SAR of Morphine (Structure Activity Relationship of Morphine)

SAR of Morphine – Structure Activity Relationship of Morphine

Opioid Analgesics

Opioid analgesics are drugs that denote all naturally occurring, semisynthetic and synthetic drugs, which have a morphine-like action, namely, relief from pain and depression of CNS associated with the drug dependence. Opium is a dark brown resinous material obtained from the poppy (Papaver somniferum) capsule. It has two types of alkaloids; Phenanthrene derivatives and Benzoisoquinoline derivatives. Opium has been known from 1500 BC. Sreturner, a pharmacist isolated the active principle of opium in 1806 and named it morphine. Narcotic analgesic agents cause sleep in conjunction with their analgesic effect. If a narcotic is used for a long time, it may become habit-forming (causing mental or psychological dependence) and physical dependence may lead to withdrawal side effects.

Opioid drugs are not only used as analgesics, but also possess numerous other useful properties. For example, morphine is used to induce sleep in the presence of pain, diarrhoea, suppress cough, and facilitate anaesthesia.

The term opioid is used generally to designate collectively the drugs, which bind speciﬁ cally to any of the subspecies of the receptors of morphine and produce morphine like actions. They tend to produce euphoria, which is an important factor in their addictive property that limits their use. Other limitations include, respiratory depression, decreased gastrointestinal motility leading to constipation, increased biliary tract pressure, and pruritis due to histamine release.

Therapeutics Uses of Opioid Analgesics

Management of acute, chronic, and severe pain of acute myocardial infarction, obstetric analgesia.
Cough suppression (codeine and dextromethorphan).
Treatment of diarrhoea (diphenoxylate and loperamide).
Management of acute pulmonary oedema.
Preoperative medication and intraoperative adjunctive agent in anaesthesia (fentanyl, alfentanyl, and sufentanyl).
Maintenance programmes for addicts (methadone).

SAR of Morphine (Structure Activity Relationship of Morphine)

SAR of Morphine was studied by

Modiﬁ cation of alicyclic ring
Modiﬁ cation of aromatic ring
Modiﬁ cation of 3 ° Nitrogen

1. Modiﬁcation on alicyclic ring

The alcoholic hydroxyl group at C-6 when methylated, esteriﬁ ed, oxydized, removed, or replaced by halogen analgesic activity as well as toxicity of the compound increased.
The reduction of C-6 keto group to C-6 β hydroxyl in oxymorphone gives Nalbupine, it shows antag- onistic action of μ receptors.
The saturation of the double bond at C-7 position gives more potent compound. Examples, Dihydro morphine and Dihydro codeine.
The 14 β hydroxyl group generally enhances μ agonistic properties and decreases antitussive activity. However, activity varies with the overall substitution on the structure.
Bridging of C-6 and C-14 through ethylene linkage gives potent derivatives.
Reaction of thebaine with dienophile (i.e diel’s alder reaction) results in 6, 14 endo etheno tetrahy- dro thebaine derivatives, which are commonly called ‘ oripavines’. Some oripavines are extremely potent μ agonist, for example, Etorphine and Buprenorphine are the best known. These derivatives are about thousand times more potent than morphine as μ agonist.

2. Modiﬁcation on phenyl ring

An aromatic phenyl ring is essential for activity.
Modiﬁcation on phenolic hydroxyl group decreases the activity.
Any other substitution on phenyl ring diminishes activity.

3. Modiﬁcation of 3° nitrogen

A tertiary amine is usually necessary for good opioid activity.
The size of the N substitution can dictate the compounds potency and its agonists and its reverse antagonistic property.
The N-methyl substitution is having good agonistic property, when increased the size of the substitution by 3–5 carbons results in antagonistic activity. Still larger substitutent on N returns agonistic property of opioids, for example, N-phenyl ethyl substitution is ten times more potent than N-methyl groups
N-allyl and N-cylo alkyl group leads to narcotic antagonistic property.

4. Epoxide Bridge

Removal of 3,4 epoxide bridge in morphine structure result in the compound that is refered to as morphinans.
The morphinans are prepared synthetically. As the synthetic procedure yielded compound is a racemic mixture, only levo isomer possesses opioid activity while the dextro isomer has useful antitussive activity, for example, Levorphanol and Butorphanol.
Levorphanol is a more potent analgesic than morphine.