3.3.1.3 Receptor binding mechanisms and affinity

Affinity and the dissociation constant

• Affinity is how strongly a drug binds its receptor; efficacy is the signalling response it produces once bound.

• At equilibrium, association and dissociation rates are equal, and the dissociation constant Kd = koff / kon.

• Kd has concentration units, and a lower Kd means higher affinity.

• Clozapine and quetiapine dissociate from D2 receptors faster than haloperidol or risperidone, which may explain their lower extrapyramidal and prolactin effects.

Potency

• Potency (EC50) is set jointly by a drug's affinity for its receptor and its efficacy once bound.

• Agonists, partial agonists, neutral antagonists and inverse agonists can have similar affinity yet different effects, because their efficacy differs.

Occupancy

• Fractional occupancy at equilibrium = [L] / ([L] + Kd), where [L] is the free concentration at the receptor, so half the receptors are occupied when [L] equals Kd.

• Occupancy rises hyperbolically: going from 50 to 90 per cent occupancy needs a ninefold rise in concentration.

D2 occupancy and antipsychotic effects

Positron emission tomography (PET) estimates occupancy in the living brain from the fall in radiotracer binding after a dose.

• Raising the dose beyond 80 per cent adds harm with little benefit, though clozapine can work at 40 to 60 per cent.

• Selective serotonin reuptake inhibitors occupy about 80 per cent of serotonin transporters at minimum effective doses.

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