Exploiting the isomerism of molecules is particularly important in medicine and biological applications because enzymes tend to interact differently from one isomer to another.
In chemistry, two molecules are isomers if their molecular formula is the same, but they differ in their spatial orientation or the bond location within the atoms. In the first case we talk about stereoisomers, while in the second case the molecules are defined as structural or constitutional isomers. [1]
It should be noticed that “isomerism” doesn’t mean that the molecules have the same chemical or physical properties: in nature there are many examples of molecules that can have completely different interactions with biological targets even due to a very small difference in the position of a single chemical bond.
Phytocannabinoids derived from cannabis, such as cannabidiol (CBD) and tetrahydrocannabinol (THC), could be taken as an example to explain isomerism. These two compounds share the same molecular structure: 21 atoms of carbon, 30 of hydrogen and two of oxygen. Nevertheless, the arrangement of these atoms is slightly different, and this structural diversity is responsible for huge differences in the biological action of these cannabinoids on our body: both molecules interact with cannabinoid receptors (CB) of our endocannabinoid system (ECS), but while THC is psychoactive and binds mainly to CB 1 in the brain producing psychotropic effects, CBD interacts differently and it is capable of modulating THC activity on CB receptors. So the similarity of their structure make CBD and THC both lipophilic and capable of crossing the blood brain barrier (BBB), while the differences affect their interaction within receptors and thus their therapeutic effects.
When THC is synthesized from CBD through intramolecular cyclization it is possible to obtain mainly two different molecules depending on how the ring fusion will occur: THC-9 or THC-8. [2]The former is the well known form of THC and also the major psychotropic substance produced by many cannabis varieties, while the latter occurs only in traces in nature and differs from THC-9 just in the position of one double bond in the cyclohexene ring. The structural difference makes THC-8 less potent in comparison with THC-9 because of the weaker interaction within the cannabinoid receptors, but it is also more chemically stable and therefor less prone to oxidation or conversion to cannabinol (CBN) over time. In addition to THC-8, there are also other isomers that can be present in trace amounts in cannabis plants, THC-10 among others.
The great challenge of scientists and researchers is to understand the differences within the molecules and to study systematically the subtle changes in molecular activity derived from the isomeric relation, which could lead to improved therapeutic benefits or reduction of unwanted side effects.
References:
[1] Chhabra, Naveen; Aseri, MadanL; Padmanabhan, Deepak (2013). A review of drug isomerism and its significance. International Journal of Applied and Basic Medical Research, 3(1), 16–. doi:10.4103/2229- 516x.112233 [Times cited = 175 ]
[2] Paola Marzullo, Francesca Foschi, Davide Andrea Coppini, Fabiola Fanchini, Lucia Magnani, Selina Rusconi, Marcello Luzzani, and Daniele Passarella, Journal of Natural Products 2020 83 (10), 2894-2901; DOI: 10.1021/acs.jnatprod.0c00436 [Journal impact factor = 4.803] [Times cited = 13]
