Synthesis of a novel water-soluble cleft-type cyclophane as an N-methyl-D-aspartate receptor antagonist.
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 microM and, 0.92 microM and 1.47 microM and, 1.49 microM, 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.
Masuko
Takashi
T
College of Pharmacy, Nihon University, Chiba, Japan.
Kusama
Tadashi
T
Namiki
Rie
R
Metori
Koichi
K
Kizawa
Yasuo
Y
Miyake
Muneharu
M
D000818:Animals; D004988:Ethers, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology*; D015394:Molecular Structure; D009865:Oocytes / Q000187:drug effects* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000235:genetics; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D012995:Solubility; D014867:Water / Q000737:chemistry*; D014982:Xenopus laevis / Q000378:metabolism
D004988:Ethers, Cyclic; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D014867:Water