title: NMDA receptor antagonists to characterize rat renal organic cation transporter function.
abstract: 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.
mesh_terms: D000547:Amantadine / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D003517:Cyclopentanes / Q000494:pharmacology; D004347:Drug Interactions; D004734:Energy Metabolism / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008559:Memantine / Q000494:pharmacology; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D003517:Cyclopentanes; D018691:Excitatory Amino Acid Antagonists; D027701:Organic Cation Transport Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C114144:neramexane; D000547:Amantadine; D008559:Memantine