Analgesics: drug discovery

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Analgesics drug discovery

• Jenny Laird
• AstraZeneca Research Development Montréal

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Choosing a target for drug discovery

• should cover an unmet medical need
• has to show demonstrable benefit over current
  treatments
• likely to make money!

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Pain is an Unmet Medical Need

• 1 in 8 of you will experience poorly relieved
  persistent pain at some point in your life
• Only 50 of patients with post-operative pain are
  satisfied with the pain therapy received
• Chronic unrelieved pain produces a disease state
  with progressive physical social dysfunction
• Reduction in Quality of Life similar to
  depression
• Heavy Socio-economic burden
• Poor choice of effective safe analgesic drugs
• The two main classes of analgesics (opiates and
  anti-inflammatories) were discovered two
  centuries ago

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PAIN
An unpleasant sensory and emotional experience
associated with actual or potential tissue
damage, or described in terms of such damage
IASP, Subcommittee on Taxonomy, 1979
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Nociceptive pathways peripheral sensory nerves
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Ascending Pain Pathways

• Topographic representation maintained
• Sites for pain modulation are spinal cord and
  thalamus

Pons
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One pain or many pains?
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Definitions

• Physiological/Normal Pain
• nociceptive pain
• related to actual or potential tissue injury
• initiates protective reflexes or behaviour
• withdrawal from stimulus or guarding of
  affected area
• Non-physiological or pathological pain
• pain which continues beyond the point where it
  serves a physiological purpose
• Neuropathic pain
• pain associated with damage to the peripheral or
  central nervous system
• often/always pathological pain

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Pain, Hyperalgesia and Allodynia
Cervero Laird (1996)
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INJURY
Spinal Cord
A? / C
N
Primary Hyperalgesia
LT
N
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Nociceptive pathways peripheral sensory nerves

• Nociceptors are sensitised after
  damage/inflammation

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Peripheral Sensitisation

• Peripheral injury or inflammation initiates
  cascades of pro-inflammatory mediators released
  from many tissues
• These agents act on Nociceptors
• decrease in threshold to stimulation
• develop spontaneous activity
• Sensory nerve terminals not only passive but
  contribute actively to the inflammatory process
• neurogenic inflammation

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Efferent functions of Nociceptors
Cervero Laird, 1996
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Pro-inflammatory mediators and nociceptors
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Prostaglandins and Arachidonic cyclo-oxygenase
(COX)

• Two isoforms of COX
• Both produce prostaglandins (PGE2, PGF2a, PGI)
• COX-1 is constitutive, expressed in most tissues
• physiological and homeostatic role, cell
  signalling
• COX-2 is inducible following inflammation, trauma
  etc
• found in immunocompetent cells (e.g. leukocytes)
• pathophysiological role, initiates, maintains
  inflammation
• Prostaglandins alone (particularly PGE2) do not
  directly excite nociceptors but sensitise them to
  other stimuli

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Responses of a C-fibre nociceptor to a mixture of
Inflammatory Mediators (10-5 M histamine,
bradykinin and serotonin)
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Migraine chronic, episodic pain of
neurovascular origin

• Exact mechanism underlying migraine not clearly
  understood
• assumed to be strong genetic linkage
• Neurogenic inflammatory mechanisms a major
  component
• Major role for 5-Hydroxytryptamine (5-HT)
• principal current therapy is based on agonists at
  5-HT1D receptor sub-type
• so far 11 5-HT receptor sub-types and still
  counting
• Trigeminal neuronal system main pathway for
  initiation and pain perception

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Central Sensitisation

• Sensitisation occurs at the level of the spinal
  cord and supra-spinally
• Persistent and/or powerful nociceptive activation
  elicits changes in the transmission of
  nociceptive information within the CNS
• Changes may last from hours to years
• In certain cases these changes can become
  pathological leading to unresolved persistent pain

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Central Sensitisation in Thalamus of Spinal Cord
in Rats
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Mechanisms of Central Sensitisation
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Mechanisms of Acute and Persistent Pain

• Some of the Main Players

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Excitatory Neurotransmitters in Dorsal Horn of
Spinal Cord

• Excitatory Amino Acids (EAAs)
• glutamate, aspartate, (homocysteate)
• vast body of literature supporting major role in
  transmission in spinal cord
• primary afferent transmitters
• EAAs act on 4 main receptor types
• ligand-gated ionotropic receptors
• kainate receptor
• AMPA receptor
• NMDA receptor
• G-protein coupled receptor
• metabotropic glutamate receptor
• Bewildering number of receptor sub-types
• individual function not clear

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NMDA receptors contribute to spinal cord
sensitisation
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Neuropeptides in Dorsal Horn

• Tachykinins
• excitatory neuropeptides localised in nociceptive
  afferents
• Substance P, Neurokinin A,
• receptors NK1 and NK2
• ? transmitters or neuromodulators
• Calcitonin Gene-Related Peptide (CGRP)
• localised in greater of nociceptive afferents
  than SP
• possibly two receptor sub-types
• excitatory centrally, powerful vasodilator
  peripherally,
• role unclear

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Opioid receptors

• 3 subtypes m, d, k
• About 60 homology between subtypes
• G protein-coupled receptors
• The Grandfather of all analgesics - Morphine -
  acts here
• Many synthetic opiates available

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Endogenous Opioid peptides

• Localised within several areas of CNS including
  dorsal horn of spinal cord
• not exclusive to nociceptive areas
• Relatively non-selective for opioid receptor
  sub-types
• Also produced by non-neuronal cells

Other opioid peptides e.g. nociceptin present in
CNS in pain pathways but significance to pain
transmission unclear
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Current Therapies for Pain

• NSAIDs (Non-Steroidal Antiinflammatory Drugs,
  COX-1 COX-2)
• Opiates (mu agonists)
• Anticonvulsants (phenytoin), antidepressant
  (amitriptyline), antiarrhythmics (mexylitine)
• Sumatriptan, Zomig (5HT agonists) etc for
  migraine
• Gabapentin (off label)
• Tramadol (mu opioid plus your guess as good as
  mine)
• Combinations (opioids plus)

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Non Steroidal Anti-inflammatory Drugs (NSAIDs)

• Most widely used of all therapeutic agents
• Over 50 NSAIDs on the market
• Three main effects
• anti-inflammatory
• antipyretic
• analgesic
• Primary mechanism of action is inhibition of
  arachidonic cyclo-oxygenase (COX) and therefore
  reduction of prostaglandin levels
• most NSAIDs block both COX-1 and -2 e.g.
  naproxen, indomethacin, ibuprofen, aspirin etc
• Two recent selective COX-2 inhibitors - Vioxx and
  Celecoxib

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Indomethacin reduces the frequency of spontaneous
discharges of sensitised nociceptors
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The Opiates

• Powerful analgesics all descended from Morphine
• All activate m receptors and varying degrees of d
  and k activation
• Pure agonist opiates
• morphine, codeine, oxymorphine, methadone,
  pethidine, fentanyl, sulfentanil, etc
• Partial/mixed agonists
• agonist on m, antagonist on d and/or k
• pentazocine, ketocyclazocine, buprenorphine etc
• Antagonists
• e.g. naloxone, naltrexone

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Morphine acts in several sites to produce
analgesia
Morphine
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So, whats wrong with current therapy?

• Lack of efficacy
• in chronic pain 40 efficacy in Visual Analogue
  Scores typical
• Nothing works well in neuropathic pain
• Dose limiting adverse effects
• not only unpleasant but life-threatening as well
• NSAIDs
• gastric haemorrhage, renal/kidney toxicity
• Opiates
• respiratory depression, nausea vomiting,
  constipation, dependency

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Sites of drug action

• non-specific
• physicochemical props.
• receptors
• neurotransmitters
• hormones
• enzymes
• transport systems
• ion channels
• active transport, eg. uptake blockers

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Ion channels

• ligand dependent
• voltage dependent
• voltage ligand (eg. cardiac Ca2 channels)

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Receptors

• ionotropic
• metabotropic
• G-protein coupled (majority)
• tyrosine kinase (eg. insulin receptor)

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Identifying novel targets from the genome

• Isolating a target related to an existing target
• e.g. cloning COX-2 isoform
• Isolating a known target of unknown sequence
• e.g. cloning capsaicin receptor
• Identifying completely unknown targets
• DNA chips
• Human genome project

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Once we have a target...

• What are our goals?

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Goals depend on mechanism of action

• Similar to current compounds
• reduce adverse effects
• increase benefits
• Novel mechanism
• proof of concept
• mechanism-based adverse effects

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Proof of concept

• animal models of human disease
• face validity
• model of mechanism
• Phase 1 models or trials
• surrogate end-points
• Humanised animals
• (transgenic technology)

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What do we need to know before going into man?

• effect at target site
• pharmacokinetics, including bioavailability
• metabolism
• safety
• dose
• effectiveness in vivo (?)

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Assays

• Binding assays
• Bioassays Functional measure
• In vivo
• In vitro

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Pharmacokinetics Drug metabolism (DMPK)

• Penetration/concentration and time course in
  different compartments
• blood brain barrier (BBB)
• synovial capsule
• Metabolism
• Active metabolites
• Drug accumulation

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Bioavailability

• Decide route of administration
• parenteral (i.v., i.m. )
• formulation
• oral
• first pass metabolism
• topical
• sensitivity reactions

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Adverse effects

• related to dose
• mechanism-based
• structure-related
• not related to dose
• eg. hypersensitivity reactions

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Summary and Conclusions

• Pain is complex, particularly chronic pain
• Transient pain is relatively well treated
• Not all pain is the same
• Present therapies are old, inadequate and
  sometimes dangerous
• There is a real need for novel, powerful, safe
  analgesics in chronic pain
• Drug discovery needs the skills of many different
  disiplines