Adrenorphin, Free Acid

Adrenorphin, also sometimes referred to as metorphamide, is an endogenous, C-terminally amidated, opioid octapeptide that is produced from proteolytic cleavage of proenkephalin A and is widely distributed throughout the mammalian brain⁽¹⁾. It was named based on the fact that it was originally detected in human phaeochromocytoma tumour derived from the adrenal medulla, and was subsequently found in normal human and bovine adrenal medulla as well. Adrenorphin exhibits potent opioid activity, acting as a balanced μ- and κ-opioid receptor agonist while having no effects on δ-opioid receptors⁽²⁾. It possesses analgesic and respiratory deppresive properties⁽³⁾.

Figure 1  proteolytic cleavage of proenkephalin A

Ref:

1. Matsuo H, Miyata A, Mizuno K (1983). "Novel C-terminally amidated opioid peptide in human phaeochromocytoma tumour". Nature 305 (5936): 721–3.

2. Weber E, Esch FS, Böhlen P et al. (December 1983). "Metorphamide: isolation, structure, and biologic activity of an amidated opioid octapeptide from bovine brain". Proceedings of the National Academy of Sciences of the United States of America 80 (23): 7362–6.

3. Xu SF, Lu WX, Zhou KR et al. (April 1985). "The analgesic and respiratory depressant actions of metorphamide in mice and rabbits". Neuropeptides 6 (2): 121–31.

Characterization of a metalloprotease from ovine chromaffin granules which cleaves a proenkephalin fragment (BAM12P) at a single arginine residue.[Pubmed:8043007]

Biochem J. 1994 Jul 15;301 ( Pt 2):607-14.

A metalloprotease has been identified in ovine chromaffin granules which cleaves the proenkephalin fragment BAM12P to produce adrenorphin-Gly. This cleavage occurs at a single arginine residue and is an intermediate step in the production of the opiate adrenorphin in vivo. The identity of the product was confirmed by reverse-phase and ion-exchange chromatography. The adrenorphin-Gly-generating enzyme (AGE) was determined by chromatofocusing to have a pI value of 5.2 and bound strongly to a metal-chelate affinity column. After purification by gel-filtration and ion-exchange chromatography AGE was free of contaminating activities, as cleavage of radiolabelled BAM12P generated a single product as judged by reverse-phase and ion-exchange chromatography. The enzyme has a molecular mass of approx. 45 kDa and a pH optimum of 8.6 in Mops, Taps and Hepes buffers, but was inhibited by phosphate buffers. It was inhibited by micromolar concentrations of copper and zinc ions, but not by millimolar concentrations of calcium or manganese ions. The addition of BAM22P, dynorphin 1-13 or dynorphin 1-8 to the incubation mixture inhibited the cleavage of radiolabelled BAM12P. The cleavage was also inhibited by the presence of catecholamines at concentrations similar to those found within the chromaffin granule. This may explain the known effect of reserpine on chromaffin cells of reducing catecholamine levels and simultaneously increasing adrenorphin levels. It may also indicate a function for AGE and adrenorphin as reporters of intragranular conditions.