Drug Targets

• Cerebral Cortex


  • Pyramidal neurons with pyramid-shaped cell bodies, long axons and apical dendrites
• Excitatory output in the brain

  • Pyramidal neurons
• Basal Ganglia (Striatum in particular)


  • Inhibitory output in the brain
  • Voluntary motor responses and finetuning of motor movement
• Higher Mental Functions


  • Concentration
  • Planning
  • Judgement
  • Emotional expression
  • Creativity
  • Inhibition
• Motor Function Areas


  • Eye movement
  • Placement of eyes
  • Ability to move muscles
• Broca's Areas


  • Ability to talk
  • Ability to write
• Association Areas


  • Short term memory
  • Emotion
• Sensory Areas


  • Touching
  • Feeling
• Wernicke's Area


  • Written and spoken
  • Language understanding
• Somatosensory Association Area


  • Understanding of weight, texture, temperature
  • For recognizing and comprehending an object
• Visual Areas


  • Sight
  • Ability to recognise pictures
  • Awareness pf size and shape
• Motor Functions


  • Coordination of movement
  • Balance
  • Posture
• Diverse Neuronal Subtypes – Diverse Functions of Brain

  • Distinct gene expression in each subclass of neurons
  • Express distinct patterns of neurotransmitter-receptors in different neuronal subtypes across different brain regions
  • Unique biochemical and functional properties
  • Unique firing pattern
• Principal cells


  Process information within their brain region, and project their axons to other brain regions, thereby innervating and regulating other brain regions
• Interneurons


  Process information within their brain region, and project their axons to local neurons only, thereby regulating activity of neighbouring principal cells
• Pyramidal Neurons


  • Principal cells in the cerebral cortex
  • Major excitatory neurons (70-85% of all neurons) in the mammalian cortex
  • Receive input from different brain regions
  • Project to different brain regions and their targets
• Neurotransmitter Receptors in Pyramidal Neurons

  • Pyramidal neurons are excitatory in nature
  • Primarily release glutamate from their axons
  • Main source of neuronal excitation in the brain
  • Diverse synaptic inputs onto different dendritic and somatic regions
  • Excitatory: glutamate receptors (NMDA, AMPA, kainate), acetylcholine (M1, nicotinic ACh), dopamine (D1 and D5), noradrenaline (α1, β1, β2), serotonin (5-HT2A)
  • Inhibitory: GABAA receptors (mainly on cell bodies and dendritic shafts)
• Basal Ganglia


  • A group of interconnected nuclei located in the subcortical brain region
  • Caudate nucleus and putamen form the dorsal striatum (MOST important integrating centre) - initiating and controlling movements of the body, limbs, and eyes
  • The ventral striatum consists of the nucleus accumbens and the olfactory tubercle - motivation, reward, reinforcement, and aversion
• Medium Spiny Neurons (MSN)

  • Principal neurons in the striatum
  • Made up of 90% of striatal neuronal population
  • Rich in dendritic spines
  • Receive synaptic inputs from cortical and neurotransmitter glutamatergic neurons
  • Release GABA as primary neurotransmitters
  • Express two distinct dopamine receptors
  • D1 receptors express in direct pathway MSNs
  • D2 receptors express in indirect pathway MSNs
• In Parkinson's Disease


  Depletion of dopamine due to the loss of dopaminergic neurons in substantia nigra
• 1. DOPA


  Precursor of dopamine
• Neurotransmitter Receptors in MSNs

  • Release GABA from its axons
  • Provide inhibitory feedback throughout the basal ganglia
  • Diverse synaptic inputs onto different dendritic and somatic regions
  • Excitatory: glutamate receptors (NMDA, AMPA), dopamine (D1), acetylcholine (M1), noradrenaline (α1, β1)
  • Inhibitory: GABAA receptors, acetylcholine (M4), dopamine (D2)
• Peripheral Nervous System (PNS)

  • Neurotransmitter-receptors widely expressed in the CNS also found in the PNS
  • Drugs that act on those neurotransmitterreceptors might have potential impact to the PNS, and their targeted organs
  • Undesirable side-effects
  • Important to know the expression patterns of these receptors in the PNS
• Autonomic Nervous System (ANS)


  • Three anatomical divisions: sympathetic, parasympathetic and enteric nervous system
  • Contraction and relaxation of vascular and visceral smooth muscle
  • Heartbeat
  • All exocrine and some endocrine secretion
  • Energy metabolism (in liver and skeletal muscle)
• Preganglionic Neurons


  • Resided in lateral horn of grey matter of the spinal cord
  • Send their axons to postganglionic neurons
  • Release acetylcholine via nicotinic ACh receptors
• Postganglionic Neurons


  • Resided outside the CNS with cell bodies in autonomic ganglion (sympathetic vs parasympathetic)
  • Parasympathetic fibres release acetylcholine via muscarinic receptors
  • Sympathetic fibres release noradrenaline via α or β adrenoceptors (except acetylcholine via mACh in sweat gland)
• Nicotinic Receptor Subtypes


  • Three main classes of nAChRs
  • Pentameric structure
  • Ligand-gated ion channels (ionotropic)
  • Ganglionic receptors: Fast transmission at sympathetic and parasympathetic ganglion
  • No second messengers are required
• (a3)2(B2)3


  • Main synaptic location – autonomic ganglia, mainly post synaptic
  • Membrane response – excitatory increased cation permeability
  • Agonists – Acetylcholine, carbachol, nicotine, epibatidine, dimethylphenylpiperazinium
  • Antagonists – Mecamylamine, trimetaphan, hexamethonium, a-conotoxin
• Muscarinic Receptor Subtypes


  • Five molecular subtypes of mAChRs
  • All are G protein coupled receptors
  • Odd numbered members (M1, M3, M5): couple with Gq to activate IP3
  • Even-numbered members (M2, M4): couple with Gi to open potassium channel, inhibit adenylyl cyclase
• M1


  • Acid secretion
  • Cellular Response – depolarisation, excitation
  • Non-Selective Agonists – Pilocarpine, Bethanechol
  • Non-Selective Antagonist – Ipratropium
• M2


  • Heart, Atria
  • Cellular Response – Inhibition
  • Functional Response – Cardiac Inhibition
• M3


  • Smooth Muscle, GI Tract, Eye, Airways, Bladder
  • Cellular Response – Stimulation
  • Functional Response – Gastric, Salivary Secretion, GI Smooth Muscle Contraction
  • Selective Agonists – Cevimeline
• Second Messengers & Effectors


  • Two subtypes (α and β adrenoceptors)
  • Two main α-adrenoceptors: α1 (α1A, α1B, α1D) and α2 (α2A, α2B, α2C)
  • Three main β-adrenoceptors: β1, β2, β3
  • All are G protein-coupled receptors
  • All require second messengers: phospholipase C activation (α1); activate (β) or inhibit (α2) adenylyl cyclase to modulate cAMP (but cAMP is usually low)
  • Stimulation: α1, β; Inhibition: α2
• A1 (A, B, D)

  • Phospholipase C Activation
  • Increase Inositol Trisphosphate
  • Increase Diacylglycerol
  • Increase Ca2+
• A2 (A, B, C)


  • Decrease cAMP
  • Decrease calcium channels
  • Increase potassium channels
• B1, B2, B3


  Increase cAMP
• Main Effects of Adrenoceptor Activations

  • A1 Receptors: Vasoconstriction, relaxation of gastrointestinal smooth muscle, salivary secretion and hepatic glycogenolysis
  • A2 Receptors: Inhibit noradrenaline and acetylcholine release from autonomic nerve caused by opening of K+ channels and inhibition of Ca2+ channel, Platelet aggregation, vascular smooth muscle contraction, inhibition of insulin release
  • B Receptors: β1-receptors: increased cardiac rate and force, β2-receptors: bronchodilation; vasodilation; relaxation of visceral smooth muscle; hepatic glycogenolysis; muscle tremor, β3-receptors: lipolysis and thermogenesis; bladder detrusor muscle relaxation
• Drugs & Actions


  • Adrenaline – Anaphylactic Shock
  • Salbutamol – B2 Agonists – Asthma, Premature Labour
  • Salmeterol – B2 Agonists – Given by Aerosol, Long Acting
  • Phenylephrine – A1 Agonists – Nasal Decongestion
  • Prazosin – A1 Antagonists – Hypertension
  • Propranolol – Anxiety
  • Metoprolol – Angina, Hypertension
  • Labetalol – A/B Antagonists – Hypertension in Preg