Table 1

Binding of various hydrophobic cyclic peptide molecules on P-glycoprotein as measured by modulation of its ATPase activity

MMLogP1-aEffect on Basal ATPase ActivityEffect on ATPase Activity Stimulated byApparent Ka
VRP (455 Da) (logP = 3.2)PRG (314 Da) (logP = 4.1)VBL (811 Da) (logP = 3.0)
Da μM μM μM μM
CSA1203–0.32Act (0.020) Inh (5–20)C (0.015)N (0.04)C (0.05–0.1)0.03
ACD1255–2.1Inh (2)C (0.5)None (<5)C (1–2)1
BCT7503.1Inh (0.3)C (0.2)N (0.1)N (< 4)0.2
PIA 8540.07None (<50)C (5)N (15–20)N (< 60)10
PIIA 5241.2None (< 30)None (< 60)N (5)None (< 60)5
TTX4150.77Act (10)None (<100)None (< 30)C1-b 10
cLF2601.6None (< 40)None (<40)None (<40)None (<40)

Apparent K a values are determined as the means of the half-maximal activating concentration for the basal ATPase activity and of the inhibition constants for the stimulated ATPase activities.

    • Act, activation of the basal ATPase activity of P-glycoprotein (half-maximal activating concentration in brackets) Inh, inhibition of the basal ATPase activity of P-glycoprotein (half-maximal inhibitory concentration in brackets); None: The basal ATPase activity of P-glycoprotein is unchanged; highest drug concentration tested in brackets; C, competitive inhibition of the stimulated ATPase activity of P-glycoprotein (inhibition constant in brackets; N, noncompetitive inhibition of the stimulated ATPase activity of P-glycoprotein (inhibition constant in brackets); MM, molecular mass.

    • 1-a Calculated according to SYBYL software.

    • 1-b Competition observed by the effect of VBL on the ATPase activation induced by TTX.