Semax

Seven residues: the ACTH 4-7 fragment with a proline-glycine-proline tail added to the C-terminus. That tail is the reason the peptide exists, since the four-residue fragment on its own is broken down very quickly.

The first four residues, Met-Glu-His-Phe, are the 4 to 7 region of adrenocorticotropic hormone, itself a product of proopiomelanocortin processing. The Pro-Gly-Pro extension is synthetic and is not part of the hormone. It is unmodified at both ends, with a free N-terminal amine and a free C-terminal acid; the N-acetylated and amidated derivative sold elsewhere as N-acetyl-Semax amidate is a chemically distinct compound with its own registry number and should not be substituted for this one.

The methionine at position one is the molecule's chemical weak point, being readily oxidised to the sulfoxide, and it is also, with the phenylalanine and histidine, part of the only aromatic content in a short and otherwise polar sequence.

The best-supported molecular observations concern neurotrophin expression. Published rodent work reports increased brain-derived neurotrophic factor protein and its receptor TrkB phosphorylation in hippocampus, with corresponding transcript increases, and in primary rat glial culture reports several-fold increases in brain-derived neurotrophic factor and nerve growth factor transcripts within thirty minutes.

A specific and reversible binding site for the peptide has been measured in rat basal forebrain preparations, with a dissociation constant in the low nanomolar range, but the authors did not identify that site as a melanocortin receptor. This is worth stating because the claim that the peptide binds the melanocortin-4 receptor is widely repeated and no primary binding or functional receptor assay supporting it was located; one paper merely speculates. A related claim linking the peptide to HIF-1 is also unsupported by the record cited for it, which measured a vascular growth factor transcript rather than HIF-1.

Its degradation has been mapped rather than assumed, which is unusual for a compound of this kind. Studies in rat basal-forebrain cultures and plasma membranes using isotopic labelling and HPLC show loss of the N-terminal dipeptide and of the C-terminal glycine-proline, with a pentapeptide as a major product, and the pattern differs between glial and neuronal preparations. The proline-glycine-proline tail slows cleavage but does not prevent it. Radiolabelled transport work using a tritiated form reports that the great majority of brain-associated radioactivity was intact peptide at two minutes, with the proline-glycine-proline fragment predominating later. As with Selank, the short plasma half-life figures in circulation trace to supplier pages rather than to published measurement.