DMP 696 is a selective corticotropin-releasing hormone receptor 1 (CRHR1) antagonist. DMP 696 displays high affinity for CRHR1, with Ki values of 3.3nM for the human cloned receptor and 4.6nM for the rat cortical receptor. Functionally, DMP 696 inhibits cAMP accumulation and Adrenocorticotropic Hormone (ACTH) release with IC₅₀ values of 83nM and 59nM, respectively. DMP 696 has potential therapeutic applications for anxiety and depression, with a low risk of behavioral side effects[1][2].
In vivo, an oral dose of 10mg/kg DMP 696 in rats produce over 90% brain CRHR1 occupancy, which peaks at 90min postdosing and cleared from brain receptor occupancy by 22h after administration[3]. DMP 696 (1-30mg/kg; 1h pretreatment; p.o.) significantly increased the duration of contextual freezing (a stationary posture characterized by cessation of movement except that required for respiration) in a dose dependent manner in conditioned fear test[3]. DMP 696 (10mg/kg; 1h pretreatment; p.o.) exhibited a significant overall reduction in cAMP response element-binding protein phosphorylation (pCREB), in both the Lateral nucleus of the amygdala (LA) and Basolateral Amygdala (BLA), but not in the Central nucleus of the Amygdala (CeA)[3]. In C57BL/6N mice, administration of DMP 696 (3mg/kg/d; p.o.; 7d) starting as late as 24 hours after foot-shock exposure attenuates the consolidation of remote fear memory, without affecting its expression or retention[1].
References:
[1] Thoeringer, Christoph K et al. “Consolidation of remote fear memories involves Corticotropin-Releasing Hormone (CRH) receptor type 1-mediated enhancement of AMPA receptor GluR1 signaling in the dentate gyrus.” Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology vol. 37,3 (2012): 787-96.
[2] Li YW, Fitzgerald L, Wong H, et al. The pharmacology of DMP696 and DMP904, non-peptidergic CRF1 receptor antagonists. CNS Drug Rev. 2005;11(1):21-52.
[3] Hubbard DT, Nakashima BR, Lee I, Takahashi LK. Activation of basolateral amygdala corticotropin-releasing factor 1 receptors modulates the consolidation of contextual fear. Neuroscience. 2007;150(4):818-828.