Synthesis of a Novel Water-Soluble Cleft-Type Cyclophane as an N-Methyl-D-aspartate Receptor Antagonist

• Published in: Chemical & Pharmaceutical Bulletin Vol. 57; no. 1; pp. 95 - 98
• Main Authors: Masuko, Takashi, Kusama, Tadashi, Namiki, Rie, Metori, Koichi, Kizawa, Yasuo, Miyake, Muneharu
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01-01-2009; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: Animals; cleft-type cyclophane; Ethers, Cyclic - chemical synthesis; Ethers, Cyclic - pharmacology; Molecular Structure; N-methyl-D-aspartate receptor; Oocytes - drug effects; Oocytes - metabolism; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - genetics; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - genetics; Solubility; voltage-clamped recording; Water - chemistry; Xenopus laevis - metabolism; Xenopus oocyte
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.57.95

Novel water-soluble N-methyl-D-aspartate (NMDA) receptor antagonists, 4,4′-bis({2-[N-(1,4,8,11-tetraazacyclotetradecan-1-yl)acetyl]-N-phenethyl}aminoethoxy)diphenylmethane octahydrochloride (1, ACPCm) and 4,4′-bis({2-[N-(1,4,7,10-tetraazacyclododecan-1-yl)acetyl]-N-phenethyl}aminoethoxy)diphenylmethane octahydrochloride (2, ACPCn), were synthesized and the effect of these cleft-type cyclophanes on NMDA receptors was then studied using voltage-clamp recordings of recombinant NMDA receptors expressed in Xenopus oocytes. ACPCm (1) and ACPCn (2) inhibited macroscopic currents in the NR1/NR2A, NR1/NR2B, NR1/NR2C and NR1/NR2D receptor subtypes in oocytes voltage-clamped at −70 mV. The IC50 values of ACPCm (1) and ACPCn (2) for NR1/NR2A and NR1/NR2B receptors were 1.06 μM and, 0.92 μM and 1.47 μM and, 1.49 μM, respectively. The inhibition by these compounds was voltage-dependent, that is, the degree of inhibition was in the order of negative holding potentials, −100 mV>−70 mV>−20 mV. These findings indicate that the cleft-type cyclophanes, ACPCm (1) and ACPCn (2) directly act on the channel pore of the NMDA receptors.