Inhibition of synaptosomal membrane Na+-Ca2+ exchange transport by amiloride and amiloride analogues.

Na+-Ca2+ exchange in rat brain synaptosomal plasmalemma vesicles is reversibly inhibited by amiloride (3,5-diamino-6-chloro-N-(diaminomethylene)pyrazinecarboxamide++ +). This drug (pKa = 8.7) inhibits Na+-dependent Ca2+ uptake more effectively at basic pH values than at neutral pH values, indicating that the positively charged form of amiloride is the active moiety. Twenty amiloride analogues were examined for ability to inhibit Na+-Ca2+ exchange. These studies demonstrate that the 6-chloro group, the 5-amino substituent, and the carbonyl guanidinium moiety are essential for drug inhibition of Na+-Ca2+ exchange. N-Benzyl amiloride derivatives such as 3,5-diamino-6-chloro-N-(benzylamino-aminomethylene)pyrazinecarb oxamide (benzamil) and 3,5-diamino-6-chloro-N-(2-phenethylamino-aminomethylene)p yrazinecarboxamide are more potent inhibitors of Na+-dependent Ca2+ uptake than is amiloride. The amiloride analogue pattern of interaction with the Na+-Ca2+ exchange system is distinct from the inhibition patterns of the epithelial Na+ channel and the Na+-H+ exchange transport system.