Smoothened agonist (SAG) was one of the first small-molecule agonists developed for the protein
Smoothened
Smoothened is a protein that in humans is encoded by the SMO gene. Smoothened is a Class Frizzled (Class F) G protein-coupled receptor that is a component of the hedgehog signaling pathway and is conserved from flies to humans. It is the molecula ...
,
a key part of the
hedgehog signaling pathway
The Hedgehog signaling pathway is a signaling pathway that transmits information to embryonic cells required for proper cell differentiation. Different parts of the embryo have different concentrations of hedgehog signaling proteins. The pathwa ...
, which is involved in brain development as well as having a number of other functions in the body.
Smoothened agonist has been shown to aid proliferation and survival of developing
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
s,
and prevent drug-induced brain injury.
When injected into the
cerebellum
The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebel ...
of newborn mice with an induced
Down syndrome
Down syndrome or Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. It is usually associated with physical growth delays, mild to moderate intellectual dis ...
-like condition, Smoothened agonist was able to stimulate normal cerebellum development, resulting in significant behavioural improvement once the mice had grown to adulthood.
Smoothened Agonist was capable of inducing
androgen
An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This inc ...
production in both prostate and bone
stromal cells
Stromal cells, or mesenchymal stromal cells, are differentiating cells found in abundance within bone marrow but can also be seen all around the body. Stromal cells can become connective tissue cells of any organ, for example in the uterine mucos ...
that was significantly greater than even similarly treated
prostate cancer
Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...
cells.
Some analogues of piperazines as a novel class of Smoothened agonists modulates Hedgehog signaling in the crypts of the small intestines by binding to Smoothened and thereby leading to intestinal stem cell compartment expansion, improved intestinal recovery, and survival of lethally irradiated animals.
[Duhachek‐Muggy S.,et al., & Pajonk F. (2019). Radiation Mitigation of the Intestinal Acute Radiation Injury in Mice by 1‐ 4‐Nitrophenyl)Sulfonyl4‐Phenylpiperazine. STEM CELLS Translational Medicine. In press https://doi.org/10.1002/sctm.19-0136]
References
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Receptor agonists
Down syndrome