21 Principles of Pharmacology - Opioid Pharmacology
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Course
Pharmacology
Institution
Pharmacology
The object of the course is to teach students an approach to the study of pharmacologic agents. It is not intended to be a review of the pharmacopoeia. The focus is on the basic principles of biophysics, biochemistry, and physiology as to the mechanisms of drug action, biodistribution and metabolis...
Harvard-MIT Division of Health Sciences and Technology
HST.151: Principles of Pharmocology
Instructor: Dr. Carl Rosow
HST-151 1
Opioid Pharmacology
Definitions
1. Opium – a mixture of alkaloids from Papaver somniferum
2. An opiate is a naturally occurring alkaloid, i.e., morphine or codeine.
3. An opioid is any natural or synthetic compound, which has morphine-like properties.
Hundreds of opioid alkaloids and peptides have been synthesized, but all clinically
available opioid analgesics are alkaloids.
Structure-Activity Relationships
1. Most opioid analgesics are related to morphine (see figure).
2. Distinctive features of morphine include 5 rings, 3- and 6-hydroxyl groups (phenolic
and alcoholic), piperidine ring with an N-methyl group, and a quaternary carbon at
position 13. Morphine is optically active, and only the levorotatory isomer is an
analgesic.
N-CH N-CH
3 3
HO O OH COOC H
2 5
MORPHINE MEPERIDINE
3. Simple modifications of morphine make active analgesics
• Codeine is morphine O-methylated at position 3.
• Heroin is morphine O-acetylated at positions 3 and 6.
4. Replacing the N-methyl with something larger (allyl, cyclopropyl, cyclobutyl)
usually produces a compound with opioid antagonist properties. N-allyl substitution
of morphine and oxymorphone produces the antagonists nalorphine and naloxone,
respectively.
5. Morphine may be modified extensively but still have agonist activity. Meperidine
(Demerol) is a synthetic opioid with only fragments of the morphine structure (see
figure above).
Opioid Classification
1. Based on intrinsic activity
• Agonists (morphine, fentanyl)
• Pure antagonists (naloxone, naltrexone)
• Mixed agonist-antagonists (nalbuphine, butorphanol)
2. Based on interaction with µ, κ, or δ opioid receptor subtypes
, HST-151 2
• All three receptors have been cloned, and knockout mice created.
• Each receptor thought to have 2-3 (or more) subtypes, but no distinct gene
products have been identified. All belong to the superfamily of G-protein
coupled receptors.
• Most opioid analgesics are relatively selective µ opioid agonists. The various
µ effects are discussed below.
• A few analgesics (pentazocine, nalbuphine, butorphanol) are κ agonists,
although they are not highly selective. Experimental selective κ drugs
produce analgesia, but also unique effects like diuresis and dysphoria.
• The selective δ agonists are mainly peptides. Receptor may function
permissively with µ receptor (allosteric interaction?).
Endogenous Opioid Peptides
1. Enkephalins include several compounds derived from a large proenkephalin molecule
(also called proenkephalin A).
• Most important compounds are pentapeptides, methionine- and leucine-
enkephalin. Relatively selective δ ligands.
• Widely distributed in CNS
• Act like morphine to modulate neurotransmitter release (see p. 3)
• Found with catecholamines in sympathetic terminals and adrenal.
2. Endorphins (chiefly β-endorphin) are derived from the large precursor molecule pro
opiomelanocortin (POMC).
• POMC also the precursor for ACTH and MSH, which are found together with
β-endorphin.
• β-endorphin is a 31 amino acid peptide which has analgesic activity in man
and animals. It binds preferentially to µ receptors.
• Localized primarily in pituitary and hypothalamus.
3. Dynorphins are derived from a prodynorphin molecule (also called proenkephalin B).
• Dynorphin A is a 17 amino-acid peptide which is a potent and highly
selective agonist at κ receptors.
• Similar distribution to the enkephalins.
4. Opioid peptides are located in places which allow them to function as
neurotransmitters or neuromodulators.
5. Probably modulate pain transmission in the cord and alter acetylcholine release in the
myenteric plexus.
6. Postulated to play fundamental roles in areas as diverse as hormonal secretion,
thermoregulation, and cardiovascular control.
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