2003
DOI: 10.1124/jpet.102.045914
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Receptor Occupancy of Nonpeptide Corticotropin-Releasing Factor 1 Antagonist DMP696: Correlation with Drug Exposure and Anxiolytic Efficacy

Abstract: 4-(1,3-Dimethoxyprop-2-ylamine)-2,7-dimethyl-8-(2,4-dichlorophenyl)-pyrazolo[1,5-a]-1,3,5-triazine (DMP696) is a highly selective and potent, nonpeptide corticotropin-releasing factor 1 (CRF 1 ) antagonist. In this study, we measured in vivo CRF 1 receptor occupancy of DMP696 by using ex vivo ligand binding and quantitative autoradiography and explored the relationship of receptor occupancy with plasma and brain exposure and behavioral efficacy. In vitro affinity (IC 50 ) of DMP696 to brain CRF 1 receptors mea… Show more

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Cited by 60 publications
(84 citation statements)
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“…These studies support the strategic use of robust methodologies for the assessment of ex vivo rodent CNS occupancy, and subsequent PK/PD analysis, as a means for the prospective prediction of CNS occupancy in humans. Accurate assessment of transporter (or receptor) occupancy using ex vivo methodology is sensitive to many factors including the temporal effects of tissue processing (Li et al, 2003(Li et al, , 2006. Time-dependent decreases in apparent transporter occupancy have been observed for SERT and NET by using venlafaxine and nomifensine, respectively (Lengyel et al, 2008).…”
Section: Discussionmentioning
confidence: 99%
“…These studies support the strategic use of robust methodologies for the assessment of ex vivo rodent CNS occupancy, and subsequent PK/PD analysis, as a means for the prospective prediction of CNS occupancy in humans. Accurate assessment of transporter (or receptor) occupancy using ex vivo methodology is sensitive to many factors including the temporal effects of tissue processing (Li et al, 2003(Li et al, , 2006. Time-dependent decreases in apparent transporter occupancy have been observed for SERT and NET by using venlafaxine and nomifensine, respectively (Lengyel et al, 2008).…”
Section: Discussionmentioning
confidence: 99%
“…Methods for in vitro CRF1 binding autoradiography in post-mortem human brain samples were adapted from three reports [9,44,45]. Human and baboon brain sections cut at 20-µm thick were pre-incubated for 30 min at 23° C in 50 mM HEPES buffer (pH 7.2) containing 10 mM MgCl 2 , 2 mM EGTA, 100 mM KIU/ml aprotinin, 0.1 mM bacitracin, 0.1 mM ovalbumin.…”
Section: Autoradiographical Analysismentioning
confidence: 99%
“…The procedure described by Li et al (2003) was used. Briefly, following testing in the defensive withdrawal procedure (75 min following oral administration of DMP904), animals were decapitated, and brain tissue was excised, frozen, and sectioned.…”
Section: Methodsmentioning
confidence: 99%
“…The procedure described by Li et al (2003) was used to determine systemic DMP904 exposure levels immediately after behavioral testing (75 min after oral administration). DMP904 concentration in the plasma was measured using a liquid chromatography tandem mass spectrometric method (LC/MS/ MS).…”
Section: Methodsmentioning
confidence: 99%