Design and Synthesis of a Novel Water-Soluble NMDA Receptor Antagonist with a 1,4,7,10-Tetraazacyclododecane Group

• Published in: Chemical & pharmaceutical bulletin Vol. 53; no. 4; pp. 444 - 447
• Main Authors: Masuko, Takashi, Metori, Koichi, Kizawa, Yasuo, Kusama, Tadashi, Miyake, Muneharu
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01-04-2005; Japan Science and Technology Agency
• Subjects: 1,4,7,10-tetraazacyclododecane; Animals; Excitatory Amino Acid Antagonists - chemical synthesis; Excitatory Amino Acid Antagonists - pharmacology; Heterocyclic Compounds - chemical synthesis; Heterocyclic Compounds - pharmacology; Indicators and Reagents; N-methyl-D-aspartate (NMDA) receptor; Oocytes - metabolism; Patch-Clamp Techniques; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Xenopus; Xenopus oocytes
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.53.444

Polyamines, especially spermine, inhibit N-methyl-D-aspartate (NMDA) receptors as open channel blockers. Two types of water-soluble NMDA receptor antagonist, ACCn (1) and TGCn (2), with a 1,4,7,10-tetraazacyclododecane cyclic polyamine group, were synthesized and the effects of both compounds on NMDA receptors were studied using voltage-clamp recordings of recombinant NMDA receptors expressed in Xenopus oocytes. These compounds inhibited macroscopic currents in both NR1/NR2A and NR1/NR2B receptor subtypes in oocytes voltage-clamped at −70 mV. Inhibition by the compounds of NR1/NR2A receptors were more prominent than that of NR1/NR2B receptors. The inhibitory effects of ACCn (1) on both NMDA receptors were more potent than those of TGCn (2).