The relationship of in vivo central CB1 receptor occupancy to changes in cortical monoamine release and feeding elicited by CB1 receptor antagonists in rats

Need, Anne B.; Davis, R. J.; Alexander-Chacko, Jesline; Eastwood, Brian J.; Chernet, Eyassu; Phebus, Lee A.; Sindelar, Dana K.; Nomikos, George G.

doi:10.1007/s00213-005-0234-x

Cited by 58 publications

(39 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, body weight phenotype of the heterozygous mice has not been reported. In addition, it has not been reported whether complete blockade or partial inhibition of CB1R is required for chronic weight loss efficacy, whereas variable occupancy has been reported for different compounds to achieve acute food intake inhibition (Need et al, 2006). In the present study, we evaluated the in vitro and in vivo pharmacological properties of a novel compound MK-0364 (Lin et al, 2006).…”

mentioning

confidence: 96%

Antiobesity Efficacy of a Novel Cannabinoid-1 Receptor Inverse Agonist, N-[(1S,2S)-3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364), in Rodents

Fong

Guan²,

Marsh³

et al. 2007

J Pharmacol Exp Ther

View full text Add to dashboard Cite

The cannabinoid-1 receptor (CB1R) has been implicated in the control of energy balance. To explore the pharmacological utility of CB1R inhibition for the treatment of obesity, we evaluated the efficacy of N- [(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364) and determined the relationship between efficacy and brain CB1R occupancy in rodents. MK-0364 was shown to be a highly potent CB1R inverse agonist that inhibited the binding and functional activity of various agonists with a binding K i of 0.13 nM for the human CB1R in vitro. MK-0364 dose-dependently inhibited food intake and weight gain, with an acute minimum effective dose of 1 mg/kg in diet-induced obese (DIO) rats. CB1R mechanism-based effect was demonstrated for MK-0364 by its lack of efficacy in CB1R-deficient mice. Chronic treatment of DIO rats with MK-0364 dose-dependently led to significant weight loss with a minimum effective dose of 0.3 mg/kg (p.o.), or a plasma C max of 87 nM. Weight loss was accompanied by the loss of fat mass. Partial occupancy (30 -40%) of brain CB1R by MK-0364 was sufficient to reduce body weight. The magnitude of weight loss was correlated with brain CB1R occupancy. The partial receptor occupancy requirement for efficacy was also consistent with the reduced food intake of the heterozygous mice carrying one disrupted allele of CB1R gene compared with the wild-type mice. These studies demonstrated that MK-0364 is a highly potent and selective CB1R inverse agonist and that it is orally active in rodent models of obesity.Cannabinoid-1 receptor (CB1R) is a G protein-coupled receptor predominantly expressed in the nervous system, and it has been identified as the brain receptor for exogenous molecules such as tetrahydrocannabinol (Berry and Mechoulam, 2002;Howlett et al., 2002;Pertwee, 2005;Thakur et al.,

show abstract

mentioning

confidence: 96%

Antiobesity Efficacy of a Novel Cannabinoid-1 Receptor Inverse Agonist, N-[(1S,2S)-3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364), in Rodents

Fong

Guan²,

Marsh³

et al. 2007

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…The 1-hour time point was chosen to be at the upper end of the post-tracer survival interval we routinely use in our RO experiments (Chernet et al, 2005;Need et al, 2006). The lowest dose we could measure at this time point is a function of the LC/MS/MS equipment available to us and the ionizability of the tracer molecule in the mass spectrometer source.…”

Section: Discussionmentioning

confidence: 99%

In vivo rat brain opioid receptor binding of LY255582 assessed with a novel method using LC/MS/MS and the administration of three tracers simultaneously

et al. 2007

Self Cite

View full text Add to dashboard Cite

“…Hence, the lower tissue concentration of tracer measured in these animals is only reflective of C nonspec and is assigned to a value of 100% occupancy. An appropriate time period, a so-called post-tracer survival interval, is needed after tracer administration for the tracer to bind the receptor and for the nonspecific binding to decrease such that a high ratio of total to nonspecific binding is achieved (Need et al, 2006). Consequently, once a promising tracer candidate has been identified, several tracer doses-and sometimes also post-tracer survival intervals-are tested to develop experimental procedures that yield a high ratio of total to nonspecific binding.…”

Section: Development Of a Pulmonary In Vivo Receptor Occupancy Methodmentioning

confidence: 99%

A Novel In Vivo Receptor Occupancy Methodology for the Glucocorticoid Receptor: Toward An Improved Understanding of Lung Pharmacokinetic/Pharmacodynamic Relationships

Boger

Ewing

Eriksson

et al. 2015

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Investigation of pharmacokinetic/pharmacodynamic (PK/PD) relationships for inhaled drugs is challenging because of the limited possibilities of measuring tissue exposure and target engagement in the lung. The aim of this study was to develop a methodology for measuring receptor occupancy in vivo in the rat for the glucocorticoid receptor (GR) to allow more informative inhalation PK/PD studies. From AstraZeneca's chemical library ofpropoxy]indazol-1-yl]-N-methyl-benzamide] was identified to have properties that are useful as a tracer for GR in vitro. When given at an appropriate dose (30 nmol/kg) to rats, compound 1 functioned as a tracer in the lung and spleen in vivo using liquid chromatography-tandem mass spectrometry bioanalysis. The methodology was successfully used to show the dose-receptor occupancy relationship measured at 1.5 hours after intravenous administration of fluticasone propionate (20, 150, and 750 nmol/kg) as well as to characterize the time profile for receptor occupancy after a dose of 90 nmol/kg i.v. The dose giving 50% occupancy was estimated as 47 nmol/kg. The methodology is novel in terms of measuring occupancy strictly in vivo and by using an unlabeled tracer. This feature confers key advantages, including occupancy estimation not being influenced by drug particle dissolution or binding/dissociation taking place postmortem. In addition, the tracer may be labeled for use in positron emission tomography imaging, thus enabling occupancy estimation in humans as a translatable biomarker of target engagement.

show abstract

The relationship of in vivo central CB1 receptor occupancy to changes in cortical monoamine release and feeding elicited by CB1 receptor antagonists in rats

Abstract: The occupancy method described here is an effective tool for interrelating central CB(1) receptor occupancy with neurobiological actions of CB(1) receptor antagonists and for furthering our understanding of the role of CB(1) receptors in central nervous system physiology and pathology.

Cited by 58 publications

References 40 publications

Antiobesity Efficacy of a Novel Cannabinoid-1 Receptor Inverse Agonist, N-[(1S,2S)-3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364), in Rodents

Antiobesity Efficacy of a Novel Cannabinoid-1 Receptor Inverse Agonist, N-[(1S,2S)-3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364), in Rodents

In vivo rat brain opioid receptor binding of LY255582 assessed with a novel method using LC/MS/MS and the administration of three tracers simultaneously

A Novel In Vivo Receptor Occupancy Methodology for the Glucocorticoid Receptor: Toward An Improved Understanding of Lung Pharmacokinetic/Pharmacodynamic Relationships

Contact Info

Product

Resources

About