Differentiating between drugs with short and long residence times

Abstract

The kinetic aspects of the ligand–receptor interaction, characterising the residence time of a ligand in its binding site, play an important role in drug effectiveness.

Small Structural Changes at the N‐position of the Tropane Core Control the Mechanism of Nortropane Derivatives Binding to Dopamine Transporter

“…This effect is caused by the fact that the protein is depleted faster in the presence of unlabeled compound, which also induces a slowly dissociating complex, leaving less free DAT in the protein pool for the radioligand to bind to, resulting in an increase of k obs . This indicates the presence of a slow step in unlabeled ligand binding and it is similar to the effect caused by PE2I, as reported before ,. For these ligands, the K L and K i values are not similar, i. e. without the isomerization step the protein's affinity for the compounds would be much lower.…”

“…We report the results of a systematic kinetic analysis of the interaction of a series of N ‐substituted 2β‐carbomethoxy‐3β‐(4′‐methylphenyl)‐nortropane derivatives with DAT, using [ 3 H]PE2I as the reporter ligand as described in our previous report . It was shown that ligands can interact with DAT by two different mechanisms: (i) a one‐step equilibrium binding process and (ii) a two‐step process where the second step is a slow isomerization of the complex (Scheme ), and these two mechanisms can be differentiated by kinetic study of the ligand–receptor interaction ,…”

“…If K isom is large, K i = K L , and the affinity can be determined by displacement experiments. Therefore, the kinetic approach used in this study differentiates between ligands that can or cannot induce the slow isomerization step and allows determination of the K L , k i , and k −i values of the binding reaction by studying the influence of ligands on the kinetics of a radioligand interaction with DAT …”

In Vitro Ligand Binding Kinetics Explains the Pharmacokinetics of [18F]FE-PE2I in Dopamine Transporter PET Imaging

“…This fast step is followed by the slow step of the PE2I-DAT* complex isomerization, and the proposed methods of kinetic analysis allow for the determination of the parameters K L , k i , and k −i . 20 The presence of the slow, complex isomerization process significantly shifts the equilibrium between the free and ligand-bound DAT sites. Therefore, it is possible that this process also affects tracer trafficking between compartments C ND and C S in Scheme 2.…”

“…As the values of these rate constants increase hyperbolically with increasing ligand concentration (Figure 1, right panel), it can be concluded that FE-PE2I interaction with DAT follows the reaction mechanism shown in Scheme 3, as this ligand induces the slow isomerization step, characterized by rate constants k i and k −i . 21 Principles of this experimental approach were described in detail in our previous works, 20 and the results obtained were used for calculation of kinetic parameters K L , k i , and k −i for FE-PE2I interaction with DAT by using eqs 2 and 3 (see Supporting Information).…”