Potency and safety analysis of hemp-derived delta-9 products: The hemp vs. cannabis demarcation problem

IUPAC name
(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-3-methyl-2-[[(2S)-pyrrolidine-2-carbonyl]amino]butanoyl]amino]-4-oxo-butanoyl]amino]-3-phenyl-propanoyl]amino]hexanoyl]amino]-3-phenyl-propanoyl]amino]-4-methyl-pentanoyl]amino]-3-hydroxy-propanoyl]amino]-3-(1H-imidazol-5-yl)propanoic acid
3D model (JSmol)
  • InChI=1S/C53H77N13O12/c1-30(2)22-37(47(71)65-42(28-67)51(75)64-41(53(77)78)25-34-27-56-29-58-34)60-49(73)39(24-33-16-9-6-10-17-33)61-46(70)36(18-11-12-20-54)59-48(72)38(23-32-14-7-5-8-15-32)62-50(74)40(26-43(55)68)63-52(76)44(31(3)4)66-45(69)35-19-13-21-57-35/h5-10,14-17,27,29-31,35-42,44,57,67H,11-13,18-26,28,54H2,1-4H3,(H2,55,68)(H,56,58)(H,59,72)(H,60,73)(H,61,70)(H,62,74)(H,63,76)(H,64,75)(H,65,71)(H,66,69)(H,77,78)/t35-,36-,37-,38-,39-,40-,41-,42-,44-/m0/s1 ☒N
  • InChI=1/C53H77N13O12/c1-30(2)22-37(47(71)65-42(28-67)51(75)64-41(53(77)78)25-34-27-56-29-58-34)60-49(73)39(24-33-16-9-6-10-17-33)61-46(70)36(18-11-12-20-54)59-48(72)38(23-32-14-7-5-8-15-32)62-50(74)40(26-43(55)68)63-52(76)44(31(3)4)66-45(69)35-19-13-21-57-35/h5-10,14-17,27,29-31,35-42,44,57,67H,11-13,18-26,28,54H2,1-4H3,(H2,55,68)(H,56,58)(H,59,72)(H,60,73)(H,61,70)(H,62,74)(H,63,76)(H,64,75)(H,65,71)(H,66,69)(H,77,78)/t35-,36-,37-,38-,39-,40-,41-,42-,44-/m0/s1
  • CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)O)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CCCCN)NC(=O)[C@H](Cc3ccccc3)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]4CCCN4
Molar mass 1088.25838
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Hemopressin (Hp) is an alpha hemoglobin fragment with the sequence PVNFKFLSH, originally identified in extracts of rat brain using an enzyme capture technique.[1] It binds cannabinoid receptors, acting as an inverse agonist at CB1 receptors.[2] Longer forms of hemopressin containing 2-3 additional amino acids on the N-terminus have been identified in extracts of mouse brain. These longer hemopressin peptides, named RVD-Hpα and VD-Hpα, bind to CB1 receptors and were originally reported to be agonists.[3] In addition to the Hp peptides from alpha hemoglobin, a related peptide from beta hemoglobin has been found in mouse brain extracts; this peptide, named VD-Hpβ, is also an agonist at CB1 cannabinoid receptors.[3] Hemopressin is not an endogenous peptide but rather an extraction artefact.[4] The only endogenous peptide found endogenously at physiological conditions is RVD-hemopressin (pepcan-12), which has more recently been shown to be a negative allosteric modulator of CB1 receptors and positive allosteric modulator of CB2 receptors.[4][5] RVD-hemopressin (pepcan-12) is generated from a pro-peptide called pepcan-23 and these peptides are exclusively found in noradrenergic neurons in the brain and in the adrenal medulla.[6]

The original Hp peptide reduces sensitivity to painful stimuli in an experimental model of hyperalgesia.[7] Hp also reduces food intake in mice.[8] However, it remains to be shown if Hp is an endogenous brain peptide. The original purification used boiling acid to extract the peptide from rat brain, and hot acid can specifically cleave D-P bonds. The N-terminally-extended forms RVD-Hpα and VD-Hpα may represent the true endogenous forms.[9]

Role in diet

Scientists at the University of Manchester have discovered that hemopressin could be used as an appetite suppressant without having the side effects of many other drugs that are used for this purpose. In laboratory tests hemopressin was administrated to mice and rats, which significantly reduced food intake. Hemopressin works by affecting the reward centres of the brain which make us feel happy when we eat too much. A further research should be carried out in order to confirm these effects and the safety on people.[10]

See also


  1. ^ Rioli V, Gozzo FC, Heimann AS, et al. (March 2003). "Novel natural peptide substrates for endopeptidase 24.15, neurolysin, and angiotensin-converting enzyme". J. Biol. Chem. 278 (10): 8547–55. doi:10.1074/jbc.M212030200. PMID 12500972.
  2. ^ Heimann AS, Gomes I, Dale CS, et al. (December 2007). "Hemopressin is an inverse agonist of CB1 cannabinoid receptors". Proc. Natl. Acad. Sci. U.S.A. 104 (51): 20588–93. Bibcode:2007PNAS..10420588H. doi:10.1073/pnas.0706980105. PMC 2154475. PMID 18077343.
  3. ^ a b Gomes I, Grushko JS, Golebiewska U, et al. (September 2009). "Novel endogenous peptide agonists of cannabinoid receptors". FASEB J. 23 (9): 3020–9. doi:10.1096/fj.09-132142. PMC 2735371. PMID 19380512.
  4. ^ a b Bauer, Mark; Chicca, Andrea; Tamborrini, Marco; Eisen, David; Lerner, Raissa; Lutz, Beat; Poetz, Oliver; Pluschke, Gerd; Gertsch, Jürg (2012). "Identification and Quantification of a New Family of Peptide Endocannabinoids (Pepcans) Showing Negative Allosteric Modulation at CB1 Receptors". Journal of Biological Chemistry. 287 (44). Elsevier BV: 36944–36967. doi:10.1074/jbc.m112.382481. ISSN 0021-9258. PMC 3481297. PMID 22952224.
  5. ^ Petrucci, Vanessa; Chicca, Andrea; Glasmacher, Sandra; Paloczi, Janos; Cao, Zongxian; Pacher, Pal; Gertsch, Jürg (2017-08-25). "Pepcan-12 (RVD-hemopressin) is a CB2 receptor positive allosteric modulator constitutively secreted by adrenals and in liver upon tissue damage". Scientific Reports. 7 (1). Springer Science and Business Media LLC: 9560. Bibcode:2017NatSR...7.9560P. doi:10.1038/s41598-017-09808-8. ISSN 2045-2322. PMC 5573408. PMID 28842619.
  6. ^ Hofer, Stefanie C.; Ralvenius, William T.; Gachet, M. Salomé; Fritschy, Jean-Marc; Zeilhofer, Hanns Ulrich; Gertsch, Jürg (2015). "Localization and production of peptide endocannabinoids in the rodent CNS and adrenal medulla". Neuropharmacology. 98. Elsevier BV: 78–89. doi:10.1016/j.neuropharm.2015.03.021. ISSN 0028-3908. PMID 25839900. S2CID 43599023.
  7. ^ Dale CS, Pagano Rde L, Rioli V, et al. (March 2005). "Antinociceptive action of hemopressin in experimental hyperalgesia". Peptides. 26 (3): 431–6. doi:10.1016/j.peptides.2004.10.026. PMID 15652650. S2CID 1402750.
  8. ^ Dodd GT, Mancini G, Lutz B, et al. (May 2010). "The peptide hemopressin acts through CB1 cannabinoid receptors to reduce food intake in rats and mice". J. Neurosci. 30 (21): 7369–76. doi:10.1523/JNEUROSCI.5455-09.2010. PMC 6632410. PMID 20505104.
  9. ^ Gelman JS, Sironi J, Castro LM, et al. (May 2010). "Hemopressins and other hemoglobin-derived peptides in mouse brain: comparison between brain, blood, and heart peptidome and regulation in Cpefat/fat mice". J. Neurochem. 113 (4): 871–80. doi:10.1111/j.1471-4159.2010.06653.x. PMC 2867603. PMID 20202081.
  10. ^ "Health | Life | UK Life".