Pituitary adenylate cyclase-activating polypeptide (PACAP) is a highly conserved pleiotropic neuropeptide, implicated in emotional stress responses and anxiety-related disorders. Here, we examined whether our recently developed small-molecule non-peptide PACAP receptor antagonists could ameliorate anxiety-like behaviors induced by acute restraint stress in mice. The antagonists PA-9 and its derivative PA-915 improved anxiety-like behaviors in mice subjected to restraint stress. An anxiolytic effect was observed with single acute dose, suggesting their fast-acting properties. PA-915 demonstrated a statistically significant anxiolytic effect whereas fluoxetine did not. These results indicate the potential of PAC1 antagonists as a novel treatment for anxiety.

10.1016/j.bbrc.2022.09.079

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2(3H)- and 2(5H)-Furanones. VII. Chirality Transfer on the Tetronic Acid Templates

Heterocycles (1999)

Naoki Toyooka Takefumi Momose Morihiro Nishio Hiroyuki Shinoda Hiromi Fujii

The chirality transfer on the P-tetronic acid templates has been examined via highly diastereoselective alkylation or the Michael reaction at the aposition of the acids.Synthetic utility of this transfer procedure was demonstrated by the formal synthesis of (+)-cassiol and enantiodivergent synthesis of 0-methyljoubertiamine.P-Teuonic acids (1) are one of the attractive building blocks for the syntheses of several classes of natural products2due to the presence of multifunctionality in the molecule.Previously, we have demonstrated the efficient preparation of 1 (R1, R2 = H),3 and investigated the reactivity of its congeners at the aposition?However, most fundamental studies in the alkylation on the system have been reported only to a small extent.5Recently, we reponed our preliminary results on the selective allylation at the aposition of optically active a-methyltemnic acids via direct allylation and the Claisen rearrangement of allyl teuonates concomitantly formed in the preceding direct a1l~lation.6In this paper, we wish to repon a full account of detail examination on the alkylation of optically active a,y-disubstituted teuonic acids and the Michael reaction as another cirbon-chain homologation at the a-position.As a synthetic utility of this method, formal synthesis of (+)-cassio17 and enantiodivergent synthesis of 0-methyljoubemamine8 were accomplished.The starting optically active a,y-disubstituted temnic acids ( l a ) -( l e ) were prepared from commercially available methyl lactate, L-phenylalanine and L-valine by employing the intramolecular Reformatsky reaction9 as shown below.

Chirality

Template

Chiral auxiliary

Michael reaction

10.3987/com-99-8494

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2(3H)- and 2(5H)-Furanones. VIII. Preparation and a Nucleophilicity of (S)-g-Isopropyl-a-methyl-b-tetramic Acid

Heterocycles (1999)

Naoki Toyooka Morihiro Nishio Hiroyuki Shinoda Takefumi Momose

An efficient preparation of (S)-y-isopropyl-a-methyl-P-tetramic acid has been established, and the a nucleophilicity of the acid has been also examined.In the preceding paper,' we reported the chirality transfer on the tetronic acid templates using the alkylation or the Michael reaction at the a-position.P-Tetramic acid nucleus, the nitrogen homologue of tetronic acid, has been found in the biologically active natural products, such as tirandamycin, enhroskyrine, tenuazonic acid, ikarugamycin, and althiomycin, therefore, numerous efforts to prepare this ring system have been reported.However, no example of the fundamental study on the alkylation of this acid has been reported.In this Note, we wish to repon an efficient preparation of (S)-y-isopropyl-a-methyl-pteuamic acid (1) and the chimlity transfer on the acid using the alkylation or Michael reaction at the aposition.The first method2 for the preparation of the acid is the Dieckmann cyclization of the m i & ester.This method, however, is not applicable to the preparation of optically active tetramic acid because of racemization at the y-position.3The second method4 is the condensation of amino acid with meldrum's acid to give a y-substituted a-tetramic acid.This condensation is an excellent methodfor the preparation of optically active p-tetramic acid, however, not applicable to the preparation of a,y-disubstituted tebamic acid.The third method5 is the cyclization of amino P-keto ester.This method seems to be applicable to wide variety of optically active mono-or disubstituted p-tetramic acids.Therefore, we applied the third method for the preparation of 1. Protection of amino group in L -d i n e with carbobenzyloxy chloride (CbzCI) afforded the carboxylic acid (2).Construction of the P-keto ester moiety was performed by the sequence of activation of the carboxyl with carbonyldiimidazole (CDI) followed by the substitution of the resulting imidazolide with lithium enolate of methyl propionate to give the P-keto ester (3).Finally, hydrogenolysis of 3 and spontaneous cyclization of the resulting amino ester furnished the desired tetramic acid (1) in good yield.

Isopropyl

Racemization

Aldol condensation

Chirality

10.3987/com-99-8495

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Citations (2)