Signaling molecules targeting cannabinoid receptors: Hemopressin and related peptides

Cannabinoid receptors (CBRs) are part of the endocannabinoid system, which is involved in various physiological processes such as nociception, inflammation, appetite, stress, and emotion regulation. Many studies have linked the endocannabinoid system to neuroinflammatory and neurodegenerative disorders such as Parkinson's disease, Huntington's chorea, Alzheimer's disease, and multiple sclerosis. Hemopressin [Hp; a fragment of the hemoglobin α1 chain (95–103 amino acids)] and related peptides [VD-Hpα and RVD-Hpα] are peptides that bind to CBRs. Hp acts as an inverse agonist to CB1 receptor (CB1R), VD-Hpα acts as an agonist to CB1R, and RVD-Hpα acts as a negative allosteric modulator of CB1R and a positive allosteric modulator of CB2R. Because of the critical roles of CBRs in numerous physiological processes, it is appealing to use Hp and related peptides for therapeutic purposes. This review discusses their discovery, structure, metabolism, brain exposure, self-assembly characteristics, pharmacological characterization, and pharmacological activities. •Cannabinoid receptors (CBRs) are involved in various processes, e.g., nociception.•Hemopressin acts as a CB1R inverse agonist.•RVD-hemopressin acts in a manner consistent with allosteric modulators of CBRs.•It is appealing to use hemopressin and related peptides for therapeutic purposes.