RVD-Hpα

RVD-Hpα (also known as RVD-hemopressin or Pepcan-12) is an endogenous neuropeptide found in human and mammalian brain, which was originally proposed to act as a selective agonist for the CB1 cannabinoid receptor. It is a 12-amino acid polypeptide having the amino acid sequence Arg-Val-Asp-Pro-Val-Asn-Phe-Lys-Leu-Leu-Ser-His and is an N-terminal extended form of hemopressin, a 9-AA polypeptide derived from the α1 subunit of hemoglobin which has previously been shown to act as a CB1 inverse agonist. All three polypeptides have been isolated from various mammalian species, with RVD-Hpα being one of the more abundant neuropeptides expressed in mouse brain, and these neuropeptides represent a new avenue for cannabinoid research distinct from the previously known endogenous lipid-derived cannabinoid agonists such as anandamide. 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). 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. RVD-hemopressin has also been shown to block the TRPV1 channel, which is a target shared with other endocannabinoid ligands such as anandamide and N-Arachidonoyl dopamine.

Pepcan-12 is the major peptide of a family of endogenous peptide endocannabinoids (pepcans) shown to act as negative allosteric modulators (NAM) of cannabinoid CB1 receptors. It has more recently been discovered that pepcan-12 also acts as a potent CB2 cannabinoid receptor positive allosteric modulator (PAM), thus reducing CB1 mediated signalling while simultaneously increasing signalling mediated by CB2. This peptide is specifically expressed in the noradrenergic neurons in the brain, mainly the locus coeruleus and its projections and in the adrenal medulla. As a positive allosteric modulator of CB2, RVD-Hpα has been shown to significantly potentiate the effects of CB2 receptor agonists, including the endocannabinoid 2-arachidonoyl glycerol (2-AG), for GTPγS binding and cAMP inhibition (5–10 fold). The precursor pepcan-23 was identified with pepcan-12 in brain, liver and kidney in mice, and is cleaved to release pepcan-12. RVD-Hpα was increased upon endotoxemia and ischemia reperfusion damage where CB2 receptors play a protective role. The wide occurrence of this endogenous hormone-like CB2 receptor PAM, with unforeseen opposite allosteric effects on cannabinoid receptors, suggests its potential role in peripheral pathophysiological processes.

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. Hybrid peptides combining VD-Hpα with peptide agonists for neuropeptide VF and opioid receptors have also been developed to produce dual acting compounds.