MEDICINAL CHEMISTRY-MEDICINAL CHEMISTRY-IIIIII

Lecture 4 Sat. 19/ 5/ 1432H

Analgesics The analgesics may be divided into two The analgesics may be divided into two

main classes: main classes:

a) Opium and its alkaloids [morphine a) Opium and its alkaloids [morphine & related compounds] ……..Narcotics & related compounds] ……..Narcotics Analgesics or Opiate DrugsAnalgesics or Opiate Drugs

b) Non-Opiate Drugs [Aspirin & b) Non-Opiate Drugs [Aspirin & Phenacetin] ……… ……..Analgesic Phenacetin] ……… ……..Analgesic AntipyreticsAntipyretics

Centrally Acting Analgesic(Narcotic analgesic)

The term centrally acting analgesic is used for compounds which inhibit the pain reaction within the central nervous system.

Opium contains more than 25 alkaloids. There are two types of ring systems found in opium alkaloids

Phenatheren ring system e.g. Morphine, Codeine, Thebaine

Isoquinoline ring system e.g. Papaverine

Centrally Acting Analgesic

I.I. Opioid agonistsOpioid agonistsa. Morphine and morphinan derivativesa. Morphine and morphinan derivatives e.g. Morphine, Codeine ………… e.g. Morphine, Codeine …………

b. Piperidine derivatives b. Piperidine derivatives Mepiridine and congenersMepiridine and congeners

Methadone and congenersMethadone and congeners

Other structures e.g. TramadolOther structures e.g. Tramadol

II Mixed Opioid Agonist-Antagonist and Partial Agonists

e.g. Nalorphine

II Opioid Antagonists e.g. Levallorphan

III Nonopioid compounds e.g. Nefopam

Opioid AgonistsMorphine

7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol

It is the principle alkaloid obtained from the dried latex (opium) from the unripe fruit of poppy (papaver somniferum)

Morphine is one of the most effective pain killers in medicine. It is used in treating dull constant pain.

Other effects:

Respiratory depression Constipation Tolerance and physical dependence Euphoria Nausea and vomiting Dull Pupil constriction Biliary colic Flushing and warming

1, 3, 5, are the most dangerous side effects. Withdrawal symptoms are also dangerous, they include anorexia, pupil dilatation, chills, excessive sweating, cramps, muscle spasms, irritability, tremors etc……………..

Structure activity relationships:-

Stereochemistry: Natural morphine is levo (-), the dextro

isomeris has been synthesized and it is devoid of analgesic and other opioid activities.

1. Alkylation of OH at C-3

Methylation

Codeine

Codeine has less analgesic activity & used mainly as antitussive drug.

7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol

Codeine …………… Prodrug…………..metabolized ……………Morphine

(CH3I)

Morphine

Methylation

O-demethylation (HI)

Codiene

Ethylation Dionine (ethyl morphine)

7,8-didehydro-4,5-epoxy-3-ethoxy-17-methylmorphinan-6-ol

Dionine is used in ophthalmology as analgesic, especially in glucoma

Alkylation with Alkylation with morphoine ethyl morphoine ethyl chloridechloride

PholcodinePholcodine

7,8-didehydro-4,5-epoxy-3-O- (2-morphoinoethyl)-17- methylmorphinan-6-ol

Pholcodine used as antitussivePholcodine used as antitussive

OOH

N

CH3

O

NO

2. Acetylation: at C-3 & C-6 (Diamorphine, Heroin) (diacetyl morphine)(Diamorphine, Heroin) (diacetyl morphine)

Characters: - more potent analgesic than morphine due to its high lipid solubility. - more addictive. - weaker antitussive. - metabolism ………….. 6-acetyl morphine which is more

active than morphine. …………… diacetylation of acetyl group at C-3

& C-6 giving morphine.

7,8-didehydro-4,5-epoxy-3,6-diacetyloxy-17-methylmorphinan.

7,8-double bond

Reduction of 7,8 double bond ……………….dihydromorphine

………………..dihydrocodiene

4,5-epoxy-17-methylmorphinan 4,5-epoxy-3-methoxy-17-methyl-

3,6-diol morphinan-6-ol is more active than morphine antitussive, analgesic

If the reduction is accompanied by oxidation of OH at C-6 to ketone…………………….. activity toxicity

Hydromorphone Hydrocodone 4,5-epoxy-3-hydroxy-17- 4,5-epoxy-3-methoxy-

17- methylmorphinan-6-one methylmorphinan-6-

one