ANA-12

ANA-12 is a brain-penetrant, selective TrkB antagonist with IC₅₀ values of 45.6 nM and 41.1 μM, and K_d values of 10 nM and 12 μM, for high- and low-affinity sites, respectively. ANA-12 specifically inhibits BDNF-induced TrkB receptor activation and its downstream signaling cascades by directly and non-competitively binding to the TrkB receptor, without affecting the functions of TrkA and TrkC. ANA-12 is used in research concerning neuropsychiatric disorders (such as depression and anxiety), acute and chronic pain, neuroimmune inflammation, and the mechanisms of learning and memory^{[1][2][3][4][5][6][7]}. In Vitro:ANA-12 (1 μM; 24 h) inhibits the inflammatory response, glial cell activation, and the expression of pro-inflammatory proteins in IL-1β-induced human glioma U251 cells^[1].
ANA-12 exhibits dissociation constants (K_d) of 10 nM and 12 μM for the high- and low-affinity binding sites of TrkB, respectively, in a cell-free system^[4].
ANA-12 (0.1 nM-100 μM; 20 min) inhibits BDNF-induced TrkB receptor autophosphorylation in TetOn-rhTrkB cells expressing human recombinant TrkB (IC₅₀ values: 45.6 nM for the high-affinity site; 87.0 μM for the low-affinity site) and inhibits BDNF-induced TrkB receptor activation in primary mouse cortical neurons (IC₅₀ values: 45.6 nM for the high-affinity site; 41.1 μM for the low-affinity site)^[4].
ANA-12 (0.01 μM-100 μM; 3 days) dose-dependently blocks BDNF (1 nM) (HY-P7116)-induced neurite outgrowth in nnr5 PC12-TrkB cells stably transfected with TrkB, but does not exert this inhibitory effect in cells expressing TrkA or TrkC^[4]. In Vivo:ANA-12 (0.5 mg/kg; i.p.; once daily for 7 consecutive days (days 15–21); tested 4 hours after administration) exhibits significant analgesic activity and improves motor coordination in a type II collagen (HY-NP003)-induced arthritis (CIA) mouse model; it also significantly inhibits central glial cell activation and reduces neuroinflammation^[1]. ANA-12 (0.25 μg; intra-NAc shell microinjection; administered 30 minutes prior to stress on days 1, 4, 7, and 10) enhances social interaction, improves conditioned place preference, and facilitates passive avoidance memory in adult male Wistar rats subjected to 10 days of chronic unpredictable stress^[2].
ANA-12 (0.5-1.0 mg/kg; i.p.; single dose; administered immediately or 6 hours after the memory reactivation phase) impairs memory reconsolidation in the novel object recognition (NOR) test using ICR mice^[3].
ANA-12 (0.5 mg/kg; i.p.; single dose; tested 4 hours post-administration) exhibits significant anxiolytic and antidepressant effects in normal mice^[4].
ANA-12 (0.5-2.0 mg/kg; i.p.; once daily for 7 days) demonstrates a favorable in vivo safety profile in normal mice^[4].
ANA-12 (0.5 mg/kg; i.p.; single dose; administered 2 days after the final stress session) exhibits rapid antidepressant activity in a social defeat stress model using male C57BL/6 mice^[5].
ANA-12 (0.5 mg/kg; i.p.; single dose; administered on day 8 post-injury) did not ameliorate the anhedonia-like phenotype induced by neuropathic pain in a spared nerve injury (SNI) rat model, but it significantly attenuated the SNI-induced abnormal elevation of BDNF-TrkB signaling in the nucleus accumbens (NAc)^[7].