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 17th century – Tobacco comes to China 1644 – Chinese emperor bans tobacco 19th 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. 1830s – £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. 19th 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 Euphoria Nausea Pupil constriction Constipation Tolerance and Dependence Depression of breathing Maximize Minimize

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

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

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

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: 2x 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” Heroine

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

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

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

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”, OxyContin, “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 μ κ δ Most strongly binds morphine Receptor type Location Effects μ Brain, spinal cord Analgesia, Respiratory depression, euphoria, addiction, ALL pain messages blocked κ Analgesia, sedation, all non-thermal pain messages blocked δ Brain Analgesia, antidepression, dependence Best bet for a safe analgesic

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

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

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 δ-receptor Alternative method of pain relief  inhibit the peptidases that degrade them  thiorphan (still new) 3 types of EOPs: Enkephalins Dynorphins Endorphins Met-enkephalin

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