Receptor Pharmacology Tulasi Raman.P Moderator: Dr. Kartik Salwe
Definition• The term receptor is used in pharmacology to denote a class of cellular macromolecules that are concerned speciﬁcally and directly with chemical signaling between and within cells.
• Affinity: – The capability of a drug to form the complex (Drug Receptor Complex) with its receptor.• Intrinsic activity: – The ability of a drug to trigger the pharmacological response after making the drug-receptor complex. D + R DR D: Drug or endogenous ligand R: Receptor DR: Drug-Receptor Complex
• Agonist: – These are the drugs which have both high affinity as well as high intrinsic activity.• Antagonist: – These are the drugs which have only the affinity but no intrinsic activity.
When two drugs are binding to the same receptorand at the same site, why is it that one is actingas an agonist while other is serving as anantagonist...?
The concept of dual nature of receptors• Receptors usually exists in two conformations – The active (Ra) state – Inactive (Ri) state If Ra and Ri conframations are in equlibrium, the extent to which this equilibrium perturbed shall be determined by the relative affinity of the drug for these two conframations
• Agonist: – These drugs have high affinity for the active conformation (Ra) than for inactive (Ri)• Antagonist: – These drugs bind to either of these conformations (Ra & Ri) with equal affinity. • It will not shift the equilibrium to any side
Partial agonist– These have slightly higher affinity for Ra than for Ri and hence shift the eaulibrium toward Ra to a lesser extent than true agonist.– Such drugs therefore display an intermediate effectivesss between the agonist and antagonist
Inverse agonist• There are certain receptors which remain inherently in the Ra state even in the absence of an endogenous ligand or an exogenous agonist.• Inverse agonists inactivate such constitutively active receptors and therefore prevent its basal activity.• As a result inverse agonist produce an effect opposite to that of an agonist / drug even in its absence.
Receptor Types1. Ion-channel Receptors (Ionotropic Receptors)2. G-Protein Coupled Receptors (Metabotropic receptors)3. Kinase-linked Receptors4. Intracellular Receptors (Cytosolic Receptors)5. Enzymes as Receptors6. Drugs which act through Modulation of Voltage Gated Ion Channels (Voltage-Operated Channels)
Ion-channel• Localised on the cell membrane• Coupled directly to an ion channel• It is a channel with a receptor site.• Agonists opens the channel.• Antagonists prevents agonist from opening the channel• Inverse agonist closes an open channel
• Multiple subunit proteins which form cation or anion channels• Channel properties are determined by the composition of subunit isoforms – agonist affinity – ion permeabilities – conductance properties – activation and deactivation times – desensitisation kinetics• Activity can be regulated by varying composition of different subunits
Two main families1. Nicotinic receptor family (include nACh receptors, GABAA, GABAC, glycine receptors and the 5-HT3 receptor)2. Glutamate receptor family (several different receptor types classified into NMDA receptors and non-NMDA receptors)
G-Protein Coupled Receptors• GPCRs are composed of 7 transmembrane helices which have an extracellular domain as drug or neurotransmitter binding site and an intracellular domain that couples to G-protein
Why do GPCRs not act directly on effectors?1. Means of amplifying signal2. G proteins can act as integrators of inputs from several stimuli (convergence)3. G proteins can regulate more than one effector (divergence)
Three main variants of GPCRs1. Gs: Stimulation of Adenyl cyclase2. Gi: Inibition of Adenyl cyclase3. Gq: Controls phospholipase-C activity
Kinase-linked Receptors• These receptors are directly linked to: 1. Tyrosine kinase (e.g. receptors for insulin and various growth factors) Or 2. Guanylate cyclase (e.g. receptors for atrial natriuretic peptide)
Intracellular ReceptorsThis nuclear receptor family senses signals fromthe lipid soluble substances (e.g. Vit A & D) andother hormonal substances to influence the geneexpression.
Enzymes as Receptors• Drugs can either mimic the enzyme’s substrate or may bind to its allosteric site to produce the effect E.g. Angiotensin-converting enzyme Acetylcholinesterase enzyme
Voltage-Operated Channels• VOC’s like ROC’s are ion channels that are gated only by voltage.• While ROC’s assume only 2 states: Open or Close; VOC’s also assumes a third state called ‘refractory’ (inactivated) state.
Refractory State• In this state the channel is unable to ‘open’ (or reactivate) for a certain period of time even when the membrane potential returns to a voltage that normally opens or activates the channel.• State Dependent Binding
Down-regulation of Receptors• Prolonged exposure to high concentration of agonist causes a reduction in the number receptors available for activation.• This results due to endocytosis or internalisation of the receptors from the cell surface
Up-regulation of Receptors• Prolonged occupation of receptors by a blocker leads to an increase in the number of receptors with subsequent increase in receptor sensitivity.• This is due to externalisation of the receptors from inside of the cell surface.
Spare Receptors• A drug can produce the maximal response when even less than 100% of the receptors are occupied. The remaining unoccupied receptors are just serving as receptor reserve are called spare receptors
Receptor Related Diseases• Myasthenia Gravis: – Antibodies against the cholinergic nicotinic receptors at motor end plate.• Insulin Resistant Diabetes• Testicular feminisation• Familial Hypercholesterolaemia