Use of an inverse agonist radioligand [3H]A-317920 reveals distinct pharmacological profiles of the rat histamine H3 receptor

Witte, David G.; Miller, Thomas R.; Carr, Tracy L.; Kang, Chae Hee; Cassar, Steven; Faghih, Ramin; Bennani, Youssef L.; Surber, Bruce W.; Hancock, Arthur A.; Esbenshade, Timothy A.

doi:10.1016/j.neuropharm.2005.10.008

Cited by 12 publications

(11 citation statements)

References 30 publications

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“…However, inverse agonist radioligands label a much larger population of H 3 Rs than agonist radioligands such as [ 125 I]iodoproxyfan Yao et al, 2006;Mezzomo et al, 2007). Therefore, inactive conformations with high affinity for betahistine are not expected to be labeled by [ 125 I]iodoproxyfan.…”

Section: Discussionmentioning

confidence: 99%

Effects of Betahistine at Histamine H₃Receptors: Mixed Inverse Agonism/Agonism In Vitro and Partial Inverse Agonism In Vivo

Gbahou

Davenas²,

Morisset-Lopez³

et al. 2010

J Pharmacol Exp Ther

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We previously suggested that therapeutic effects of betahistine in vestibular disorders result from its antagonist properties at histamine H 3 receptors (H 3 Rs). However, H 3 Rs exhibit constitutive activity, and most H 3 R antagonists act as inverse agonists. Here, we have investigated the effects of betahistine at recombinant H 3 R isoforms. On inhibition of cAMP formation and [3 H]arachidonic acid release, betahistine behaved as a nanomolar inverse agonist and a micromolar agonist. Both effects were suppressed by pertussis toxin, were found at all isoforms tested, and were not detected in mock cells, confirming interactions at H 3 Rs. The inverse agonist potency of betahistine and its affinity on [125 I]iodoproxyfan binding were similar in rat and human. We then investigated the effects of betahistine on histamine neuron activity by measuring tele-methylhistamine (t-MeHA) levels in the brains of mice. Its acute intraperitoneal administration increased t-MeHA levels with an ED 50 of 0.4 mg/kg, indicating inverse agonism. At higher doses, tMeHA levels gradually returned to basal levels, a profile probably resulting from agonism. After acute oral administration, betahistine increased t-MeHA levels with an ED 50 of 2 mg/kg, a rightward shift probably caused by almost complete first-pass metabolism. In each case, the maximal effect of betahistine was lower than that of ciproxifan, indicating partial inverse agonism. After an oral 8-day treatment, the only effective dose of betahistine was 30 mg/kg, indicating that a tolerance had developed. These data strongly suggest that therapeutic effects of betahistine result from an enhancement of histamine neuron activity induced by inverse agonism at H 3 autoreceptors.

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Section: Discussionmentioning

confidence: 99%

Effects of Betahistine at Histamine H₃Receptors: Mixed Inverse Agonism/Agonism In Vitro and Partial Inverse Agonism In Vivo

Gbahou

Davenas²,

Morisset-Lopez³

et al. 2010

J Pharmacol Exp Ther

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“…This inverse agonist exhibiting good overall pharmacokinetic properties to become a potent (pK i ϭ 8.2), short acting ligand is a substrate of gp-1, which makes peroral application difficult. 143) More approaches to developing non-imidazole-containing PET [144][145][146] or fluorescence ligands have been reported. [147][148][149] Fluorescence-like ligands published by Schering Plough contain 2-(pyridin-2-yl)-1H-benzo[d]imidazoles added to the piperidine-propoxy-phenyl H 3 R scaffold.…”

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 identification of two distinct binding sites at the same receptor is somehow surprising, but it is supported by experimental results. First, by competition experiments [27,28,29], different agonists (imetit, (R)-amethylhistamine, N-a-amethylhistamine) have been shown to recognize two sites. On the contrary, a unique site has been described for antagonists [28,29].…”

Section: Resultsmentioning

confidence: 99%

“…First, by competition experiments [27,28,29], different agonists (imetit, (R)-amethylhistamine, N-a-amethylhistamine) have been shown to recognize two sites. On the contrary, a unique site has been described for antagonists [28,29]. In accordance with these observations, agonists may bind the A or B site in our model, but antagonists are specific to the A site.…”

Section: Resultsmentioning

confidence: 99%

Refined Docking as a Valuable Tool for Lead Optimization: Application to Histamine H₃ Receptor Antagonists

Levoin

Calmels

Poupardin-Olivier

et al. 2008

Archiv der Pharmazie

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Drug-discovery projects frequently employ structure-based information through protein modeling and ligand docking, and there is a plethora of reports relating successful use of them in virtual screening. Hit/lead optimization, which represents the next step and the longest for the medicinal chemist, is very rarely considered. This is not surprising because lead optimization is a much more complex task. Here, a homology model of the histamine H(3) receptor was built and tested for its ability to discriminate ligands above a defined threshold of affinity. In addition, drug safety is also evaluated during lead optimization, and "antitargets" are studied. So, we have used the same benchmarking procedure with the HERG channel and CYP2D6 enzyme, for which a minimal affinity is strongly desired. For targets and antitargets, we report here an accuracy as high as at least 70%, for ligands being classified above or below the chosen threshold. Such a good result is beyond what could have been predicted, especially, since our test conditions were particularly stringent. First, we measured the accuracy by means of AUC of ROC plots, i. e. considering both false positive and false negatives. Second, we used as datasets extensive chemical libraries (nearly a thousand ligands for H(3)). All molecules considered were true H(3) receptor ligands with moderate to high affinity (from microM to nM range). Third, the database is issued from concrete SAR (Bioprojet H(3) BF2.649 library) and is not simply constituted by few active ligands buried in a chemical catalogue.

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Use of an inverse agonist radioligand [3H]A-317920 reveals distinct pharmacological profiles of the rat histamine H3 receptor

Cited by 12 publications

References 30 publications

Effects of Betahistine at Histamine H₃Receptors: Mixed Inverse Agonism/Agonism In Vitro and Partial Inverse Agonism In Vivo

Effects of Betahistine at Histamine H₃Receptors: Mixed Inverse Agonism/Agonism In Vitro and Partial Inverse Agonism In Vivo

Histamine H3 Receptor Antagonists Go to Clinics

Refined Docking as a Valuable Tool for Lead Optimization: Application to Histamine H₃ Receptor Antagonists

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Use of an inverse agonist radioligand [3H]A-317920 reveals distinct pharmacological profiles of the rat histamine H3 receptor

Cited by 12 publications

References 30 publications

Effects of Betahistine at Histamine H3Receptors: Mixed Inverse Agonism/Agonism In Vitro and Partial Inverse Agonism In Vivo

Effects of Betahistine at Histamine H3Receptors: Mixed Inverse Agonism/Agonism In Vitro and Partial Inverse Agonism In Vivo

Histamine H3 Receptor Antagonists Go to Clinics

Refined Docking as a Valuable Tool for Lead Optimization: Application to Histamine H3 Receptor Antagonists

Contact Info

Product

Resources

About

Effects of Betahistine at Histamine H₃Receptors: Mixed Inverse Agonism/Agonism In Vitro and Partial Inverse Agonism In Vivo

Effects of Betahistine at Histamine H₃Receptors: Mixed Inverse Agonism/Agonism In Vitro and Partial Inverse Agonism In Vivo

Refined Docking as a Valuable Tool for Lead Optimization: Application to Histamine H₃ Receptor Antagonists