Title:The Kinetic Component in Drug Discovery: Using the Most Basic Pharmacological Concepts to Advance in Selecting Drugs to Combat CNS Diseases
Volume: 18
Issue: 3
Author(s): Rafael Franco*, Josema Castelló and Enric I. Canela
Affiliation:
- Department of Biochemistry and Molecular Biomedicine, Molecular Neurobiology Laboratory, Biology School, University of Barcelona, Barcelona,Spain
Keywords:
Agonist binding, association, dissociation, equilibrium constant, GPCR, rate constants.
Abstract: To reach the central nervous system (CNS), drugs must cross the brain-blood barrier and
have appropriate pharmacokinetic/dynamic properties. However, in early drug discovery steps, the
selection of lead compounds, for example, those targeting G-protein-coupled receptors (GPCRs), is
made according to i) affinity, which is calculated in in vitro equilibrium conditions, and ii) potency,
a signal transduction-related parameter, usually quantified at a fixed time-point in a heterologous
expression system. This paper argues that kinetics must be considered in the early steps of lead
compound selection. While affinity calculation requires the establishment of a ligand-receptor equilibrium,
the signal transduction starts as soon as the receptor senses the agonist. Taking cAMP production
as an example, the in vitro-measured cytoplasmic levels of this cyclic nucleotide do not
depend on equilibrium dissociation constant, KD. Signaling occurs far from the equilibrium and
correlates more with the binding rate (kon) than with KD. Furthermore, residence time, a parameter
to consider in lead optimization, may significantly vary from in vitro to in vivo conditions. The
results are discussed from the perspective of dopaminergic neurotransmission and dopaminereceptor-
based drug discovery.
