NMDA receptor antagonists to characterize rat renal organic cation transporter function

We hypothesized that uncompetitive NMDA glutamate receptor antagonists memantine (2,5-dimethyl-1-adamantanamine), and amino-alkyl-cyclohexane compounds: MRZ 2/579 (1-amino-1,3,3,5,5-pentamethylcyclohexane HCl), MRZ 2/600 (1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane HCl), and MRZ 2/615 (1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane HCl), all derivatives of amantadine (1-adamantanamine HCl), would inhibit the energy-dependent uptake of amantadine into rat renal tubules. All compounds displayed a concentration-dependent inhibition of amantadine uptake in the proximal and distal renal tubules. MRZ 2/579 showed a novel distal tubule selectivity of inhibition (P < 0.001). At a therapeutic amantadine concentration, bicarbonate-dependent transporter inhibition selectivity was observed with all compounds (P < 0.05) except MRZ 2/600, the only compound with a sterically bulky group next to the amino group of the cyclohexane ring structure. Steric hindrance around the ionized amino group of the cyclohexane ring appears to prevent bicarbonate-mediated organic cation transport. Furthermore, the distal tubule inhibition selectivity with MRZ 2/579 provides a novel tool to study the relative importance of organic cation transporters (OCTs) in proximal vs. distal renal tubules.