Carbon monoxide-releasing molecules
CORMs are being developed as potential therapeutic agents to locally deliver CO to cells and tissues, thus overcoming limitations of CO gas inhalation protocols.
[4][5] The majority of therapeutically relevant CORMs are transition metal complexes primarily based on iron, molybdenum, ruthenium, manganese, cobalt, and rhenium.
These carriers are called photoCORMs and include both metal complexes and metal-free (organic) compounds of various structural motifs classified as a special type of photolabile protecting group.
Some ET-CORM prodrugs are activated by esterase enzymes for site specific liberation of CO.[8] Methylene chloride was the first organic CORM orally administered based on previous reports of carboxyhemoglobin formation via metabolism.
[9] Based on the synergism of the heme oxygenase system and CO delivery, a molecular hybrid-CORM (HYCO) class emerged consisting of a conjoined HO-1 inducer and CORM species.
The majority of the remaining 20% of heme derived CO production is attributed to hepatic catabolism of hemoproteins (myoglobin, cytochromes, catalase, peroxidases, soluble guanylate cyclase, nitric oxide synthase) and ineffective erythropoiesis in bone marrow.
[22][23] Other contributing sources include: the microbiome, cytochrome P450 reductase, human acireductone dioxygenase, tyrosinase, lipid peroxidation, alpha-keto acids, and other oxidative and redox mechanisms.
The first evidence of CO as a signaling molecule occurred upon observation of CO stimulating soluble guanylate cyclase and subsequent cyclic guanosine monophosphate (cGMP) production to serve as a vasodilator in vascular smooth muscle cells.
While CO commonly interacts with the ferrous iron atom of heme in a hemoprotein,[24] it has been demonstrated that CO activates calcium-dependent potassium channels by engaging in hydrogen-bonding with surface histidine residues.
The equilibrium dissociation constant for the reaction Hb-CO ⇌ Hb + CO strongly favours the CO complex, thus the release of CO for pulmonary excretion generally takes some time.
