Guidance For Industry - Assessment Of Abuse Potential Of Drugs - U.s. Department Of Health And Human Services - 2017 Page 16
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37Contains Nonbinding Recommendations
B. Screening with Receptor-Ligand Binding Studies
Comprehensive screening using in vitro receptor-ligand binding studies should be conducted to
determine the pharmacological site(s) of action of the test drug, as well as its major human
metabolites, in the brain. Possible CNS sites of action include receptors, transporters, and ion-
gated channel systems. Notably, novel pharmacological mechanisms of action may be associated
with previously unrecognized abuse potential in humans. The outcome of receptor-ligand
binding studies can help determine which in vitro functional assays should be conducted.
Although a CNS-active drug may have a single high-affinity site, it is often the case that drugs
have multiple mechanisms of action with varying degrees of affinity. Some examples of
neuronal systems related to abuse potential that should be assayed include the following:
• Dopamine
• Serotonin
• Gamma-aminobutyric acid (GABA)
• Opioid
• Cannabinoid
• N-methyl-D-aspartate (NMDA)
• Ion-channel complexes (e.g., calcium, potassium, chloride)
• Transporters (e.g., dopamine, serotonin, GABA)
A comprehensive binding assay typically assesses many dozens of sites in the CNS, only some
of which are currently known to be associated with abuse potential. However, mechanisms of
action not previously associated with abuse potential may produce abuse-related signals with a
novel drug. Even though most of the assayed sites will not be predictive of drug abuse, they can
be predictive of certain animal behaviors and AEs in humans that may be observed during abuse-
related studies.
General scientific principles, including the use of appropriate positive controls and internal
standards, should be applied. Highly selective radioligands should be used whenever available.
The concentration of the ligand should be at least 10 μM (or should be equivalent to many-fold
greater than the anticipated therapeutic exposure).
In vivo receptor-ligand binding techniques, such as positron emission tomography (PET) or
single photon emission computed tomography (SPECT), can also provide information about the
localized action of drugs. These studies are typically conducted in humans (where they have
been validated), although animal applications are possible. Studies using these techniques may
be useful in contributing important information about the whole-body pharmacokinetic and
pharmacodynamic properties of the drug.
Data from receptor-ligand binding assays should be evaluated on the basis of both specificity
(whether the ligand binds at one or many sites) and selectivity (the relative affinity of a ligand
for different binding sites).
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