RVD-Hpα (also known asRVD-hemopressin orPepcan-12) is anendogenousneuropeptide found in human and mammalian brain, which was originally proposed to act as a selectiveagonist for theCB1cannabinoid receptor. It is a 12-amino acidpolypeptide having the amino acid sequence Arg-Val-Asp-Pro-Val-Asn-Phe-Lys-Leu-Leu-Ser-His and is anN-terminal extended form ofhemopressin,[1] a 9-AA polypeptide derived from theα1 subunit ofhemoglobin which has previously been shown to act as a CB1 inverse agonist.[2] All three polypeptides have been isolated from various mammalian species, with RVD-Hpα being one of the more abundant neuropeptides expressed inmouse brain, and these neuropeptides represent a new avenue for cannabinoid research distinct from the previously known endogenouslipid-derived cannabinoid agonists such asanandamide.[3] Recently it was shown that RVD-Hpα (also called Pepcan-12) is a potent negative allosteric modulator at CB1 receptors, together with other newly described N-terminally extended peptides (pepcans).[4][5] However other research suggests that RVD-hemopressin may sometimes act as a positive allosteric modulator of CB1 in certain tissues or under certain conditions, and its effects can be blocked by CB1 antagonists.[6][7][8] RVD-hemopressin has also been shown to block theTRPV1 channel, which is a target shared with otherendocannabinoid ligands such as anandamide andN-Arachidonoyl dopamine.[9]
Pepcan-12 is the major peptide of a family of endogenous peptideendocannabinoids (pepcans) shown to act as negativeallosteric modulators (NAM) of cannabinoid CB1 receptors. It has more recently been discovered that pepcan-12 also acts as a potentCB2 cannabinoid receptor positive allosteric modulator (PAM), thus reducing CB1 mediated signalling while simultaneously increasing signalling mediated by CB2.[10] This peptide is specifically expressed in the noradrenergic neurons in the brain, mainly the locus coeruleus and its projections and in the adrenal medulla.[11] As a positive allosteric modulator of CB2, RVD-Hpα has been shown to significantly potentiate the effects of CB2receptor agonists, including the endocannabinoid2-arachidonoyl glycerol (2-AG), forGTPγS binding andcAMP inhibition (5–10 fold). The precursor pepcan-23 was identified with pepcan-12 inbrain,liver andkidney in mice, and is cleaved to release pepcan-12. RVD-Hpα was increased uponendotoxemia andischemia reperfusion damage where CB2 receptors play a protective role. The wide occurrence of this endogenoushormone-like CB2 receptor PAM, with unforeseen opposite allosteric effects oncannabinoid receptors, suggests its potential role inperipheralpathophysiological processes.[12]
In contrast to RVD-Hpα which produces antagonist or inverse agonist activity at CB1 under most conditions but acts as an agonist at CB2, the shorter 11-amino acid peptide fragment VD-Hpα produces agonist effects at CB1 but has little or no activity at CB2, producing centrally mediated analgesic effects, hypothermia and increased sleep in animal studies through activation of the CB1 receptor.[13][14][15][16] Hybrid peptides combining VD-Hpα with peptide agonists forneuropeptide VF andopioid receptors have also been developed to produce dual acting compounds.[17][18]
^Macedonio G, Stefanucci A, Maccallini C, Mirzaie S, Novellino E, Mollica A (2016). "Hemopressin Peptides as Modulators of the Endocannabinoid System and their Potential Applications as Therapeutic Tools".Protein and Peptide Letters.23 (12):1045–1051.doi:10.2174/0929866523666161007152435.PMID27748182.
^Zhang, Ruisan; Lao, Kejing; Lu, Baiyu; Guo, Huifang; Cheng, Jianghong; Chen, Peng; Gou, Xingchun (2021). "(m)RVD-hemopressin (α) and (M)VD-hemopressin (α) improve the memory-impairing effect of scopolamine in novel object and object location recognition tasks in mice".Peptides.136 170442.doi:10.1016/j.peptides.2020.170442.PMID33171279.
^Zhang, R; He, X; Cheng, J; Zhang, X; Han, C; Liu, Y; Chen, P; Wang, Y (2023). "(m) RVD-hemopressin (α) Ameliorated Oxidative Stress, Apoptosis and Damage to the BDNF/TrkB/Akt Pathway Induced by Scopolamine in HT22 Cells".Neurotox Res.41:627–637.doi:10.1007/s12640-023-00677-w.PMID37971633.
^Hofer SC, Ralvenius WT, Gachet MS, Fritschy JM, Zeilhofer HU, Gertsch J (November 2015). "Localization and production of peptide endocannabinoids in the rodent CNS and adrenal medulla".Neuropharmacology.98:78–89.doi:10.1016/j.neuropharm.2015.03.021.PMID25839900.S2CID43599023.
^Han, Z. L.; Fang, Q.; Wang, Z. L.; Li, X. H.; Li, N.; Chang, X. M.; Pan, J. X.; Tang, H. Z.; Wang, R. (2014). "Antinociceptive effects of central administration of the endogenous cannabinoid receptor type 1 agonist VDPVNFKLLSH-OH (M)VD-hemopressin(α), an N-terminally extended hemopressin peptide".The Journal of Pharmacology and Experimental Therapeutics.348 (2):316–323.doi:10.1124/jpet.113.209866.PMID24307201.
^Zheng, T.; Zhang, T.; Zhang, R.; Wang, Z. L.; Han, Z. L.; Li, N.; Li, X. H.; Zhang, M. N.; Xu, B.; Yang, X. L.; Fang, Q.; Wang, R. (2017). "Pharmacological characterization of rat VD-hemopressin(α), an α-hemoglobin-derived peptide exhibiting cannabinoid agonist-like effects in mice".Neuropeptides.63:83–90.doi:10.1016/j.npep.2016.12.006.PMID28010996.
^Zheng, T.; Zhang, R.; Zhang, T.; Zhang, M. N.; Xu, B.; Song, J. J.; Li, N.; Tang, H. H.; Wang, P.; Wang, R.; Fang, Q. (2018). "CB(1) cannabinoid receptor agonist mouse VD-hemopressin(α) produced supraspinal analgesic activity in the preclinical models of pain".Brain Research.1680:155–164.doi:10.1016/j.brainres.2017.12.013.PMID29274880.
