Purmorphamine is the first small-molecule agonist developed for the protein Smoothened [1]. Purmorphamine activates the Hedgehog (Hh) signaling pathway, resulting in the up- and downregulation of its downstream target genes, including Gli1 and Patched. Purmorphamine may ultimately be useful in the treatment of bone-related disease andneurodegenerative disease [2].
In vitro: Purmorphamine activated the Hedgehog pathway by directly bound and activated Smoothened with the IC50value of ~ 1.5 μM in competing with cyclopamine, a Smo antagonist [1]. In multi-potent C3H10T1/2 cells, purmorphamine was a potent inducer of osteogenesis. In C3H10T1/2 cells, The EC50 values assessed based on ALP expression for purmorphamine was 1 μM. Purmorphamine (1 μM) in combination with BMP-4 (100 ng/mL) increased ALP activity more than 90-fold in 3T3-L1 cells [3].Administration of purmorphamine at 3 and 5 μM up-regulated the level of osteocalcin on day 14 (P ≤ 0.05)[4].
In vivo: In rats transplanted with stem cell-based constructs subcutaneously, treatment with purmorphamine tended to up-regulate ALP transcripts when compared with those injected by either dexamethasone or injection water (P ≤ 0.05) [4].
References:
[1]. Sinha S, Chen J K. Purmorphamine activates the Hedgehog pathway by targeting Smoothened[J]. Nature chemical biology, 2006, 2(1): 29.
[2]. Wu X, Walker J, Zhang J, et al. Purmorphamine induces osteogenesis by activation of the hedgehog signaling pathway[J]. Chemistry & biology, 2004, 11(9): 1229-1238.
[3]. Wu X, Ding S, Ding Q, et al. A small molecule with osteogenesis-inducing activity in multipotent mesenchymal progenitor cells[J]. Journal of the American Chemical Society, 2002, 124(49): 14520-14521.
[4]. Faghihi F, Eslaminejad M B, Nekookar A, et al. The effect of purmorphamine and sirolimus on osteogenic differentiation of human bone marrow-derived mesenchymal stem cells[J]. Biomedicine & Pharmacotherapy, 2013, 67(1): 31-38.
