Opioid Analgesics Mallika Doss April 10 2008 Overview

Opioid Analgesics Mallika Doss April 10, 2008

Overview • History • Morphine – SAR of Morphine – Drug Dissection of Morphine • Morphine Analogues • Opioid Receptors & Receptor Binding • Agonists and Antagonists • Why you feel “happy” • Endogenous Opioid peptides • The Future

The History • • First use in Mesopotamia First recorded use in China 632 AD – Opium reaches Spain, Persia, and India 17 th century – Tobacco comes to China 1644 – Chinese emperor bans tobacco 19 th century – China closes its doors to the world Deprived of tobacco, Chinese people start smoking opium! • Opium production in China couldn’t keep up with demand. British East India company sees opportunity. • 1830 s – £ 1 million of opium smuggled into China via Port Canton.

The History • Chinese authorities burnt down the port; British traders outraged. • 1839 -42 – Opium Wars; Chinese were defeated and forced to lease trading port to Britain. • 19 th century – Opium dens common in Britain. • 1882 – Addictive properties of opium discovered but largely ignored. • 1909 – IOC set up to curb opium production • 1924+ – Opium production went underground

Morphine • Named after the Greek God, Morpheus (God of dreams) • Good for treating dull, constant pain rather than sharp, periodic pain • Side effects: – Excitation Maximize – Euphoria – Nausea – Pupil constriction – Constipation – Tolerance and Dependence Minimize – Depression of breathing

Morphine - SAR Phenolic OH Required Ether bridge Not Required 6 -alcohol Not Required Aromatic ring Required N-methyl group Required Double bond at 7 -8 Not Required

Morphine – Drug Dissection Activity retained E D B C Methadone Morphinans Benzomorphans 4 -phenylpiperidines Loss of activity

Morphine Analogues - Codeine • How it’s related – Methyl ether of morphine • Activity – 20% that of morphine • Pro-drug of morphine – Metabolized by Odemethylation in the liver to make morphine

Morphine Analogues - Codeine • Treats: – Moderate pain – Coughs – diarrhea • Marketed as: – Tylenol® with Codeine – Hydrocodone – Vicodin® (with Thebaine)

Morphine Analogues - Heroine • How it’s related: – 3, 6 -diacetyl ester of morphine • Activity: – 2 x that of morphine • Polar groups are hidden, making it easy to cross BBB. • Treats: – Pain in terminally ill patients • Side effects – Euphoria, addiction, tolerance • Marketed as: – Heroin, “dope”

Morphine Analogues - Heroine 6 -acetylmorphine • How it’s related: – 6 -acetyl of morphine • Activity – 4 x that of morphine! • Polarity decreased, but phenol is ready to bind receptor 6 -acetylmorphine • Side effects: Very potent!! – Euphoria, addiction, etc. • Marketed as: – NOTHING! It’s banned from production in many countries

Morphine Analogues - Morphinans Levorphanol • How it’s related: – Ether bridge removed • Activity: – 5 x that of morphine • Advantage: – It can be taken orally – Lasts longer – Easier to synthesize • Side effects: – High toxicity, comparable dependence • Marketed as – Levo-Dromoran®

• • • Morphine Analogues Benzomorphans How it’s related – Rings C and D removed Activity – 4 x + that of morphine Advantages – No addictive properties – Does not depress breathing – Lasts longer Side effects – Hallucinogenic Marketed as – Prinadol, Norphen – Fortal, Talwin NX Phenazocine Pentazocine

Morphine Analogues – 4 phenylpiperidines Fentanyl • How it’s related: – Rings B, C, D removed • Activity: – 100 x that of morphine • Advantages: – Cross BBB efficiently – Really easy to make – Rapid onset, short duration – Can be administered any way (IV, oral, transdermal, buccal)

Morphine Analogues – 4 phenylpiperidines • Used for: – Anesthesia – Chronic pain management • Side effects: – Sudden respiratory depression – More addictive than heroin – Less euphoria, more sedation • Marketed as: – Sufenta (used in ♥ surgery) – Carfentanil (used in vet practice) – “Percopop”, Oxy. Contin, “magic” (heroin/cocaine)

Morphine Analogues - Methadone • How its related: – Rings B, C, D, E opened • Activity – < Morphine • Used to: – Ween addicts off heroine or morphine • Advantages: – Can be given orally – Less severe side effects • Marketed as – Dolophine®, Amidone®, Methadose®

Morphine analogues - Naltrexone • How it’s related: – Cyclopropylmethylene added to morphine • Activity: – None? ! • Morphine antagonists • Used to treat: – Morphine overdose – Heroin addicts post-rehab • Advantages: – No side effects • Marketed as: – Revia, Depade, Vivitrol Naltrexone Nalorphine

Agonists and Antagonists Equatorial Antagonist binding area Axial Agonist binding area

SIDE NOTE: • Other factors important to receptor binding: – Stereochemistry • Enantiomers of many of the analogues were tested for analgesic activity. Overall, they didn’t have any. – Rigidification • Used to maintain active formation and eliminate alternative conformations • Increases selectivity for receptors

Opioid Receptors • Receptor-binding motif: – Phenol OH – Aromatic ring – Amine group

Opioid Receptors Most strongly Receptor Location binds type morphine Best bet for a safe analgesic Effects μ Brain, spinal cord Analgesia, Respiratory depression, euphoria, addiction, ALL pain messages blocked κ Brain, spinal cord Analgesia, sedation, all nonthermal pain messages blocked δ Brain Analgesia, antidepression, dependence

Receptor binding - μ • Opening of the K+ channel hyperpolarizes the membrane Morphine • Action potential not sent μ • Ca+2 not released Hyperpolarized! • Reduces neurotransmitter release

Receptor Binding - κ Morphine κ • Binding causes closing of Ca+2 channels • Neurotransmitters not released • Pain message not sent

Why you feel “happy”

Why you feel “happy” • Heroin modifies the action of dopamine in the brain. • Once crossing the blood-brain barrier, heroin is converted to morphine, which acts as an agonist. • This binding inhibits the release of GABA from the nerve terminal, reducing the inhibitory effect of GABA on dopaminergic neurones. • The increased activation of dopaminergic neurones and the release of dopamine into the synaptic cleft results in activation of the post-synaptic membrane. • Continued activation of the dopaminergic reward pathway leads to the feelings of euphoria and the ‘high’ associated with heroin use.

Endogenous Opioid Peptides • Your body’s natural painkillers • Have a preference for the δreceptor • Alternative method of pain relief inhibit the peptidases Met-enkephalin that degrade them thiorphan (still new) • 3 types of EOPs: – Enkephalins – Dynorphins – Endorphins

The Future • Find an agonist that solely binds to the κ-receptor • Explore the μ-receptor subtypes further to see if any of them don’t cause harmful side effects • Peripheral opiate receptors – avoid BBB obstacle • Block postsynaptic receptors involved in the transmission of a pain signal • GABA • Agonists for the cannabinoid receptor

References