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

Abstract

NotesThe ionotropic glutamate receptors are ligand-gated ion channels that mediate the vast majority of excitatory neurotransmission in the brain. The three pharmacologically defined classes of ionotropic glutamate receptor were originally named after the reasonably selective agonists N-methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), and kainite. It turned out that NMDA, AMPA, and kainite receptor subunits are encoded by at least six gene families as defined by sequence homology: a single family for the AMPA receptors, two for kainite, and three for NMDA.1) The NMDA receptor combines to form heteromeric complexes containing NR1 and NR2 subunits. The NR1 subunit is ubiquitous and assembles with a second family of subunits termed NR2, including NR2A, NR2B, NR2C and NR2D.In the central nervous system (CNS), the NMDA receptor plays a critically important role in a variety of neurophysiological phenomena, including neuronal development, synaptic plasticity, and excitotoxicity. Glutamate is known to be neurotoxic under certain circumstances, in particular when energy supply is compromised. Thus some researchers now believe that the neurodegeneration associated with a variety of acute and chronic disorders (ischemic stroke, Parkinson's disease, Alzheimer's disease, dementia, etc.) may be caused in part by overactivation of glutamate receptors. Alzheimer's disease is a neurodegenerative disorder characterized by irreversible, progressive loss of memory followed by complete dementia. The cognitive decline is accompanied by impaired performance of daily activities, behavior, speech and visualspatial perception. Glutamate excitotoxicity as a result of blockade of glutamate uptake into astrocytes by Ab aggregates induces excessive Ca influx through mainly the NMDA receptors, followed by neuronal cell death.2) The NMDA receptor subtype has been found to play a key role in glutamate promotion of synaptic plasticity, long-term potentiation and neuronal cell death. 1)We previously reported the synthesis of two cleft-type cyclophanes ACCn 3,4) and ATGDMAP 5) which inhibited the activity of the NR1/NR2A and NR1/NR2B receptors at Ϫ70 mV. The IC 50 values for ACCn and ATGDMAP were 7.0 and 4.9 mM respectively against the NMDA receptors. The inhibition of the activity of the NR1/NR2A and NR1/NR2B receptors by N- (2-{4-[4-(2-{[(1,4,7,10- 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 IC 50 ...

Reinvestigation of Supramolecular Complexes with Cyclophanes of the Stetter and Koga Type: Agreement and Disagreement with Solid‐State Structures

“…Large cyclophanes, which were synthesized a long time ago,1 exhibit a sizeable cavity that has been the starting point for many studies of supramolecular complexes 2,3. Many new publications illustrate the continuing interest in cyclophanes; they lead to more insight in the mechanisms of the corresponding noncovalent interactions,4 as well as to many new applications 5. Generally, one assumes that cavity size determines which guest molecules will be complexed, for aromatic molecules driven π–π interactions, in aqueous solution also by hydrophobic contributions.…”