Structurally novel histamine H3 receptor antagonists GSK207040 and GSK334429 improve scopolamine-induced memory impairment and capsaicin-induced secondary allodynia in rats

Medhurst, Andrew D.; Briggs, Michael A.; Bruton, Gordon; Calver, Andrew R.; Chessell, Iain P.; Crook, Barry; Davis, John B.; Davis, Robert P.; Foley, Andrew; Heslop, Teresa; Hirst, Warren D.; Medhurst, Stephen J.; Ociepka, Sandrine; Ray, Alison M.; Regan, Ciaran M.; Sargent, Becky; Schogger, Joanne; Stean, Tania O.; Trail, Brenda; Upton, Neil; White, Trevor; Orlek, Barry S.; Wilson, David M.

doi:10.1016/j.bcp.2007.01.007

Cited by 58 publications

(42 citation statements)

References 68 publications

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“…Because many of these drugs are new, however, their pain-relieving properties have not been fully evaluated. Two new orally active H 3 inverse agonists had no activity on mechanical paw withdrawal thresholds in normal rats, but inhibited capsaicin-induced mechanical allodynia by 20 to 65% over a range of doses (Medhurst et al, 2007). In a follow-up study (Medhurst et al, 2008), chronic oral dosing (5-8 days) with brain-penetrating H 3 inverse agonists reversed mechanical hyperalgesia in the chronic constriction injury model.…”

Section: Downloaded Frommentioning

confidence: 96%

H₃ Receptors and Pain Modulation: Peripheral, Spinal, and Brain Interactions

Hough¹,

Rice²

2010

J Pharmacol Exp Ther

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Histamine H 3 receptors (H 3 Rs), distributed within the brain, the spinal cord, and on specific types of primary sensory neurons, can modulate pain transmission by several mechanisms. In the skin, H 3 Rs are found on certain A␤ fibers, and on keratinocytes and Merkel cells, as well as on deep dermal, peptidergic A␦ fibers terminating on deep dermal blood vessels. Activation of H 3 Rs on the latter in the skin, heart, lung, and dura mater reduces calcitonin gene-related peptide and substance P release, leading to anti-inflammatory (but not antinociceptive) actions. However, activation of H 3 Rs on the spinal terminals of these sensory fibers reduces nociceptive responding to lowintensity mechanical stimuli and inflammatory stimuli such as formalin. These findings suggest that H 3 R agonists might be useful analgesics, but these drugs have not been tested in clinically relevant pain models. Paradoxically, H 3 antagonists/ inverse agonists have also been reported to attenuate several types of pain responses, including phase II responses to formalin. In the periaqueductal gray (an important pain regulatory center), the H 3 inverse agonist thioperamide releases neuronal histamine and mimics histamine's biphasic modulatory effects in thermal nociceptive tests. Newer H 3 inverse agonists with potent, selective, and brain-penetrating properties show efficacy in several neuropathic and arthritis pain models, but the sites and mechanisms for these actions remain poorly understood. Histamine and PainHistamine, found throughout the body in both neuronal and non-neuronal sources, can modify pain transmission by actions at multiple receptors in the skin, spinal cord, and brain. Rapidly expanding information on the distribution and functions of H 3 receptors (H 3 Rs) and the recent development of new H 3 R ligands have heightened interest in the possible modulation of pain by H 3 R-acting drugs. The present article provides a short, integrative overview of relevant studies (for review see also Sander et al., 2008;Tiligada et al., 2009;Gemkow et al., 2009). Measuring Pain in the LaboratoryPain, which can be defined as the central representation of tissue-damaging stimuli with sensory-discriminative, motivational, and cognitive components (Besson and Chaouch, 1987), is readily understood by humans as a sensory experience. Ideally, evaluation of the pain-relieving properties of drugs should directly measure reductions in pain perception. Instead, assessment of analgesic drug action in nonverbal subjects relies heavily on measures of behavioral, often reflexive, responses. Because drugs can modify these responses (but not necessarily the underlying perceptions), results from pain testing in laboratory animals can be misleading. The present limitations of preclinical methodologies for identifying pain-relieving drugs have been discussed previously Vierck et al., 2008).Notwithstanding the limitations in state-of-the-art analgesic testing, many factors must be considered when evaluating

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Section: Downloaded Frommentioning

confidence: 96%

H₃ Receptors and Pain Modulation: Peripheral, Spinal, and Brain Interactions

Hough¹,

Rice²

2010

J Pharmacol Exp Ther

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“…dementia. 164) In contrast to the latter, GSK334429 is a less rigidized 1,4-diazepane possessing comparable properties to that of GSK189254. It is active in attention and cognition models but what is more important, both, GSK189254 and GSK334429, have recently shown to be efficacious in models of neuropathic pain 165) pointing out a possible additive indication for these short-acting and poor brain penetrating ligands as H 3 R modulates pain reception in the dorsal horn and spinal cord 48) (Fig.…”

Section: )mentioning

confidence: 99%

“…However, recent studies on selective H 3 R inverse agonists, GSK189254 and GSK334429, demonstrate efficacy in models of acute and neuropathic pain. 164,165) In this context, autoradiography studies with [ 3 H]GSK189254 show a distinct H 3 R expression pattern in the dorsal horn of human and rat spinal cord and in human dorsal root ganglion. These areas are generally associated with neurochemical processes on nociceptive conduction by cross-linking peripheral and central pathways of sensitisation.…”

Section: )mentioning

confidence: 99%

Histamine H3 Receptor Antagonists Go to Clinics

Sander

Kottke

Stark

2008

Biological & Pharmaceutical Bulletin

185

118

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INTRODUCTIONThe biogenic amine histamine, 2-(1H-imidazol-4-yl)-ethanamine, is produced by decarboxylation of L-histidine and is implicated in a wide range of physiological and pathophysiological functions. It is metabolised by histamine N tmethyltransferase (HMT) and mono-or diaminoxidase. Histamine is mainly acting via four distinct metabotropic histamine receptor subtypes (H 1 R-H 4 R), which have meanwhile all been cloned. Whereas antagonists for H 1 R and H 2 R subtypes have been blockbusters in therapy of allergy and ulcer, respectively, antagonists for H 3 R and H 4 R subtypes are not on the market. The recently described H 4 R seems to be involved in inflammatory and immunomodulatory processes. H 3 Rs play a central role in neurotransmission of histamine and in control of many other neurotransmitters. Several antagonists are in preclinical and some in clinical stage of development. PHARMACOLOGICAL BACKGROUND Auto-and HeteroreceptorThe H 3 R was first described in 1983 as a presynaptic autoreceptor, which mediates synthesis of histamine and inhibition of its release from histaminergic neurons in slices of rat cerebral cortex. 1) Localisation studies in rodents show a predominance in distinct regions of the central nervous system (CNS) as the H 3 R is mainly located in cerebral cortex, hippocampus, amygdala, nucleus accumbens, globus pallidus, striatum, and hypothalamus 2-5) ( Fig. 1). In addition, it is expressed in the peripheral nervous system, e.g. in gastrointestinal tract, airways and cardiovascular system. 6) Molecular aspects of the receptor, [7][8][9][10] structure-activity relationships (SAR) of ligands, [11][12][13][14][15][16][17][18][19] and pharmacology [20][21][22][23][24][25][26] have recently been resumed in many excellent reviews. This contribution focuses on the development of clinical candidates and the multifaceted potential indications targeted.In mammalian brain histaminergic neurons originate in the tuberomammillary nucleus (TMN) spreading into above mentioned brain regions, where they control histamine levels by regulation of synthesis and liberation rates 27) and modulate different neuronal systems. 28) H 3 R expression is not solely restricted to histaminergic neurons: due to its function as a heteroreceptor it can be found on colocalised neurons, and H 3 R activation modulates the release of various important neurotransmitters, i.e. dopamine, [29][30][31][32][33] acetylcholine, [34][35][36][37] norepinephrine, 38,39) serotonin, 40,41) GABA, [42][43][44] glutamate, 45) and substance P. [46][47][48] Therefore, histaminergic neurons and the cross-linkage between major neurotransmitter systems are involved in many (patho)physiological brain functions, including vigilance, memory processes, feeding behaviour and locomotor activity (Fig. 2). Interneuron cross-talk and adaptive processes seem to be important factors in H 3 Rmediated signalling. Molecular AspectsThe human histamine H 3 receptor (hH 3 R) cDNA firstly described 1999 encodes a 445 amino acid protein and belongs to the his...

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“…The receptor has been associated with cognition and sleep (Onodera et al, 1998;Giovannini et al, 1999;Passani et al, 2004;Fox et al, 2005;Komater et al, 2005;Esbenshade et al, 2008), but more recently there has been emerging data pointing to a role for H 3 in pain modulation (Cannon et al, 2003(Cannon et al, , 2007Cannon and Hough, 2005;Medhurst et al, 2007Medhurst et al, , 2008Hsieh et al, 2010). The H 3 receptor is localized to key sites in the nociceptive system such as the dorsal horn of the spinal cord and several supraspinal regions including the locus coeruleus (LC) (Pillot et al, 2002;Korotkova et al, 2005;Cannon et al, 2007;Medhurst et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…The H 3 receptor is localized to key sites in the nociceptive system such as the dorsal horn of the spinal cord and several supraspinal regions including the locus coeruleus (LC) (Pillot et al, 2002;Korotkova et al, 2005;Cannon et al, 2007;Medhurst et al, 2008). Although there has been some conflicting pharmacological data with H 3 agonists and a nonselective antagonist (Owen et al, 1994;Farzin et al, 2002;Cannon and Hough, 2005), more recent data with selective H 3 receptor antagonists demonstrate a consistent level of efficacy in reducing allodynia and hyperalgesia in models of neuropathic, osteoarthritic, and inflammatory pain (Medhurst et al, 2007(Medhurst et al, , 2008Hsieh et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Antagonism of Supraspinal Histamine H₃ Receptors Modulates Spinal Neuronal Activity in Neuropathic Rats

McGaraughty

Chu

Cowart

et al. 2012

J Pharmacol Exp Ther

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There is growing evidence supporting a role for histamine H 3 receptors in the modulation of pathological pain. To further our understanding of this modulation, we examined the effects of a selective H 3 receptor antagonist, 6-((3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy)-N-methyl-3-pyridinecarboxamide (GSK189254), on spinal neuronal activity in neuropathic (L5 and L6 ligations) and sham rats. Systemic administration of GSK189254 (0.03-1 mg/kg i.v.) dose-dependently decreased both evoked (10-g von Frey hair for 15 s) and spontaneous firing of wide dynamic range (WDR) neurons in neuropathic, but not sham-operated, animals. The effects on spontaneous firing suggest that H 3 receptors may have a role in central sensitization and/or modulating non-evoked pain. Transection of the spinal cord (T9-T10) completely eliminated the effects (both evoked and spontaneous) of systemic GSK189254 (1 mg/kg, i.v.) on WDR neuronal firing in neuropathic rats, indicating that the descending modulatory system has an important role in the H 3 -related dampening of spinal neuronal activity. Subsequently, lesions of the locus coeruleus, or direct GSK189254 (3 and 10 nmol/0.5 l) injections into this site, demonstrate that the locus coeruleus is a key component of the H 3 descending modulatory pathway. In summary, blockade of H 3 receptors reduces spontaneous firing as well as the responses of spinal nociceptive neurons to mechanical stimulation. This effect is in large part mediated via supraspinal sites, including the locus coeruleus, that send descending projections to modulate spinal neuronal activity.

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Structurally novel histamine H3 receptor antagonists GSK207040 and GSK334429 improve scopolamine-induced memory impairment and capsaicin-induced secondary allodynia in rats

Cited by 58 publications

References 68 publications

H₃ Receptors and Pain Modulation: Peripheral, Spinal, and Brain Interactions

H₃ Receptors and Pain Modulation: Peripheral, Spinal, and Brain Interactions

Histamine H3 Receptor Antagonists Go to Clinics

Antagonism of Supraspinal Histamine H₃ Receptors Modulates Spinal Neuronal Activity in Neuropathic Rats

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Structurally novel histamine H3 receptor antagonists GSK207040 and GSK334429 improve scopolamine-induced memory impairment and capsaicin-induced secondary allodynia in rats

Cited by 58 publications

References 68 publications

H3 Receptors and Pain Modulation: Peripheral, Spinal, and Brain Interactions

H3 Receptors and Pain Modulation: Peripheral, Spinal, and Brain Interactions

Histamine H3 Receptor Antagonists Go to Clinics

Antagonism of Supraspinal Histamine H3 Receptors Modulates Spinal Neuronal Activity in Neuropathic Rats

Contact Info

Product

Resources

About

H₃ Receptors and Pain Modulation: Peripheral, Spinal, and Brain Interactions

H₃ Receptors and Pain Modulation: Peripheral, Spinal, and Brain Interactions

Antagonism of Supraspinal Histamine H₃ Receptors Modulates Spinal Neuronal Activity in Neuropathic Rats