Dorsomorphin 2HCl

Dorsomorphin inhibits ACC inactivation by AICAR, and also attenuates AICAR’s effect to increase fatty acid oxidation or suppress lipogenic genes in hepatocytes. ^[1]

Inhibition of AMPK activity by Dorsomorphin almost completely inhibits autophagic proteolysis in HT-29 cells. ^[2]

In addition, Dorsomorphin selectively inhibits the BMP type I receptors ALK2, ALK3 and ALK6, and thus blocks BMP-mediated SMAD1/5/8 phosphorylation, target gene transcription and osteogenic differentiation. ^[3]

Dorsomorphin (10 mg/kg) reduces basal levels of hepcidin expression and increases serum iron concentrations in adult mice. ^[3]

Dorsomorphin (0.2 mg/kg, i.v.) significantly reduces VCAM-1 and ICAM-1 expression in the thoracic aorta of LPS-treated rats. ^[4]

• AMPK partial purification and in vitro kinase assay.

  Liver AMPK is partially purified from male SD rats to the blue-Sepharose step. The 100-μl reaction mixture contains 100 μM AMP, 100 μM ATP (0.5 μCi ³³P-ATP per reaction), and 50 μM SAMS in a buffer (40 mM HEPES, pH 7.0, 80 mM NaCl, 0.8 mM EDTA, 5 mM MgCl₂, 0.025% BSA, and 0.8 mM DTT). The reaction is initiated with addition of the enzyme. After 30-minute incubation at 30°C, the reaction is stopped by addition of 80 μl 1% H₃PO₄. Aliquots (100 μl) are transferred to 96-well MultiScreen plates. The plate is washed three times with 1% H3PO4 followed by detection in a Top-count. The in vitro AMPK inhibition data obtained with compound C — (6-[4-(2-Piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyyrazolo[1,5-a] pyrimidine — are fit to the following equation for competitive inhibition by nonlinear regression using a least-squares Marquardt algorithm in a computer program written by N. Thornberry of Merck Research Laboratories: Vi/Vo = (K_m + S)/[S + K_m × (1 + I/K_i)], where Vi is the inhibited velocity, Vo is the initial velocity, S is the substrate (ATP) concentration, K_m is the Michaelis constant for ATP, I is the inhibitor (compound C) concentration, and K_i is the dissociation constant for compound C.

• Cell lines

  NIH3T3 cells 

• Concentrations

  10 μM

• Incubation Time

  3 days

• Method

  Cells were treated with hydrogen peroxide and incubated in complete medium with or without treatment with the AMPK activators, AICAR (10 μM), alone or plus AMPK inhibitor Compound C (CC, 10 μM) for 3 days.

• Animal Models

  Iron-replete mice

• Dosages

  ~10 mg/kg

• Administration

  i.v.