Essay on Opioid Analgesics

Morphine is an opiate which is derived from poppy plant, Papaver somniferum . Extracts of this plant (opium) were used by a Greek scientist Galen to treat Vertigo, epilepsy, deafness, venom poisoning, asthma, jaundice among many other ailments. In 1800s, opium was used as a painkiller but its used was limited by the unpredictability of its effects CITATION Jos15 \l 1033 (Hudlicky, 2015).

Morphine was discovered by a German pharmacist, Friedrich Wilhelm Adam Serturner. In 1799, Friedrich began working as an apothecarys apprentice in Paderborn, Germany. During his service as an apprentice, Friedrich watched as physicians lamented about the unpredictability of opium to his boss. Realizing that this unpredictability could only be solved through standardization of dosages, he resorted to isolate the active ingredient in opium. Utilizing his bosss equipment, he isolated a yellow-white crystal after submersion in ammoniated water. This crystal became the first ever alkaloid isolated from a plant source CITATION AFC13 \l 1033 (A.F. Casy, 2013).

He then conducted a few experiments on dogs with a few of them dying until the doses were accurately adjusted. He named the isolated crystals, Morphine after the Greek god of dreams, Morpheus owing the crystals sleep-inducing effects CITATION AFC13 \l 1033 (A.F. Casy, 2013).

However, due to his inexperience and lack of proper equipment, his invention was not readily received by the medical community. He thus conducted further research on it. Years later, when he was having a severe toothache, he used a small amount of morphine on himself. That heralded the analgesic use of morphine CITATION AFC13 \l 1033 (A.F. Casy, 2013). Addiction was a side effect of morphine use.

Generic, chemical and trade names of morphine

Generic name: Morphine

Chemical name: (5a,6a)-7,8-didehydro- 4,5-epoxy-17-methylmorphinan-3,6-diol

Trade name: Roxanol, Kadian, MS Contin, Morphine Sulfate ER, Morphabond, Oramorph SR, MSIR,

Describe the method of molecular modification of at least 5 analogs to morphine (Write the structure, generic, chemical and trade names and method of synthesis of all compounds)

Codeine: Synthesized by heating morphine under reflux with concentrated sulfuric acid and acetic acid. An esterification reaction occurs.

Chemical Name: (5a,6a)-7,8-didehydro-4,5-epoxy- 3-methoxy-17-methylmorphinan-6-ol

Generic Name: MethylmorphineTrade Name: Ascoril C, Altec, Codifen

Heroin

It is formed from a reaction between morphine and acetic anhydride;

Chemical Name: (5a,6a)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol diacetateGeneric Name: Diamorphine, Diacetylmorphine

Trade Name: Heroin

Oxycodone

It is synthesized from oxidation of thebaine to form 14-Hydroxycodeinone which is reacted with a reducing agent to form Oxycodone.

Chemical Name: 4, 5a-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride.

Generic Name: dihydrohydroxycodeinoneTrade Name: Oxycontin,

ThebaineObtained from methylation of the potassium form of Codeine to form codeine methyl ether with is oxidized to give thebaine.

Chemical Name: 6,7,8,14-tetradehydro-4,5a-epoxy-3,6-dimethoxy-17-methylmorphinan

Generic Name: DimethylmorphineTrade Name: Vivitrol (When thebaine is converted to Naltrexone)

Hydrocodone

It is synthesized by subjecting thebaine to palladium catalyst in aqueous medium.

Chemical Name: 4,5a-epoxy-3-methoxy-17-methylmorphinan-6a-olGeneric Name: DihydrocodeinoneTrade Name: Vircodin, LortabDescribe the type of bioisosterism of at least 5 analogs to morphine (Write the structure, generic, chemical and trade names and method of synthesis of all compounds)

Among the 4-Anilinopiperidine group of opioids, substituting the N-phenethyl group with biososteres gives the Fentanyl congeners; Sufentanil, Alfentanyl, Remifentanyl, Lofentanyl.

SulfentanylWith an isosteric replacement of the phenyl of the phenethyl group with a thiophene ring, the resulting compound is about 7 times more potent than fentanyl with an immediate onset of action and a similar recovery time compared with fentanyl.It is synthesized from thiophenylethylamine through a six step process.

Trade Name: SufentaChemical Name: N-[4-(Methoxymethyl)-1-(2-thiofuran-2-ylethyl)-4-piperidyl]-N-phenylpropanamide

Generic Name: SulfentanilRemifentanylIt undergoes faster metabolism and has a shorter duration of action.

Chemical Name: Methyl 1-(3-methoxy-3-oxopropyl)-4-(N-phenylpropanamido) piperidine-4-carboxylate

Trade Name: UltivaGeneric Name: Remifentanil.

LofentanylChemical Name: methyl (3S,4R)-3-methyl-1-(2-phenylethyl)-4-[phenyl(propionyl)amino]piperidine-4-carboxylate

Trade Name: Wildnil.

Alfentanyl The substitution of the phenethyl ring for an ethyl-substituted tetrazole-one yielded a compound with about one fourth to one third the potency of fentanyl. Although less potent, it has a quicker onset of action, a shorter duration of action, and thus a better, safety profile for use as an anesthetic adjunct.

Trade Name: AlfentaChemical Name: AlfentanilMention 2 pro-drugs of some analogs and illustrate the objectives of designing these pro-drugs (Write the structure, generic, chemical and trade names and method of synthesis of all compounds)

Codeine

Codeine, a pro-drug, has no analgesic activity. In the body, about 10% of Codeine is converted to Morphine, an active analgesic.

Tramadol, a pro-drug is converted in the liver to O-Desmethyltramadol (O-DSMT). O-DSMT is a more potent m opioid agonist than tramadol.

Synthesis: Made from catalytic hydrogenation of Salicylic acid followed by reacting the intermediate with a Grignard reagent.

Chemical Name: (a) cis-2-[(dimethylamino) methyl]-1-(3-methoxyphenyl cyclohexanolGeneric Name: Tramadol

Trade Name: Ultram, ZytramOutline the possible types of interactions involved in the drug receptor complex of at least 5 analogs to morphine. (Write the structure, generic, chemical and trade names and method of synthesis of all compounds)

There are three ways in which analogues of morphine interact with the opioid receptors; agonism, antagonism, Partial agonist antagonism

Agonists are drugs which bind to an opioid receptor and activate the same receptor. Examples of opioid agonists include; Codeine, Oxycodone, fentanyl, Hydrocodone.

Codeine

It is synthesized by heating morphine under reflux with concentrated sulfuric acid and acetic acid. An esterification reaction occurs.

Chemical Name: (5a,6a)-7,8-didehydro-4,5-epoxy- 3-methoxy-17-methylmorphinan-6-ol

Generic Name: MethylmorphineTrade Name: Ascoril C, Altec, Codifen

Oxycodone

It is synthesized from oxidation of thebaine to form 14-Hydroxycodeinone which is reacted with a reducing agent to form Oxycodone.

Chemical Name: 4, 5a-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride.

Generic Name: dihydrohydroxycodeinoneTrade Name: Oxycontin,

Opioid antagonists on the other hand bind to the opioid receptor in the same manner as agonists but they dont activate the receptor. They prevent binding of the opioid agonist to the receptor. Examples include; Naloxone, Naltrexone, Nalophine

Naloxone

It is made from reacting Oxymorphone with Grignard reagent.

Trade Name: NarcanChemical Name: (4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-prop-2-enyl-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one

Generic Name: Naloxone

It is synthesized by acylation of oxymorphone in the presence of Palladium catalyst.

Trade Name: ReviaChemical Name: 17-(cyclopropylmethyl)-4,5a-epoxy- 3,14-dihydroxymorphinan-6-one

Generic Name: Naltrexone

Partial agonists-antagonists; These drugs either block the binding of other drugs to the opioid receptor or produce a much smaller effect compared to a full agonist. Examples include; Pentazocine, nalbuphine, butorphanol, and Buprenorphine.

ButorphanolIt is made from reacting Oxymorphone with Grignard reagent.

Trade Name: StadolChemical Name: (4bR,8aR,9S)-11-(cyclobutylmethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3,8a-diol

Generic Name: Butorphanol

References

A.F. Casy, R. P. (2013). Opioid Analgesics: Chemistry and Receptors. New York: Springer Science & Business Media.

Hudlicky, J. R. (2015). The Quest for a Practical Synthesis of Morphine Alkaloids and Their Derivatives by Chemoenzymatic Methods. American Chemical Society, 674-687.