Abstract
Rate theory does not contradict occupation theory; instead, it contains it as a special case. The 'rate theory' of drug action proposes that drug-induced pharmacologic stimulus (and consequent effect) tracks better with the rate of drug-receptor complex formation than with the fraction of receptors occupied at equilibrium, as proposed in classical 'occupation theory.' But rate theory was initially framed phenomenologically, in terms of two empirical rate constants (k1, k2) rather than from an underlying physical basis. Here, we show that rate theory's main postulate follows directly from standard chemical transition-state theory once k1 and k2 are recognized as transition-state rate constants governed by the free energies of association, ΔG‡ 1, and dissociation, ΔG‡ 2. This reframing reveals the classical equilibrium affinity constant, KA, to be the difference between the two activation barriers, ΔG‡ 1 - ΔG‡ 2; shows that a drug's pharmacologic characterization as a full agonist, partial agonist, or antagonist is determined by the reverse barrier ΔG‡ 2 (equivalently, by 1/residence time) rather than by affinity; shows that occupation theory is the steady-state limit of rate theory; and can be easily extended to encompass access-limited pharmacokinetics and to the separation of ligand binding from transduction. The latter provides a thermodynamic account of why affinity and efficacy are not in general independent quantities. The derivation is extended to demonstrate how it unifies rate kinetic theory with modern approaches to drug-receptor residence time in drug discovery. These concepts are illustrated, including a free-energy reaction-coordinate diagram, a free-energy well with residence time, and a simulated time-course comparison of stimulus versus occupancy.