Hemopressin Peptides as Modulators of the Endocannabinoid System and their Potential Applications as Therapeutic Tools

Abstract

The endocannabinoid system (ECS) is activated when natural arachidonic acid derivatives (endogenous cannabinoids or endocannabinoids) bind as lipophilic messengers to cannabinoid receptors CB1 and CB2. The ECS comprises many hydrolytic enzymes responsible for the endocannabinoids cleavage. These hydrolases, such as fatty acid amide hydrolase (FAAH) and monoacylglyceride lipase (MAGL), are possible therapeutic targets for the development of new drugs as indirect cannabinoid agonists. Recently, a new family of endocannabinoid modulators was discovered; the lead structure of this family is the nonapeptide hemopressin produced from enzymatic cleavage of the α-chain of hemoglobin and acting as negative allosteric modulator of CB1. Hemopressin shows several physiological effects, e.g., antinociception, hypophagy, and hypotension. However, it is still a matter of debate whether this peptide, isolated from the brain of rats, is a real neuromodulator of the ECS. Recent evidence indicates that hemopressin could be a by-product formed by chemical degradation of a longer peptide RVD-hemopressin during the extraction from the brain homolysate. Indeed, RVD-hemopressin is more active than hemopressin in certain biological tests and may bind to the same subsite as Rimonabant, which is an inverse agonist of CB1 and a μ-opioid receptor antagonist. These findings have stimulated several studies to verify this hypothesis and to evaluate possible therapeutic applications of hemopressin, its peptidic derivatives, and synthetic analogues, opening new perspectives to the development of novel cannabinoid drugs.

Pepcan-12 (RVD-hemopressin) is a CB2 receptor positive allosteric modulator constitutively secreted by adrenals and in liver upon tissue damage

“…For instance, the handling of these peptides is hampered by aggregation 27 , 38 . Moreover, the metabolic stability of these peptides is limited in vivo and data from uncontrolled pharmacological experiments performed in mice 39 are difficult to interpret without pharmacokinetics, which may have added to the confusion in the literature 40 . Although different in vivo studies have been carried out with hemopressin and RV-hemopressin 39 , 40 , the only endogenous peptides present at physiological levels appear to be pepcan-12 (i.e., RVD-hemopressin) and pepcan-23 as reconfirmed by the present study.…”

Endocannabinoids in Body Weight Control

“…Another structurally similar peptide called hemopressin is also considered as an allosteric CB1 inhibitor. When compared to CB1 inverse agonists, hemopressin also shows a dose-dependent hypotensive effect in mice [ 423 , 424 ]. It further decreased food intake in normal and obese rodents without any adverse side effects [ 424 ].…”

“…When compared to CB1 inverse agonists, hemopressin also shows a dose-dependent hypotensive effect in mice [ 423 , 424 ]. It further decreased food intake in normal and obese rodents without any adverse side effects [ 424 ]. However, many allosteric ligands so far being described and tested in vitro have not yet shown a sustained effect on CB1 signaling in vivo [ 425 ].…”

Disordered Peptides Looking for Their Native Environment: Structural Basis of CB1 Endocannabinoid Receptor Binding to Pepcans

“…The name “pepcans” (endocannabinoid peptides) refers to a family of hemoglobin-derived peptides that act as endogenous ligands of the cannabinoid (CB) receptor CB1 (Bauer et al, 2012 ; Macedonio et al, 2016 ). This G-protein coupled receptor (GPCR) is widely expressed in the nervous system and, together with the CB2 receptor, mostly expressed by immune cells, is the primary target of endocannabinoids, such as anandamide and 2-arachidonoylglylcerol (2-AG), and of phytocannabinoids, among which Δ 9 -tetrahydrocannabinol (THC), the main active component of marijuana (Mechoulam and Parker, 2013 ; Macedonio et al, 2016 ).…”

“…The name “pepcans” (endocannabinoid peptides) refers to a family of hemoglobin-derived peptides that act as endogenous ligands of the cannabinoid (CB) receptor CB1 (Bauer et al, 2012 ; Macedonio et al, 2016 ). This G-protein coupled receptor (GPCR) is widely expressed in the nervous system and, together with the CB2 receptor, mostly expressed by immune cells, is the primary target of endocannabinoids, such as anandamide and 2-arachidonoylglylcerol (2-AG), and of phytocannabinoids, among which Δ 9 -tetrahydrocannabinol (THC), the main active component of marijuana (Mechoulam and Parker, 2013 ; Macedonio et al, 2016 ). The ensemble of endocannabinoids and their receptors constitutes the Endocannabinoid System (ECS), which is involved in a wide range of physiological processes and manifestations, including cognitive function, pain, anxiety and appetite regulation (Pagotto et al, 2006 ; Watkins and Kim, 2015 ; Reddy and Golub, 2016 ; Leone et al, 2017 ).…”