Nervous Systems and Histamine Receptors

• Somatic nervous system: no synapses en route to the skeletal muscle, voluntary control.
• Autonomic nervous system: synapses en route to smooth muscle, heart and adrenal gland, involuntary control.
• Parasympathetic nervous system: first synapse some distance from CNS, autonomic.
• Sympathetic nervous system: first synapse close to CNS, autonomic.
• Nerve impulses are electrical in nature (action potential) and transmitted via neurons.

  • Action potential induces release of neurotransmitter across the synapse
  • Activates ACh receptors (Na+ ion channels) on postsynaptic neuron
  • Stimulates sodium ion ingress into neuron
  • New action potential generated in each dendrite of next neuron

  
• Sympathetic system:

  • Regulated by noradrenaline
  • Adrenergic receptors in target organs
  • Cardiac muscle contraction
  • Relaxes smooth muscle
  • Dilates peripheral blood vessels
• Parasympathetic system:

  • Regulated by acetylcholine
  • Cholinergic receptors in the same target organs
  • Opposite effects to stimulation
• GPCRs:

  • Cell membrane bound protein receptors
  • Seven transmembrane helices
  • Single polypeptide that is folded
  • Can be activated by monoamines, hormones and glutamate
  • Contain G-protein binding region
• GPCRs are targets for approximately 30% of all marketed drugs, with 390 encoded in the human genome.
• Rhodopsin branch of GPCRs is most important in medicinal chemistry.
• G-proteins are released from GPCRs by the exchange of GDP for GTP via fragmentation. This allows continuation of the signal transduction process as a secondary messenger.

  
• Peripheral nervous system: between CNS and body, including the enteric system in the walls of the intestine. Responds to motor nerves and local effects.
• Sympathetic nerves release acetylcholine at the adrenal medulla, stimulating the release of adrenaline.

  
• Neurotransmitter: released from sympathetic nerves directly into smooth/cardiac muscle, e.g., noradrenaline.

  
• Hormone: released from adrenal medulla, reaches adrenergic receptors via blood supply e.g., adrenaline.

  
• Adrenergic receptors are all GPCRs:

  • Alpha adrenoceptors have two subtypes
  • Beta adrenoceptors have three subtypes
  • All have structural variations and uneven distributions
• Alpha receptors:

  • Alpha-1 produce two secondary messengers, IP3 and DG
  • Alpha-2 inhibit production of secondary messenger, CAMP
• Beta receptors:

  • Three subtypes of beta-1, 2, 3
  • All activate production of cAMP
• Adrenaline synthesis:

  • l-tyrosine to levodopa by tyrosine hydroxylase
  • Levodopa to dopamine by dopa decarboxylase
  • Dopamine to noradrenaline by dopamine beta-hydroxylase
  • Noradrenaline to adrenaline by N-methyl transferase in the adrenal medulla

  
• Metabolism of noradrenaline to adrenaline is mediated by monoamine oxidase (MAO) and catechol O-methyltransferase (COMT). COMT is selective of the meta position.

  
• Hydrogen bonding from the catechol is essential for binding:

  • Protonated amine must be primary or secondary
  • Aromatic ring involved in van der Waals interactions
  • Meta OH can be modified with other H-bonding groups
  • Both OH involved in H-bonding especially in binding to beta-receptors
  • One or two alkyl substituents are required on the amine group
  • Amine group involved in ionic bonding
  • Methylation at alpha to amine increases alpha-2 selectivity

  
• Neurotransmitter activities:

  • Adrenaline has the same activity for alpha and beta
  • Noradrenaline has greater activity for alpha
  • N-alkyl substitutions increase beta selectivity
  • Adding a terminal polar group dramatically increases activity

  
• The most useful adrenergic agonists are beta-2 agonists (bronchodilators).
• Adrenaline is used as a bronchodilator in emergencies:

  1. N-functionalisation is beta non-selective but selective towards beta than alpha
  2. Side chain alkylation enhances differentiation between beta-subtypes
  3. Isosteres of phenol increase metabolic stability and duration of action

  
• Long lasting beta-agonists:

  • N-alkyl group extension increases lipophilicity
  • N-arylalkyl substituents with polar end-group e.g., salmefamol
  • Need long-lasting agonist to treat 'nocturnal asthma' e.g., salmeterol
  • Drive for a once-daily dose agonist e.g., indacaterol (for COPD)
• Peptic ulcers: localised erosion of mucous membrane of the stomach or duodenum.
• NSAIDS: Non-steroidal anti-inflammatory drugs e.g., ibuprofen.
• NSAIDS inhibit cyclooxygenase 1 (COX-1), responsible for prostaglandin synthesis. Prostaglandins inhibit acid secretion/protect mucosa.
• Peptic ulcers are most commonly caused by NSAIDS or Helicobacter pylori.

  
• Histamine receptor agonists:

  • Histamine released when cells are damaged (inflammation)
  • Dilates and increases permeability of small blood vessels
  • Allows white blood cells to target the area of damage
  • Early antihistamine drugs were used for hay fever, rashes, insect bites etc

  
• Histamine antagonists must contain:

  • Positively charged nitrogen atom with at least one proton
  • Flexible chain between cation and heterocycle
  • H1 - heteroaromatic with nitrogen ortho side chain
  • H2 - heteroaromatic with two nitrogens e.g., amidine

  
• N alpha-guanyl histamine: partial agonist of H2 receptors.
• Isothiourea: a histamine receptor partial agonist with greater antagonist activity due to guanidinium charge.

  
• Methylisothiourea/amidine: weaker antagonist activity compared to isothiourea, partial histamine agonist.

  
• Extending the chain from C2 to C3 units will enhance antagonist activity towards a histamine receptor.

  • C3 increases antagonist activity for guanidine but decreases for isothiourea
  • Opposite effect to C2 chain

  
• Position and orientation of a chelating group is important for antagonist activity. For histamine receptors:

  • C3 unit and guanidine/amidine best combination
  • Replacement of guanidinium with non-charged group such as thiourea, e.g., SKR 91581
  • Much less basic but planar
  • Weak antagonist with no agonist activity
  • Ionic interaction specific for agonism
  • Increasing chain length to C4 gives burimamide

  
• Burimamide: histamine receptor antagonist with increased hydrophobicity with addition of Me compared to SKR 91581.
• Burimamide:

  • Contains an imidazole ring: two tautomers I and II, and protonated form III. pKa of imidazole:
  • Histamine = 5.74 at pH 7.4
  • Burimamide = 7.25 at pH 7.4
  • Form III is favoured in burimamide but not for histamine
  • Making the side chain electron-withdrawing can lower the pKa and favours tautomers I and II
  • Sulfur is a good bioisostere for CH2, making thiaburimamide

  
• Adding a slightly EWG makes nitrogen less basic, favouring protonation and therefore tautomeric form I.

  • Increasing basicity with an adjacent methyl group giving metiamide - enhances antagonistic activity
  • Increase in tautomer I over II outweighs increase in pKa and % protonation (III)
• Metiamide: histamine antagonist with increased basicity by methyl group adjacent to imidazole ring.