3.1.2. Monoamine uptake inhibition in transfected HEK293 cells
The corresponding IC50 values and hDAT/hSERT inhibition
ratios are presented in Table 1 and concentration-response curves are
depicted in Figure S2. While assessing uptake-1 assays, all tested drugs
displayed low IC50 values for hDAT and negligible
activity at hSERT. Additionally, the order of potencies for hDAT was as
follows:
α-PVP≈N-ethylpentedrone≈α-PpVP>pentedrone>N,N-diethyl-pentedrone
;F(4,10)=30.61). The order of potency for hSERT was as
follows:
pentedrone≈N-ethyl-pentedrone>>α-PVP>N,N-diethyl-pentedrone≈α-PpVP;
F(4,10)=179.1). It is important to point out the very
low inhibitory potencies of N,N-diethyl-pentedrone, α-PVP and α-PpVP
when studying [3H]5-HT uptake inhibition at hSERT.
However, an estimation of the IC50 values, as well as
hDAT/hSERT ratios, were calculated in order to perform the corresponding
correlation analysis. Accordingly, all compounds appeared to be
>100-fold more potent blocking capacity at hDAT over hSERT.
Molecular and physicochemical descriptors were also calculated for the
different amino-substituents, correlating them with some QSAR parameters
such as CLogP, total surface area, volume and CMR. As shown in Table 2,
hSERT, but not hDAT IC50 values, significantly
correlated with CLogP, total surface area, volume and CMR of the
amino-substituents. In addition, the hDAT/hSERT ratios also correlated
with CLogP.
With regards to uptake-2 inhibition experiments (Table 1; Figure S2),
α-aminovalerophenone derivatives blocked hOCT-2
within the IC50value range of 10–60 µM, with no considerable effect on hOCT-3.