共查询到20条相似文献,搜索用时 15 毫秒
1.
Background and purpose:The histamine H 3 receptor antagonist radioligand [ 3H]-A-349821 was characterized as a radiotracer for assessing in vivo receptor occupancy by H 3 receptor antagonists that affect behaviour. This model was established as an alternative to ex vivo binding methods, for relating antagonist H 3 receptor occupancy to blood levels and efficacy in preclinical models. Experimental approach:In vivo cerebral cortical H 3 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 H 3 receptors. Comparisons were made to relate antagonist H 3 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 H 3 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 H 3 receptor antagonists inhibited H 3 receptor occupancy by [ 3H]-A-349821 in a dose-dependent manner. Blood levels of the antagonists corresponding to H 3 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 H 3 receptor occupancy, which may be helpful in guiding and interpreting clinical studies of H 3 receptor antagonists. 相似文献
2.
Introduction: Histamine H 4 receptor (H 4R) has been shown to be involved in various inflammatory conditions. Ligands acting on H 4R show therapeutic potential in various diseases. For the first time, the positive proof-of-concept clinical trials of the H 4 antagonist JNJ39758979 have demonstrated this potential in histamine-induced pruritus. Besides role of H 4R in inflammatory conditions, preclinical results in cancer, neuropathic pain, vestibular disorders and type 2 diabetes show the diverse signaling network modulated by H 4R. This suggests further potential for H 4 ligands in such diseases. Areas covered: In this review, we have summarized patent applications and papers of the H 4R field published between 2012 and 2014. Additionally, we have analyzed the quality of the already described H 4 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 H 4 ligands in development shows promise for the upcoming human clinical trials. 相似文献
3.
The central histaminergic actions are mediated by H 1, H 2, H 3 and H 4 receptors. The histamine H 3 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 H 3 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, H 3 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 H 3 receptor antagonists, thus improving their utility in epilepsy and associated neurotoxicity. 相似文献
4.
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. 相似文献
5.
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. 相似文献
6.
This application claims dual receptor specificity antihistamines, active as H 1 and H 3 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. 相似文献
7.
Two applications claim a novel class of muscarinic M 3 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. 相似文献
8.
BACKGROUND AND PURPOSEInositol 1,4,5-trisphosphate receptors (IP 3Rs) are intracellular Ca 2+ channels. Interactions of the commonly used antagonists of IP 3Rs with IP 3R subtypes are poorly understood. EXPERIMENTAL APPROACHIP 3-evoked Ca 2+ release from permeabilized DT40 cells stably expressing single subtypes of mammalian IP 3R was measured using a luminal Ca 2+ indicator. The effects of commonly used antagonists on IP 3-evoked Ca 2+ release and 3H-IP 3 binding were characterized. KEY RESULTSFunctional analyses showed that heparin was a competitive antagonist of all IP 3R subtypes with different affinities for each (IP 3R3 > IP 3R1 ≥ IP 3R2). This sequence did not match the affinities for heparin binding to the isolated N-terminal from each IP 3R subtype. 2-aminoethoxydiphenyl borate (2-APB) and high concentrations of caffeine selectively inhibited IP 3R1 without affecting IP 3 binding. Neither Xestospongin C nor Xestospongin D effectively inhibited IP 3-evoked Ca 2+ release via any IP 3R subtype. CONCLUSIONS AND IMPLICATIONSHeparin competes with IP 3, but its access to the IP 3-binding core is substantially hindered by additional IP 3R residues. These interactions may contribute to its modest selectivity for IP 3R3. Practicable concentrations of caffeine and 2-APB inhibit only IP 3R1. Xestospongins do not appear to be effective antagonists of IP 3Rs. 相似文献
9.
Background and purpose:Histamine H 3 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 H 3 receptors in AD. Experimental approach:In the present study we used the radiolabelled H 3 receptor antagonist [ 3H]GSK189254 to investigate H 3 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 H 3 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 H 3 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 H 3 receptor integrity observed in the various stages of AD in this study is important, given the potential use of H 3 antagonists as a novel therapeutic approach for the symptomatic treatment of AD. 相似文献
10.
BACKGROUND AND PURPOSEPreclinical pharmacological characterization of GSK1004723, a novel, dual histamine H 1 and H 3 receptor antagonist. EXPERIMENTAL APPROACHGSK1004723 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 RESULTSIn cell membranes over-expressing human recombinant H 1 and H 3 receptors, GSK1004723 displayed high affinity, competitive binding (H 1 p Ki = 10.2; H 3 p Ki = 10.6). In addition, GSK1004723 demonstrated slow dissociation from both receptors with a t1/2 of 1.2 and 1.5 h for H 1 and H 3 respectively. GSK1004723 specifically antagonized H 1 receptor mediated increases in intracellular calcium and H 3 receptor mediated increases in GTPγS binding. The antagonism exerted was retained after cell washing, consistent with slow dissociation from H 1 and H 3 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 IMPLICATIONSGSK1004723 is a potent and selective histamine H 1 and H 3 receptor antagonist with a long duration of action and represents a potential novel therapy for allergic rhinitis. 相似文献
11.
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. 相似文献
12.
Introduction: Since years, ligands blocking histamine H 3 receptor (H 3R) 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 H 3R 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 A2A) 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 相似文献
13.
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. 相似文献
14.
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. 相似文献
16.
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. 相似文献
17.
Background and PurposeConflicting 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, H 3 receptors in alcohol dependence-related behaviours, which represent the addictive effects of alcohol. Experimental ApproachAlcohol-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 ResultsLow doses of H 3 receptor antagonists, JNJ-10181457 and JNJ-39220675, inhibited alcohol reward in wild-type (WT) mice. However, these H 3 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 H 3 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 D 1 and D 2 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 ImplicationsThese data suggest that histamine is required for the H 3 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 H 3 receptor blockade could therefore be a novel way of treating alcohol dependence. Linked ArticlesThis 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 相似文献
18.
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-HT1AR 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. 相似文献
19.
BACKGROUND AND PURPOSEVasopressin 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 APPROACHWe 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 RESULTSBoth 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). CONCLUSIONTASP0233278 and TASP0390325 are potent and orally active V 1B receptor antagonists with antidepressant and anxiolytic activities in rodents. 相似文献
20.
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 CB 1 antagonist AM251. Similarly, the effects of the phytocannabinoid Δ 9-tetrahydrocannabivarin (Δ 9-THCV), which behaves like a CB 1 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 Δ 9-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 Δ 9-THCV-rich cannabis-extract failed to suppress food intake and weight gain, possibly due to residual Δ 9-tetrahydrocannabinol (Δ 9-THC) in the extract. This Δ 9-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 Δ 9-THCV is a novel compound with hypophagic properties and a potential treatment for obesity. 相似文献
|