Pinoline, also known as 6-methoxytryptoline or as 6-methoxy-1,2,3,4-tetrahydro-β-carboline (6-MeO-THβC), is a β-carboline long-claimed to be produced in the pineal gland during the metabolism of melatonin, however its pineal occurrence remains controversial. Its more common name is a contraction of "pineal β-carboline". The biological activity of this molecule is of interest as a potential free radical scavenger, also known as an antioxidant, and as a monoamine oxidase A inhibitor.
Use and effects It remains unknown whether pinoline has hallucinogenic effects in humans.
Pharmacology Pharmacodynamics Pinoline shows affinity for serotonin receptors, including the serotonin 5-HT1A, 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT7 receptors (Ki = 156–4,335nM). It is a high-efficacy partial agonist of the serotonin 5-HT2A receptor, an antagonist of the serotonin 5-HT2B receptor, and a full agonist of the serotonin 5-HT2C receptor, with () values of 2,140nM (75%) at the serotonin 5-HT2A receptor and 33nM (95%) at the serotonin 5-HT2C receptor and an of 1,120nM at the serotonin 5-HT2B receptor. Hence, pinoline appears to act as a potent and selective serotonin 5-HT2C receptor agonist.
The drug shows affinity for the serotonin transporter (SERT) (Ki = 172–572nM). It is a serotonin reuptake inhibitor, with an value of 1,100nM. Pinoline shows affinity for the imidazoline I2 receptor (Ki = 1,640nM) and for the α2-adrenergic receptor (Ki = 7,830nM). Conversely, it shows no affinity for the dopamine D2 receptor (Ki = >10,000nM). The drug is a weak monoamine oxidase inhibitor (MAOI), with an value for inhibition of of 41,500nM.
Both pinoline and tryptoline partially substitute for the psychedelic drug LSD in rodent drug discrimination tests. The substitution by tryptoline was further assessed and was found to be blocked by the serotonin receptor antagonist pizotifen and by the serotonin synthesis inhibitor para-chlorophenylalanine (PCPA). Pinoline has also been reported to produce anxiogenic-like effects in rodents, which theoretically might be mediated by agonism of serotonin 5-HT2C receptors. In addition, it has been reported to produce antidepressant-like effects in rodents.
Other actions One of pinoline's pharmacological properties is its ability to promote neurogenesis in vitro; even at trace concentrations.
Aluminium toxicity causes an increase in lipid peroxidation, with most damage occurring in the brain. A recent review of studies shows pinoline and melatonin to be effective at reducing the lipid peroxidation. Studies included both human and animal subjects. The studies’ results support that pinoline has antioxidant properties.
Lipopolysaccharide is produced by Gram-negative bacteria and stimulates the production of free radicals which in turn cause lipid peroxidation. A recent study compared the effectiveness of melatonin and other similar compounds on the lipopolysaccharide induced lipid peroxidation. The results showed support for pinoline’s ability to reduce damage from lipid peroxidation. Pinoline was also shown to be more effective than vitamin E at reducing lipopolysaccharide activity in the retina.
A 2010 study compared the antioxidant properties of compounds from the tryptophan metabolic pathway in the pineal gland against oxidative damage to the lipids and proteins of synaptosomes. Synaptosomes isolated from rat brains were used in an experiment assessing damage by measuring malondialdehyde, 4-hydroxyalkenal, and carbonyl content in the proteins. Pinoline was shown to be the most powerful antioxidant. These results support the evidence for pinoline’s antioxidant abilities and the potential to protect against oxidative damage.
Pharmacokinetics Pinoline is a substrate for CYP2D6.
Chemistry Synthesis The chemical synthesis of pinoline has been described.
Analogues Analogues of pinoline include tryptoline, 6-MeO-THH, shepherdine, 1-ethyl-6-hydroxytryptoline, tetrahydroharmine (THH or 7-MeO-THH), and tetrahydroharmol, among others.
History Pinoline was first described int he scientific literature by at least 1969.Taylor, D. P. (1969). Metabolism of 6-methoxy 1, 2, 3, 4 tetrahydro-[beta]-carboline: a specific serotonin elevator (Doctoral dissertation, University of Texas Health Science Center at Houston. Graduate School of Biomedical Sciences.).
Research Bausch & Lomb filed a patent for a drug delivery device utilizing this molecule, designed to treat various ophthalmic disorders in 2006.Bartels, S. P. (2006) U.S. Patent No. 20,060,292,202 Washington, DC: U.S.
See also Substituted β-carboline List of miscellaneous serotonin 5-HT2A receptor agonists
References
External links 6-MeO-THβC (Pinoline) - Isomer Design