MEDICINAL CHEMISTRY-III Lecture 5 Wed. 23/ 5/ 1432H Prof. Dr. Wafaa Zaghary

Analgesic 1. A basic center ….. 2. A flat aromatic structure, ……. 3. A suitably positioned projecting hydrocarbon moiety ….

Morphine has 3 receptors:- Receptor of opiates Morphine has 3 receptors:- Mu (µ) the main receptor for analgesic & side effects Kappa (ķ) weak analgesic effect Delta (δ) weak analgesic effect Morphine binds to its receptors in the brain through 3 main binding sites:- a. Van der Waal forces Ring A b. H Bonding Phenolic OH c. Ionic bonding and cavity for C-15 and C-16

Structure Activity Relationships Modification at 3-oH and 6-OH Methylation of the phenolic OH reduces the analgesic activity considerably (thus codeine is about 6-10 times less potent) N.B. Alkylation of phenolic OH e.g. Codeine, Dionine, Pholcodine decrease activity due to …………………….. Larger group than reduces activity methoxy drastically

Diacetylation (heroin) yields a more potent drug than morphine Diacetylation (heroin) yields a more potent drug than morphine. This may be due to the fact that the phenolic acetate, which is cleaved in-vivo yields the potency intermediate 6-acetymorphine (4x) Heroin (2-3 x). 6-acetyl morphine present the desirable features of increased potency due to: 1. increased lipophilicity. 2. phenolic OH is free to bind to the receptor.

Aromatic ring is essential for activity, reduction or removal abolishes activity. Ether bridge is not essential, Compounds lacking this ring are called morphinans and are several folds more active than morphine. Oxidation of the OH at 6-position to a ketonic function particularly if the 7-8 double bond is also reduced affords a more potent drug (hydromorphone).

Introduction of OH group to hydromorphone at C-14 Oxomorphone Oxocodone Oxomorphone is several times more active than morphine. Chemical Name …………………

Modification at 17-N Any exchange of N-methyl group with larger alkyl, alkenyl and arylalkyl function giving different activity depending on the size of alkyl group. the bulk of the alkyl group < 3C Activity e.g. N-CH3 N-C2H5 If the alkyl group = 3C Antagonist character. e.g. N-CH3 N-CH2-CH=CH2 , the activity is ………….

Nalorphine acts as antagonist & partial agonist. Nalorphine is used in treatment of morphine addiction and respiratory depression. Nalorphine acts at two opioid receptors, at the mu receptor it has antagonistic effects and at the kappa receptors it exerts agonistic characteristics. It is used to reverse opioid overdose and (starting in the 1950s) in a challenge test to determine opioid dependence. Block the main receptor for analgesic activity at mu Antagonist Open kappa receptor partial agonist

Antagonists Modification of Nalorphine OH at C-14 convert oh at C-6 into keto group i.e. replacement of alkyl in position 17 of Oxomorphone by allyl group Naloxone block all receptors [(µ), (ķ)& (δ) ]

Naltrexone Pure antagonist It can displace morphine from all these receptors

Removal of alkyl group Normorphine ……… demethylation at N-17 ……… more polar ………….. Lipophilicity ………. Activity. Also, quaternization at position 17 the activity due to …..

Morphine Rule From SAR of morphine, it was reached to a generalization known as morphine rule for an opioid to be active, it will have the following characteristic:- Central Quaternary carbon attached to phenyl group and separated from tert. nitrogen by a bridge of 2 carbons.

Structure Activity Relationship 1. A tertiary nitrogen, with the group on the nitrogen being relatively small 2. A central carbon atom 3. A phenyl group or isosteric group with phenyl, connected t central carbon atom 4. A two carbon chain separating the central carbon atom from the nitrogen for maximal activity