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.