Use of the H3 receptor antagonist radioligand [3H]-A-349821 to reveal in vivo receptor occupancy of cognition enhancing H3 receptor antagonists

Background and purpose:

The histamine H₃ receptor antagonist radioligand [³H]-A-349821 was characterized as a radiotracer for assessing in vivo receptor occupancy by H₃ receptor antagonists that affect behaviour. This model was established as an alternative to ex vivo binding methods, for relating antagonist H₃ receptor occupancy to blood levels and efficacy in preclinical models.

Experimental approach:

In vivo cerebral cortical H₃ receptor occupancy by [³H]-A-349821 was determined in rats from differences in [³H]-A-349821 levels in the isolated cortex and cerebellum, a brain region with low levels of H₃ receptors. Comparisons were made to relate antagonist H₃ receptor occupancy to blood levels and efficacy in a preclinical model of cognition, the five-trial inhibitory avoidance response in rat pups.

Key results:

In adult rats, [³H]-A-349821, 1.5 µg·kg⁻¹, penetrated into the brain and cleared more rapidly from cerebellum than cortex; optimally, [³H]-A-349821 levels were twofold higher in the latter. With increasing [³H]-A-349821 doses, cortical H₃ receptor occupancy was saturable with a binding capacity consistent with in vitro binding in cortex membranes. In studies using tracer [³H]-A-349821 doses, ABT-239 and other H₃ receptor antagonists inhibited H₃ receptor occupancy by [³H]-A-349821 in a dose-dependent manner. Blood levels of the antagonists corresponding to H₃ receptor occupancy were consistent with blood levels associated with efficacy in the five-trial inhibitory avoidance response.

Conclusions and implications:

When employed as an occupancy radiotracer, [³H]-A-349821 provided valid measurements of in vivo H₃ receptor occupancy, which may be helpful in guiding and interpreting clinical studies of H₃ receptor antagonists.     

Novel histamine H4 receptor ligands and their potential therapeutic applications: an update

Introduction: Histamine H₄ receptor (H₄R) has been shown to be involved in various inflammatory conditions. Ligands acting on H₄R show therapeutic potential in various diseases. For the first time, the positive proof-of-concept clinical trials of the H₄ antagonist JNJ39758979 have demonstrated this potential in histamine-induced pruritus. Besides role of H₄R in inflammatory conditions, preclinical results in cancer, neuropathic pain, vestibular disorders and type 2 diabetes show the diverse signaling network modulated by H₄R. This suggests further potential for H₄ ligands in such diseases.

Areas covered: In this review, we have summarized patent applications and papers of the H₄R field published between 2012 and 2014. Additionally, we have analyzed the quality of the already described H₄ ligands in terms of their ligand efficiency, lipophilic ligand efficiency and lipophilicity-corrected ligand efficiency.

Expert opinion: We demonstrate that the number of published patent applications reached a maximum in 2009 and showed some decrease in the last few years. On the other hand, the field is still very lively, reflected by the numerous publications on novel potential therapeutic applications. The favorable property profile of H₄ ligands in development shows promise for the upcoming human clinical trials.     

Histamine H3 receptor antagonists in relation to epilepsy and neurodegeneration: a systemic consideration of recent progress and perspectives

The central histaminergic actions are mediated by H₁, H₂, H₃ and H₄ receptors. The histamine H₃ receptor regulates the release of histamine and a number of other neurotransmitters and thereby plays a role in cognitive and homeostatic processes. Elevated histamine levels suppress seizure activities and appear to confer neuroprotection. The H₃ receptors have a number of enigmatic features like constitutive activity, interspecies variation, distinct ligand binding affinities and differential distribution of prototypic splice variants in the CNS. Furthermore, this Gi/Go-protein-coupled receptor modulates several intracellular signalling pathways whose involvement in epilepsy and neurotoxicity are yet to be ascertained and hence represent an attractive target in the search for new anti-epileptogenic drugs. So far, H₃ receptor antagonists/inverse agonists have garnered a great deal of interest in view of their promising therapeutic properties in various CNS disorders including epilepsy and related neurotoxicity. However, a number of experiments have yielded opposing effects. This article reviews recent works that have provided evidence for diverse mechanisms of antiepileptic and neuroprotective effects that were observed in various experimental models both in vitro and in vivo. The likely reasons for the apparent disparities arising from the literature are also discussed with the aim of establishing a more reliable basis for the future use of H₃ receptor antagonists, thus improving their utility in epilepsy and associated neurotoxicity.     

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

GSK207040 (5-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-2-pyrazinecarboxamide) and GSK334429 (1-(1-methylethyl)-4-({1-[6-(trifluoromethyl)-3-pyridinyl]-4-piperidinyl}carbonyl)hexahydro-1H-1,4-diazepine) are novel and selective non-imidazole histamine H(3) receptor antagonists from distinct chemical series with high affinity for human (pK(i)=9.67+/-0.06 and 9.49+/-0.09, respectively) and rat (pK(i)=9.08+/-0.16 and 9.12+/-0.14, respectively) H(3) receptors expressed in cerebral cortex. At the human recombinant H(3) receptor, GSK207040 and GSK334429 were potent functional antagonists (pA(2)=9.26+/-0.04 and 8.84+/-0.04, respectively versus H(3) agonist-induced changes in cAMP) and exhibited inverse agonist properties (pIC(50)=9.20+/-0.36 and 8.59+/-0.04 versus basal GTPgammaS binding). Following oral administration, GSK207040 and GSK334429 potently inhibited cortical ex vivo [(3)H]-R-alpha-methylhistamine binding (ED(50)=0.03 and 0.35 mg/kg, respectively). Functional antagonism of central H(3) receptors was demonstrated by blockade of R-alpha-methylhistamine-induced dipsogenia in rats (ID(50)=0.02 and 0.11 mg/kg p.o. for GSK207040 and GSK334429, respectively). In more pathophysiologically relevant pharmacodynamic models, GSK207040 (0.1, 0.3, 1 and 3mg/kg p.o.) and GSK334429 (0.3, 1 and 3mg/kg p.o.) significantly reversed amnesia induced by the cholinergic antagonist scopolamine in a passive avoidance paradigm. In addition, GSK207040 (0.1, 0.3 and 1mg/kg p.o.) and GSK334429 (3 and 10mg/kg p.o.) significantly reversed capsaicin-induced reductions in paw withdrawal threshold, suggesting for the first time that blockade of H(3) receptors may be able to reduce tactile allodynia. Novel H(3) receptor antagonists such as GSK207040 and GSK334429 may therefore have therapeutic potential not only in dementia but also in neuropathic pain.     

The histamine H3 receptor: an attractive target for the treatment of cognitive disorders

The histamine H3 receptor, first described in 1983 as a histamine autoreceptor and later shown to also function as a heteroreceptor that regulates the release of other neurotransmitters, has been the focus of research by numerous laboratories as it represents an attractive drug target for a number of indications including cognition. The purpose of this review is to acquaint the reader with the current understanding of H3 receptor localization and function as a modulator of neurotransmitter release and its effects on cognitive processes, as well as to provide an update on selected H3 antagonists in various states of preclinical and clinical advancement. Blockade of centrally localized H3 receptors by selective H3 receptor antagonists has been shown to enhance the release of neurotransmitters such as histamine, ACh, dopamine and norepinephrine, among others, which play important roles in cognitive processes. The cognitive-enhancing effects of H3 antagonists across multiple cognitive domains in a wide number of preclinical cognition models also bolster confidence in this therapeutic approach for the treatment of attention deficit hyperactivity disorder, Alzheimer's disease and schizophrenia. However, although a number of clinical studies examining the efficacy of H3 receptor antagonists for a variety of cognitive disorders are currently underway, no clinical proof of concept for an H3 receptor antagonist has been reported to date. The discovery of effective H3 antagonists as therapeutic agents for the novel treatment of cognitive disorders will only be accomplished through continued research efforts that further our insights into the functions of the H3 receptor.     

New H1/H3 antagonists for treating allergic rhinitis: WO2010094643

This application claims dual receptor specificity antihistamines, active as H₁ and H₃ antagonists, which additionally have a long duration of action that renders them suitable for once daily administration via inhalation for the treatment of allergic rhinitis. The compounds lack CNS penetration and have a high affinity for both histamine receptors.     

Long-acting muscarinic M3 receptor antagonists

Two applications claim a novel class of muscarinic M₃ receptor antagonists and their use as long-acting agents for the treatment of chronic obstructive pulmonary disease. The two applications claim closely related structures with one claiming quaternary amine salts of the tertiary amines claimed in the other. The claimed compounds comprise a biarylmethylamine core with the amino group modified by acylation or sulfonation and a tertiary or quaternary amine coupled to the distal ring of the biaryl system.     

Interactions of antagonists with subtypes of inositol 1,4,5-trisphosphate (IP3) receptor

BACKGROUND AND PURPOSE

Inositol 1,4,5-trisphosphate receptors (IP₃Rs) are intracellular Ca²⁺ channels. Interactions of the commonly used antagonists of IP₃Rs with IP₃R subtypes are poorly understood.

EXPERIMENTAL APPROACH

IP₃-evoked Ca²⁺ release from permeabilized DT40 cells stably expressing single subtypes of mammalian IP₃R was measured using a luminal Ca²⁺ indicator. The effects of commonly used antagonists on IP₃-evoked Ca²⁺ release and ³H-IP₃ binding were characterized.

KEY RESULTS

Functional analyses showed that heparin was a competitive antagonist of all IP₃R subtypes with different affinities for each (IP₃R3 > IP₃R1 ≥ IP₃R2). This sequence did not match the affinities for heparin binding to the isolated N-terminal from each IP₃R subtype. 2-aminoethoxydiphenyl borate (2-APB) and high concentrations of caffeine selectively inhibited IP₃R1 without affecting IP₃ binding. Neither Xestospongin C nor Xestospongin D effectively inhibited IP₃-evoked Ca²⁺ release via any IP₃R subtype.

CONCLUSIONS AND IMPLICATIONS

Heparin competes with IP₃, but its access to the IP₃-binding core is substantially hindered by additional IP₃R residues. These interactions may contribute to its modest selectivity for IP₃R3. Practicable concentrations of caffeine and 2-APB inhibit only IP₃R1. Xestospongins do not appear to be effective antagonists of IP₃Rs.     

Characterization of histamine H3 receptors in Alzheimer's Disease brain and amyloid over-expressing TASTPM mice

Background and purpose:

Histamine H₃ receptor antagonists are currently being evaluated for their potential use in a number of central nervous system disorders including Alzheimer''s Disease (AD). To date, little is known about the state of H₃ receptors in AD.

Experimental approach:

In the present study we used the radiolabelled H₃ receptor antagonist [³H]GSK189254 to investigate H₃ receptor binding in the amyloid over-expressing double mutant APPswe × PSI.MI46V (TASTPM) transgenic mouse model of AD and in post-mortem human AD brain samples.

Key results:

No significant differences in specific H₃ receptor binding were observed between wild type and TASTPM mice in the cortex, hippocampus or hypothalamus. Specific [³H]GSK189254 binding was detected in sections of human medial frontal cortex from AD brains of varying disease severity (Braak stages I–VI). With more quantitative analysis in a larger cohort, we observed that H₃ receptor densities were not significantly different between AD and age-matched control brains in both frontal and temporal cortical regions. However, within the AD group, [³H]GSK189254 binding density in frontal cortex was higher in individuals with more severe dementia prior to death.

Conclusions and implications:

The maintenance of H₃ receptor integrity observed in the various stages of AD in this study is important, given the potential use of H₃ antagonists as a novel therapeutic approach for the symptomatic treatment of AD.     

Pharmacological characterization of GSK1004723, a novel, long-acting antagonist at histamine H(1) and H(3) receptors

BACKGROUND AND PURPOSE

Preclinical pharmacological characterization of GSK1004723, a novel, dual histamine H₁ and H₃ receptor antagonist.

EXPERIMENTAL APPROACH

GSK1004723 was characterized in vitro and in vivo using methods that included radioligand binding, intracellular calcium mobilization, cAMP production, GTPγS binding, superfused human bronchus and guinea pig whole body plethysmography.

KEY RESULTS

In cell membranes over-expressing human recombinant H₁ and H₃ receptors, GSK1004723 displayed high affinity, competitive binding (H₁ pKi = 10.2; H₃ pKi = 10.6). In addition, GSK1004723 demonstrated slow dissociation from both receptors with a t_1/2 of 1.2 and 1.5 h for H₁ and H₃ respectively. GSK1004723 specifically antagonized H₁ receptor mediated increases in intracellular calcium and H₃ receptor mediated increases in GTPγS binding. The antagonism exerted was retained after cell washing, consistent with slow dissociation from H₁ and H₃ receptors. Duration of action was further evaluated using superfused human bronchus preparations. GSK1004723 (100 nmol·L⁻¹) reversed an established contractile response to histamine. When GSK1004723 was removed from the perfusate, only 20% recovery of the histamine response was observed over 10 h. Moreover, 21 h post-exposure to GSK1004723 there remained almost complete antagonism of responses to histamine. In vivo pharmacology was studied in conscious guinea pigs in which nasal congestion induced by intranasal histamine was measured indirectly (plethysmography). GSK1004723 (0.1 and 1 mg·mL⁻¹ intranasal) antagonized the histamine-induced response with a duration of up to 72 h.

CONCLUSIONS AND IMPLICATIONS

GSK1004723 is a potent and selective histamine H₁ and H₃ receptor antagonist with a long duration of action and represents a potential novel therapy for allergic rhinitis.     

The brain H3-receptor as a novel therapeutic target for vigilance and sleep-wake disorders

Brain histaminergic neurons play a prominent role in arousal and maintenance of wakefulness (W). H(3)-receptors control the activity of histaminergic neurons through presynaptic autoinhibition. The role of H(3)-receptor antagonists/inverse agonists (H(3)R-antagonists) in the potential therapy of vigilance deficiency and sleep-wake disorders were studied by assessing their effects on the mouse cortical EEG and sleep-wake cycle in comparison to modafinil and classical psychostimulants. The H(3)R-antagonists, thioperamide and ciproxifan increased W and cortical EEG fast rhythms and, like modafinil, but unlike amphetamine and caffeine, their waking effects were not accompanied by sleep rebound. Conversely, imetit (H(3)R-agonist) enhanced slow wave sleep and dose-dependently attenuated ciproxifan-induced W, indicating that the effects of both ligands involve H(3)-receptor mechanisms. Additional studies using knockout (KO) mice confirmed the essential role of H(3)-receptors and histamine-mediated transmission in the wake properties of H(3)R-antagonists. Thus ciproxifan produced no increase in W in either histidine-decarboxylase (HDC, histamine-synthesizing enzyme) or H(1)- or H(3)-receptor KO-mice whereas its waking effects persisted in H(2)-receptor KO-mice. These data validate the hypothesis that H(3)R-antagonists, through disinhibition of H(3)-autoreceptors, enhancing synaptic histamine that in turn activates postsynaptic H(1)-receptors promoting W. Interestingly amphetamine and modafinil, despite their potent arousal effects, appear unlikely to depend on histaminergic mechanism as their effects still occurred in HDC KO-mice. The present study thus distinguishes two classes of wake-improving agents: the first acting through non-histaminergic mechanisms and the second acting via histamine and supports brain H(3)-receptors as potentially novel therapeutic targets for vigilance and sleep-wake disorders.     

Progress in the development of histamine H3 receptor antagonists/inverse agonists: a patent review (2013-2017)

Introduction: Since years, ligands blocking histamine H₃ receptor (H₃R) activity (antagonists/inverse agonists) are interesting targets in the search for new cures for CNS disorders. Intensive works done by academic and pharmaceutical company researchers have led to many potent and selective H₃R antagonists/inverse agonists. Some of them have reached to clinical trials.

Areas covered: Patent applications from January 2013 to September 2017 and the most important topics connected with H₃R field are analysed. Espacenet, Patentscope, Pubmed, GoogleScholar or Cochrane Library online databases were principially used to collect all the materials.

Expert opinion: The research interest in histamine H₃R field is still high although the number of patent applications has decreased during the past 4 years (around 20 publications). Complexity of histamine H₃R biology e.g. many isoforms, constitutive activity, heteromerization with other receptors (dopamine D₂, D₁, adenosine A_2A) and pharmacology make not easy realization and evaluation of therapeutic potential of anti-H₃R ligands. First results from clinical trials have verified potential utility of histamine H₃R antagonist/inverse agonists in some diseases. However, more studies are necessary for better understanding of an involvement of the histaminergic system in CNS-related disorders and helping more ligands approach to clinical trials and the market.

Lists of abbreviations: hAChEI – human acetylcholinesterase inhibitor; hBuChEI – human butyrylcholinesterase inhibitor; hMAO – human monoamine oxidase; MAO – monoamine oxidase     

Novel heterocyclic-substituted benzofuran histamine H3 receptor antagonists: in vitro properties, drug-likeness, and behavioral activity

Three novel heterocyclic benzofurans A-688057 (1), A-687136 (2), and A-698418 (3) were profiled for their in vitro and in vivo properties as a new series of histamine H(3) receptor antagonists. The compounds were all found to have nanomolar potency in vitro at histamine H(3) receptors, and when profiled in vivo for CNS activity, all were found active in an animal behavioral model of attention. The compound with the most benign profile versus CNS side effects was selected for greater scrutiny of its in vitro properties and overall drug-likeness. This compound, A-688057, in addition to its potent and robust efficacy in two rodent behavioral models at blood levels ranging 0.2-19 nM, possessed other favorable features, including high selectivity for H(3) receptors (H(3), K(i)=1.5 nM) versus off-target receptors and channels (including the hERG K(+) channel, K(i)>9000 nM), low molecular weight (295), high solubility, moderate lipophilicity (logD(pH7.4)=2.05), and good CNS penetration (blood/brain 3.4x). In vitro toxicological tests indicated low potential for phospholipidosis, genotoxicity, and CYP(450) inhibition. Even though pharmacokinetic testing uncovered only moderate to poor oral bioavailability in rat (26%), dog (30%), and monkey (8%), and only moderate blood half-lives after i.v. administration (t(1/2) in rat of 2.9h, 1.7h in dog, 1.8h in monkey), suggesting poor human pharmacokinetics, the data overall indicated that A-688057 has an excellent profile for use as a pharmacological tool compound.     

Prostaglandin D2 receptor antagonists in early development as potential therapeutic options for asthma

Introduction: Asthma is a chronic inflammatory disease characterized by bronchial hyper-reactivity. Although many currently available treatment regimens are effective, poor symptom control and refractory severe disease still represent major unmet needs. In the last years, numerous molecular therapeutic targets that interfere with the innate inflammatory response in asthma have been identified. Promising preliminary results concern the signaling cascade promoted by prostaglandin D2 (PGD2) and its receptor antagonists.

Areas covered: The aim of this review is to provide the most recent clinical and preclinical data on the efficacy and safety of newly developed compounds for the treatment of allergic asthma. The authors will present an overview of the pathogenetic molecular mechanisms sustaining the chronic inflammatory response in asthma; the focus will be then directed on the mediators of the PGD2 pathway, the chemoattractant receptor-homologous molecule expressed on TH2 cells, and their latest antagonists developed.

Expert opinion: Bronchodilators and corticosteroids are not sufficient to achieve a satisfactory management of all asthmatic patients; the development of new specific treatments appears therefore essential. The good results in terms of cellular, functional and clinical outcomes, together with an acceptable safety of the CRTh2 antagonists represent a promising start for a tailored management of allergic asthma.     

Genetic knockout and pharmacological blockade studies of the 5-HT7 receptor suggest therapeutic potential in depression

The affinity of several antidepressant and antipsychotic drugs for the 5-HT7 receptor and its CNS distribution suggest potential in the treatment of psychiatric diseases. However, there is little direct evidence of receptor function in vivo to support this. We therefore evaluated 5-HT7 receptors as a potential drug target by generating and assessing a 5-HT7 receptor knockout mouse. No difference in assays sensitive to potential psychotic or anxiety states was observed between the 5-HT7 receptor knockout mice and wild type controls. However, in the Porsolt swim test, 5-HT7 receptor knockout mice showed a significant decrease in immobility compared to controls, a phenotype similar to antidepressant treated mice. Intriguingly, treatment of wild types with SB-258719, a selective 5-HT7 receptor antagonist, did not produce a significant decrease in immobility unless animals were tested in the dark (or active) cycle, rather than the light, adding to the body of evidence suggesting a circadian influence on receptor function. Extracellular recordings from hypothalamic slices showed that circadian rhythm phase shifts to 8-OH-DPAT are attenuated in the 5-HT7 receptor KO mice also indicating a role for the receptor in the regulation of circadian rhythms. These pharmacological and genetic knockout studies provide the first direct evidence that 5-HT7 receptor antagonists should be investigated for efficacy in the treatment of depression.     

Histamine is required for H3 receptor-mediated alcohol reward inhibition,but not for alcohol consumption or stimulation

Background and Purpose

Conflicting data have been published on whether histamine is inhibitory to the rewarding effects of abused drugs. The purpose of this study was to clarify the role of neuronal histamine and, in particular, H₃ receptors in alcohol dependence-related behaviours, which represent the addictive effects of alcohol.

Experimental Approach

Alcohol-induced conditioned place preference (alcohol-CPP) was used to measure alcohol reward. Alcohol-induced locomotor stimulation, alcohol consumption and kinetics were also assessed. mRNA levels were quantified using radioactive in situ hybridization.

Key Results

Low doses of H₃ receptor antagonists, JNJ-10181457 and JNJ-39220675, inhibited alcohol reward in wild-type (WT) mice. However, these H₃ receptor antagonists did not inhibit alcohol reward in histidine decarboxylase knock-out (HDC KO) mice and a lack of histamine did not alter alcohol consumption. Thus H₃ receptor antagonists inhibited alcohol reward in a histamine-dependent manner. Furthermore, WT and HDC KO mice were similarly stimulated by alcohol. The expression levels of dopamine D₁ and D₂ receptors, STEP61 and DARPP-32 mRNA in striatal subregions were unaltered in HDC KO mice. No differences were seen in alcohol kinetics in HDC KO compared to WT control animals. In addition, JNJ-39220675 had no effect on alcohol kinetics in WT mice.

Conclusions and Implications

These data suggest that histamine is required for the H₃ receptor-mediated inhibition of alcohol-CPP and support the hypothesis that the brain histaminergic system has an inhibitory role in alcohol reward. Increasing neuronal histamine release via H₃ receptor blockade could therefore be a novel way of treating alcohol dependence.

Linked Articles

This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1     

5-HT1A receptor ligands and their therapeutic applications: review of new patents

Introduction: 5-HT_1AR was one of the first discovered serotonin receptors and is one of the most thoroughly studied. Dysfunctions associated with 5-HT_1AR neurotransmission are linked to several psychiatric disorders, including anxiety, depression, and movement disorders.

Areas covered: The current review covers patent literature published between January 2012 and May 2018. Queries were performed on Espacenet, SciFinder, clinicaltrials.gov, pharmacodia.com, and the websites of pharmaceutical companies.

Expert opinion: Several novel therapeutic applications have been proposed for 5-HT_1AR ligands, i.e. prostate cancer treatment, gastrointestinal and cardiopulmonary disorders, facilitation of urination and defecation, and L-DOPA-induced dyskinesia. Interestingly, no patent application has been filed by big pharma companies, while numerous researches are being conducted in smaller companies and academia.     

Antidepressant and anxiolytic profiles of newly synthesized arginine vasopressin V1B receptor antagonists: TASP0233278 and TASP0390325

BACKGROUND AND PURPOSE

Vasopressin V_1B receptor antagonists may be effective for the treatment of depression and anxiety and the objective of this study was to characterize the pharmacological profiles of two newly synthesized arginine vasopressin receptor 1B (V_1B receptor) antagonists, TASP0233278 and TASP0390325.

EXPERIMENTAL APPROACH

We investigated the in vitro profiles of TASP0233278 and TASP0390325. In addition, the effect of TASP0390325 on the increase in plasma adrenocorticotropic hormone (ACTH) levels induced by corticotropin-releasing factor (CRF)/desmopressin (dDAVP) was investigated. We also investigated the antidepressant and anxiolytic profiles of TASP0233278 and TASP0390325 in animal models.

KEY RESULTS

Both TASP0233278 and TASP0390325 showed a high affinity and potent antagonist activity for V_1B receptors. Oral administration of TASP0390325 antagonized the increase in plasma ACTH levels induced by CRF/dDAVP in rats, indicating that TASP0390325 blocks the anterior pituitary V_1B receptor in vivo. Oral administration of TASP0233278 or TASP0390325 also exerted antidepressant effects in two models of depression (a forced swimming test and an olfactory bulbectomy model). Moreover, TASP0233278 improved depressive-like behaviour induced by repeated treatment with corticosterone, a model that has been shown to be resistant to treatment with currently prescribed antidepressants. In addition to depression models, TASP0233278 or TASP0390325 exerted anxiolytic effects in several anxiety models (social interaction, elevated plus-maze, stress-induced hyperthermia, separation-induced ultrasonic vocalization and sodium lactate-induced panic-like responses in panic-prone rats).

CONCLUSION

TASP0233278 and TASP0390325 are potent and orally active V_1B receptor antagonists with antidepressant and anxiolytic activities in rodents.     

Synthetic and plant-derived cannabinoid receptor antagonists show hypophagic properties in fasted and non-fasted mice

Background and purpose:

Obesity is a severe health problem in the modernized world and understanding the central nervous mechanisms underlying food-seeking behaviour and reward are at the forefront of medical research. Cannabinoid receptors have proven an efficient target to suppress hunger and weight gain by their pharmacological inactivation.

Experimental approach:

A standard fasted protocol and a novel long-term home-cage observation system with free-feeding animals were used to assess the feeding behaviour of mice treated with the CB₁ antagonist AM251. Similarly, the effects of the phytocannabinoid Δ⁹-tetrahydrocannabivarin (Δ⁹-THCV), which behaves like a CB₁ antagonist, were also determined in free-feeding animals.

Key results:

AM251 suppressed food intake and weight gain in fasted and non-fasted animals. The suppression of food intake by AM251 (10 mg·kg⁻¹) endured for a period of 6–8 h when administered acutely, and was continuous when injected for four consecutive days. Pure Δ⁹-THCV also induced hypophagia and weight reduction at doses as low as 3 mg·kg⁻¹. No rebound was observed on the following day with all drug groups returning to normal activity and feeding regimes. However, a Δ⁹-THCV-rich cannabis-extract failed to suppress food intake and weight gain, possibly due to residual Δ⁹-tetrahydrocannabinol (Δ⁹-THC) in the extract. This Δ⁹-THC effect was overcome by the co-administration of cannabidiol.

Conclusions and implications:

The data strongly suggest (i) the long-term home-cage observation system is a sensitive and obesity-relevant tool, and (ii) the phytocannabinoid Δ⁹-THCV is a novel compound with hypophagic properties and a potential treatment for obesity.