinatal life and to the potential role of the steroids in the aetiology of disease.

Actions of the FAAH inhibitor URB597 in neuropathic and inflammatory chronic pain models.

Abstract: While cannabinoid receptor agonists have analgesic activity in chronic pain states, they produce a spectrum of central CB(1) receptor-mediated motor and psychotropic side effects. The actions of endocannabinoids, such as anandamide are terminated by removal from the extracellular space, then subsequent enzymatic degradation by fatty-acid amide hydrolase (FAAH). In the present study, we compared the effect of a selective FAAH inhibitor, URB597, to that of a pan-cannabinoid receptor agonist HU210 in rat models of chronic inflammatory and neuropathic pain. Systemic administration of URB597 (0.3 mg kg(-1)) and HU210 (0.03 mg kg(-1)) both reduced the mechanical allodynia and thermal hyperalgesia in the CFA model of inflammatory pain. In contrast, HU210, but not URB597, reduced mechanical allodynia in the partial sciatic nerve-ligation model of neuropathic pain. HU210, but not URB597, produced a reduction in motor performance in unoperated rats. The effects of URB597 in the CFA model were dose dependent and were reduced by coadministration with the cannabinoid CB1 antagonist AM251 (1 mg kg(-1)), or the CB2 and SR144528 (1 mg kg(-1)). Coadministration with AM251 plus SR144528 completely reversed the effects of URB597. These findings suggest that the FAAH inhibitor URB597 produces cannabinoid CB1 and CB2 receptor-mediated analgesia in inflammatory pain states, without causing the undesirable side effects associated with cannabinoid receptor activation.

Trace amine-associated receptors and their ligands.

Abstract: Classical biogenic amines (adrenaline, noradrenaline, dopamine, serotonin and histamine) interact with specific families of G protein-coupled receptors (GPCRs). The term 'trace amines' is used when referring to p-tyramine, beta-phenylethylamine, tryptamine and octopamine, compounds that are present in mammalian tissues at very low (nanomolar) concentrations. The pharmacological effects of trace amines are usually attributed to their interference with the aminergic pathways, but in 2001 a new gene was identified, that codes for a GPCR responding to p-tyramine and beta-phenylethylamine but not to classical biogenic amines. Several closely related genes were subsequently identified and designated as the trace amine-associated receptors (TAARs). Pharmacological investigations in vitro show that many TAAR subtypes may not respond to p-tyramine, beta-phenylethylamine, tryptamine or octopamine, suggesting the existence of additional endogenous ligands. A novel endogenous thyroid hormone derivative, 3-iodothyronamine, has been found to interact with TAAR1 and possibly other TAAR subtypes. In vivo, micromolar concentrations of 3-iodothyronamine determine functional effects which are opposite to those produced on a longer time scale by thyroid hormones, including reduction in body temperature and decrease in cardiac contractility. Expression of all TAAR subtypes except TAAR1 has been reported in mouse olfactory epithelium, and several volatile amines were shown to interact with specific TAAR subtypes. In addition, there is evidence that TAAR1 is targeted by amphetamines and other psychotropic agents, while genetic linkage studies show a significant association between the TAAR gene family locus and susceptibility to schizophrenia or bipolar affective disorder.

A new endogenous ATP analog (ApppI) inhibits the mitochondrial adenine nucleotide translocase (ANT) and is responsible for the apoptosis induced by nitrogen-containing bisphosphonates.

Abstract: 1. Bisphosphonates are currently the most important class of antiresorptive drugs used for the treatment of diseases with excess bone resorption. On the basis of their molecular mechanism of action, bisphosphonates can be divided into two pharmacological classes; nitrogen-containing (N-BPs) and non-nitrogen-containing bisphosphonates (non-N-BP). Both classes induce apoptosis but they evoke it differently; N-BPs by inhibiting the intracellular mevalonate pathway and protein isoprenylation, and non-N-BPs via cytotoxic ATP analog-type metabolites. N-BPs are not metabolized to ATP analogs, but we report here that these bisphosphonates can induce formation of a novel ATP analog (ApppI) as a consequence of the inhibition of the mevalonate pathway in cells. We also investigated whether ApppI is involved in the apoptosis induced by N-BPs. 2. Mass spectrometry and NMR were used to identify ApppI in N-BP treated osteoclasts, macrophages and glioma cells. The potency of different bisphosphonates to promote ApppI production was tested in J774 macrophages. The effects of ApppI on ADP/ATP translocase in isolated mitochondria and its capability to induce apoptosis in osteoclasts were also studied. 3. ApppI production correlated well with the capacity of N-BPs to inhibit mevalonate pathway. ApppI inhibited the mitochondrial ADP/ATP translocase and caused apoptosis in osteoclasts. 4. In conclusion, these findings provide the basis for a new mechanism of action for N-BPs. Some of these very potent bisphosphonates, such as zoledronic acid, represent a third class of bisphosphonates that can act both via the inhibition of the mevalonate pathway and by the blockade of mitochondrial ADP/ATP translocase, which is known to be involved in the induction of apoptosis.

Purinergic signalling: Purinergic signalling

Abstract: While there were early papers about the extracellular actions of purines, the role of ATP as a purinergic neurotransmitter in nonadrenergic, noncholinergic nerves in the gut and bladder in 1972 was a landmark discovery, although it met considerable resistance for the next 20 years. In the early 1990s, receptors for purines were cloned: four P1 receptor subtypes and seven P2X ionotropic and eight P2Y metabotropic receptor subtypes are currently recognized and characterized. The mechanisms underlying ATP release and breakdown are discussed. Purines and pyrimidines have major roles in the activities of non‐neuronal cells as well as neurons. This includes fast signalling roles in exocrine and endocrine secretion, platelet aggregation, vascular endothelial cell‐mediated vasodilation and nociceptive mechanosensory transduction, as well as acting as a cotransmitter and neuromodulator in most, if not all, nerve types in the peripheral and central nervous systems. More recently, slow (trophic) purinergic signalling has been implicated in cell proliferation, migration, differentiation and death in embryological development, wound healing, restenosis, atherosclerosis, ischaemia, cell turnover of epithelial cells in skin and visceral organs, inflammation, neuroprotection and cancer.

The MC4 receptor and control of appetite

Abstract: Mutations in the human melanocortin (MC)4 receptor have been associated with obesity, which underscores the relevance of this receptor as a drug target to treat obesity. Infusion of MC4R agonists decreases food intake, whereas inhibition of MC receptor activity by infusion of an MC receptor antagonist or with the inverse agonist AgRP results in increased food intake. This review addresses the role of the MC system in different aspects of feeding behaviour. MC4R activity affects meal size and meal choice, but not meal frequency, and the type of diet affects the efficacy of MC4R agonists to reduce food intake. The central sites involved in the different aspects of feeding behaviour that are affected by MC4R signalling are being unravelled. The paraventricular nucleus plays an important role in food intake per se, whereas MC signalling in the lateral hypothalamus is associated with the response to a high fat diet. MC4R signalling in the brainstem has been shown to affect meal size. Further genetic, behavioural and brain-region specific studies need to clarify how the MC4R agonists affect feeding behaviour in order to determine which obese individuals would benefit most from treatment with these drugs. Application of MCR agonists in humans has already revealed side effects, such as penile erections, which may complicate introduction of these drugs in the treatment of obesity.

The glutamate story

Abstract: Glutamatergic synaptic transmission in the mammalian central nervous system was slowly established over a period of some 20 years, dating from the 1950s. Realisation that glutamate and like amino acids (collectively known as excitatory amino acids (EAA)) mediated their excitatory actions via multiple receptors preceded establishment of these receptors as synaptic transmitter receptors. EAA receptors were initially classified as N-methyl-D-aspartate (NMDA) and non-NMDA receptors, the latter subdivided into quisqualate (later AMPA) and kainate receptors after agonists that appeared to activate these receptors preferentially, and by their sensitivity to a range of differentially acting antagonists developed progressively during the 1970s. NMDA receptors were definitively shown to be synaptic receptors on spinal neurones by the sensitivity of certain excitatory pathways in the spinal cord to a range of specific NMDA receptor antagonists. Importantly, specific NMDA receptor antagonists appeared to be less effective at synapses in higher centres. In contrast, antagonists that also blocked non-NMDA as well as NMDA receptors were almost universally effective at blocking synaptic excitation within the brain and spinal cord, establishing both the existence and ubiquity of non-NMDA synaptic receptor systems throughout the CNS. In the early 1980s, NMDA receptors were shown to be involved in several central synaptic pathways, acting in concert with non-NMDA receptors under conditions where a protracted excitatory postsynaptic potential was effected in response to intense stimulation of presynaptic fibres. Such activation of NMDA receptors together with non-NMDA receptors led to the phenomenon of long-term potentiation (LTP), associated with lasting changes in synaptic efficacy (synaptic plasticity) and considered to be an important process in memory and learning. During the 1980s, it was shown that certain glutamate receptors in the brain mediated biochemical changes that were not susceptible to NMDA or non-NMDA receptor antagonists. This dichotomy was resolved in the early 1990s by the techniques of molecular biology, which identified two families of glutamate-binding receptor proteins (ionotropic (iGlu) and metabotropic (mGlu) receptors). Development of antagonists binding to specific protein subunits is currently enabling precise identification of discrete iGlu or mGlu receptor subtypes that participate in a range of central synaptic processes, including synaptic plasticity.

Prostaglandin E2 receptor distribution and function in the gastrointestinal tract

Abstract: Prostaglandin E2 (PGE2) is one of the most important biologically active prostanoids found throughout the gastrointestinal tract. Despite the fact that PGE2 regulates many physiological functions of the gut including mucosal protection, gastrointestinal secretion and motility, it is implicated in the pathophysiology of inflammatory bowel diseases (IBD) and colorectal neoplasia. The varied biological functions exerted by PGE2 are through the pharmacologically distinct, G-protein coupled plasma membrane receptors termed EP receptors. Disruptions of various prostanoid receptor genes have helped in unravelling the physiological functions of these receptors. To date, all four subtypes of EP receptors have been individually knocked out in mice and various phenotypes have been reported for each subtype. Similarly, in vitro and in vivo studies using EP receptor agonists and antagonists have helped in uncoupling the diverse functions of PGE2 signalling involving distinct EP receptors in the gut. In this review, we will summarize and conceptualize the salient features of EP receptor subtypes, their regional functions in the gut and how expressions of EP receptors are altered during disease states.

The effects of resveratrol, a phytoalexin derived from red wines, on chronic inflammation induced in an experimentally induced colitis model

Abstract: Neutrophil infiltration, proinflammatory cytokines, eicosanoid generation and oxidative stress have been implicated in colitis. Resveratrol is a polyphenolic compound found in grapes and wine, with multiple pharmacological actions, including anti-inflammatory, antioxidant, antitumour and immunomodulatory activities. In a previous report, we documented that resveratrol decreases the degree of inflammation associated with acute experimental colonic inflammation, but its effects on chronic experimental colitis remain undetermined. The aim of this research was to investigate the effects of resveratrol on the chronic colonic injury caused by intracolonic instillation of trinitrobenzenesulphonic acid (TNBS) in rats. The inflammatory response was assessed by histology and myeloperoxidase activity. Tumour necrosis factor alpha (TNF-alpha) production, histological and histochemical analysis of the lesions were also carried out. We determined the production of prostaglandin (PG) E2 and D2 in colon mucosa, as well as cyclooxygenase (COX)-1 and -2 and nuclear transcription factor NF-kappa B (NF-kappaB) p65 protein expression. Finally, since resveratrol has been found to modulate apoptosis, we intended to elucidate its effects on colonic mucosa under chronic inflammatory conditions. Resveratrol (10 mg kg(-1) day(-1)) significantly attenuated the damage score and corrected the disturbances in morphology associated to injury. In addition, the degree of neutrophil infiltration and the levels of TNF-alpha were significantly ameliorated. Resveratrol did not modify PGD2 levels but returned the decreased PGE2 values to basal levels and also reduced COX-2 and the NF-kappaB p65 protein expression. Furthermore, treatment of rats with resveratrol caused a significant increase of TNBS-induced apoptosis in colonic cells. In conclusion, resveratrol reduces the damage in chronic experimentally induced colitis, alleviates the oxidative events, returns PGE2 production to basal levels and stimulates apoptosis in colonic cells.