Opium has over 20 types of alkaloids. The principle alkaloid in the mixture, one of the most responsible for opium’s analgesic and sedative activity, is Morphine. The first isolation of the pure Morphine had been made in 1803. However, it has not been used in a commercial way until 1833 that chemists at Edinburgh were able to isolate and purify it in a more efficient way. Morphine can be taken orally but it will be poorly absorbed, in this way it was hardly been used in the clinical environment. However, everything changed after the Hypodermic syringe came out in 1853. This method is able to help the doctor to inject the drug directly into patients’ blood, in this way Morphine started to show out its great potent purpose of analgesic and sedative it has, which makes it a far more effective drug than the Opium. But its use still gets limited due to its cost, the risks of addiction, tolerance and respiratory depression were also slowly increased.








Different ways of showing the structure of Morphine


Morphine, a compound which has a really complex structure, and it always is a challenge for the chemists to find out the structure of the Morphine. The functional groups have only been discovered until 1881; however, after many years later the full structure of the Morphine had finally been found even though some parts of it was wrong. At the old days, the only way of identifying the structure of the compound is to break the compound into different smaller and simpler molecules such that each small molecules could be recognized and all of them make up the bigger and more complicated compound. Here is an example: the degradation of the morphine with a string base will produce an N-CH3 structure in the molecule. From this, the chemists will try to propose the structure of the compound. Once the natural structure of the compound has been found the chemists will start to synthetic the structure. If the structure which they have got has the same purpose with the original one, it shows the structure which the chemists have found is proven. Because of all these steps, they make the process becomes longer and much more complicated. Thus it will be an even longer process back in 19th century, for the chemists had fewer of the synthetic reagents which will be available for them to use compare what the chemists have nowadays. As a result, it is not until 1925 that Scientist Robert Robinson corrected the structure of Morphine. The process of synthesizing the Morphine appears until 1952. Finally, the structure has been completely being proved by using the X-ray until 1968 which took the chemists 164 years since Morphine was found at the very beginning. Morphine is a basic because of the tertiary amino group. Other structures it contains are Phenol, Alcohol, Aromatic ring, ether bridge, and the alkene double bond.














Structure of the Morphine


Following the development of the Morphine, it is normal that the chemists are trying to use the reactions which are already known for the day to synthesize various analogues and to see whether these had analgesic characters or not. Different tests have been used to assess analgesic activity. Nevertheless, some of the conclusions can be about the importance or of different functional groups. For example, that the alkene or 6-hydroxy group can be modified or removed in the structures like Heterocodeine, 6-ethylmorphine, 6-acetylmorphine, 6-oxymorphone, Hydromorphine and Dihydromorphine. In the same order from left to right top to bottom) Among all these structures the analgesic activity is maintained.






















Analogues of Morphine


However, the analgesic activity level has dropped significantly for some of the structures,  for example, the structure of the Dihydromorphine which do contain the phenolic group and this shows that the importance of the phenolic group to the analgesic activity of the drug; also there are other studies results proved that the OH phenol group is an important functional group for analgesic activity. Despite the OH phenol group, there are few other groups are important to the analgesic activity such as the aromatic ring and the tertiary amine which is protonated (Be added on H+) and ionized when the drug reacts with its target binding site. So let us move onto the stereochemistry of the Morphine. Morphine exists as a single stereoisomer which contains several chirality centres. When the Morphine is first been made it is made as a racemic mixture which means it is a mixture contains both its original enantiomer and its mirror image enantiomer. Thus, it was noticeable that the activity of the synthetic morphine was half that of natural morphine, and separation of the enantiomers revealed that unnatural enantiomer had no analgesic activity.


















Morphine enantiomers


To conclude, analgesic activity is not just depending on the presence of the important functional groups defined earlier, but to their relative position with respect to each other as well-the Pharmacophore. The Pharmacophore of Opioid is able to be defined in different ways, you can either define it as a skeleton which connects all the important functional groups or by the Pharmacophore triangles where the corners correspond to functional groups or binding interactions. So how actually the Morphine works in our bodies to kill pains? Well, Morphine acts directly on the Opioid receptors - GPCR receptors which are receptor sites of Endorphins, they are the natural body pain reducers. After Morphine acts on the GPCR it triggers an increased conduction through potassium channels, decreased conduction go through the channels. Also, an inhibition of adenylyl cyclase also called adenylate cyclase. All of these changes in our Nervous system reduce the effect of our body’s signalling systems that transmit pain.

The final thing for the Morphine is to have a word of caution regarding the importance of the phenyl group. It does not question that the Phenol group is important for the opioid pharmacophore for receptor binding, but it is not necessarily as important when one considers the analgesic activity of different opioid structures involves. It is because the pharmacokinetic factors have an important role in the level of analgesic activity observed as well.

These are all the things which I roughly want to say about Morphine which is a drug in the Opioid/ Opiates category. It is normally used to treat pains and anxiety in the clinical environment. However, it can also be abused which can act as a really addictive drug. In this case, the doctors are always really careful before they use the Morphine, maybe not only Morphine but also other types of Psychoactive drugs which always have high addictive risks.