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p.n.p.ase
contractility
outside inside
Structure-activity relationship &
drug design
Chemical structure affinity &
intrinsic activity
SAR modification
- therapeutic effect
ratio
toxic effect
- selectivity
- pharmacokinetic profile
Receptor (1)
Functional domains
1. Ligand-binding
2. Effector
cellular target(s)
Receptor occupancy effector protein(s)
second messenger(s)
transducer(s)
Receptor (2)
D-Ri D-Ra
Physiological receptors
1. Enzymes
2. Ion channels
3. G protein - coupled receptor systems
4. Transcription factors
Receptors
I. Enzymes:
- Tyrosine kinase: insulin, EGF, PDGF,
lymphokines
- Serine/threonine protein kinase: TGF
- Guanylyl cyclase: ANF receptor, guanylin
receptor
- Tyrosine phosphatase
II.Ligand-gated ion channels
- Nicotinic Ach receptor
- GABAA receptor
- Glutamate, aspartate, glycine
III. G protein-coupled receptors
- Biogenic amines
- Eicosanoids
- Peptide hormones
Effectors:
- Enzymes: adenylyl cyclase, PLA2, C, D
- Ion channels: Ca++, K+, Na+
- Transport proteins
IV. Transcription factors
Cytosolic receptors: thyroid hormone, steroid,
retinoid, vitamin D
Enzymes (protein kinase)
Mw : 43.000 - 50.000
Time of interactions
Thrombin receptor
G protein - adenylyl cyclase
G protein - phospholipase C
Transcription factors
Characteristics
Very low concentration
Rapidly produced
Recycling mechanism
Second messenger(s)
cAMP
cGMP
Inositol trisphosphate, diacylglycerol
Ca++
NO
Phosphoinositides
adrenergic agents cAMP CH & TG breakdown
HR & contractility
Feedback inhibition
- homologous desensitization (from the stimulated
receptor)
- heterologous desensitization (from all receptors
sharing a common signalling pathway)
Regulation of receptors (3)
Supersensitization
Chronic reduction of receptor stimulation
(eg. -blocker)
Diseases resulting from receptor
malfunction
Testicular feminization syndrome deficiency of
androgen receptors
Myasthenia gravis autoimmune depletion of
nicotinic cholinergic receptors
Insulin-resistant DM autoimmune depletion of
insulin receptors
Multiple endocrine disorders deficiency of Gs
(heterozygous)
Malignancy aberrant receptors oncogenes
Subtle mutation in receptors activation of G
protein-coupled receptors retinitis pigmentosa,
precocious puberty, malignant hyperthyroidism.
Actions of drugs not mediated by
receptors
Binding to other molecules or ions : antacid
Colligative effects : mannitol
Structural analogs of biological chemicals :
some antiviral & anticancer agents
Desinfectants, detergent, alcohol, etc.