Three-Component, Diastereoselective Prins–Ritter Reaction for <i>cis</i>-Fused 4‑Amidotetrahydropyrans toward a Precursor for Possible Neuronal Receptor Ligands

Here, we report an unprecedented, highly diastereoselective Prins–Ritter reaction of aldehydes, homoallylic alcohols, and nitriles in a three-component coupling reaction for the synthesis of tetra-<i>cis</i>-substituted 4-amidotetrahydropyrans. In this study, the reaction was not only applied for carbohydrate-based heterobicycles but also for more complex heterotricycles, showing acceptable levels of conversion yield (42–97% BRSM) and exclusive diastereoselectivity. Furthermore, the latter heterotricycles were converted to nine analogues of our neuronal receptor ligands IKM-159 and MC-27. An in vivo assay by intracerebroventricular injection in mice suggested that the substituent at C9 of the novel analogues interferes with the molecular interactions with the AMPA receptor, which was originally observed in the complex of IKM-159 and the GluA2 ligand binding domain. Our research has thus shown the power of a multicomponent coupling reaction for the preparation of a structurally diverse compound collection to study structure–activity relationships of biologically active small molecules

Protoaculeine B, a Putative <i>N</i>‑Terminal Residue for the Novel Peptide Toxin Aculeines

A new polyamine-modified indole derivative protoaculeine B (<b>1</b>) was isolated from Okinawan marine sponge <i>Axinyssa aculeata</i>. The structure of <b>1</b> was assigned on the basis of spectral data along with chemical transformations. Because the structure of <b>1</b> greatly inferred the <i>N</i>-terminal amino acid for highly modified peptide toxin aculeines, the probable structure for aculeine B was proposed on the basis of high-resolution mass spectral analysis

Studies on Aculeines: Synthetic Strategy to the Fully Protected Protoaculeine B, the <i>N</i>‑Terminal Amino Acid of Aculeine B

A synthetic strategy for accessing protoaculeine B (<b>1</b>), the <i>N</i>-terminal amino acid of the highly modified peptide toxin aculeine, was developed via the synthesis of the fully protected natural homologue of <b>1</b> with a 12-mer poly­(propanediamine). The synthesis of mono­(propane­diamine) analog <b>2</b>, as well as core amino acid <b>3</b>, was demonstrated by this strategy. New amino acid <b>3</b> induced convulsions in mice; however, compound <b>2</b> showed no such activity

Studies on an (<i>S</i>)‑2-Amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic Acid (AMPA) Receptor Antagonist IKM-159: Asymmetric Synthesis, Neuroactivity, and Structural Characterization

IKM-159 was developed and identified as a member of a new class of heterotricyclic glutamate analogues that act as AMPA receptor-selective antagonists. However, it was not known which enantiomer of IKM-159 was responsible for its pharmacological activities. Here, we report in vivo and in vitro neuronal activities of both enantiomers of IKM-159 prepared by enantioselective asymmetric synthesis. By employment of (<i>R</i>)-2-amino-2-(4-methoxyphenyl)­ethanol as a chiral auxiliary, (2<i>R</i>)-IKM-159 and the (2<i>S</i>)-counterpart were successfully synthesized in 0.70% and 1.5% yields, respectively, over a total of 18 steps. Both behavioral and electrophysiological assays showed that the biological activity observed for the racemic mixture was reproduced only with (2<i>R</i>)-IKM-159, whereas the (2<i>S</i>)-counterpart was inactive in both assays. Racemic IKM-159 was crystallized with the ligand-binding domain of GluA2, and the structure revealed a complex containing (2<i>R</i>)-IKM-159 at the glutamate binding site. (2<i>R</i>)-IKM-159 locks the GluA2 in an open form, consistent with a pharmacological action as competitive antagonist of AMPA receptors

Studies on an (<i>S</i>)‑2-Amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic Acid (AMPA) Receptor Antagonist IKM-159: Asymmetric Synthesis, Neuroactivity, and Structural Characterization

IKM-159 was developed and identified as a member of a new class of heterotricyclic glutamate analogues that act as AMPA receptor-selective antagonists. However, it was not known which enantiomer of IKM-159 was responsible for its pharmacological activities. Here, we report in vivo and in vitro neuronal activities of both enantiomers of IKM-159 prepared by enantioselective asymmetric synthesis. By employment of (<i>R</i>)-2-amino-2-(4-methoxyphenyl)­ethanol as a chiral auxiliary, (2<i>R</i>)-IKM-159 and the (2<i>S</i>)-counterpart were successfully synthesized in 0.70% and 1.5% yields, respectively, over a total of 18 steps. Both behavioral and electrophysiological assays showed that the biological activity observed for the racemic mixture was reproduced only with (2<i>R</i>)-IKM-159, whereas the (2<i>S</i>)-counterpart was inactive in both assays. Racemic IKM-159 was crystallized with the ligand-binding domain of GluA2, and the structure revealed a complex containing (2<i>R</i>)-IKM-159 at the glutamate binding site. (2<i>R</i>)-IKM-159 locks the GluA2 in an open form, consistent with a pharmacological action as competitive antagonist of AMPA receptors