12 ヒンバシン類縁体の合成とそのムスカリンM_2サブタイプ受容体拮抗作用(口頭発表の部)

抄録

Himbacine 1 is a piperidine alkaloid isolated in 1956 from the bark of Galbulimima Baccata in magnolia family. It is reported that 1 behave as a potent antagonist of the muscarinic receptor of M_2 subtype with 10-20 fold selectivity toward the M_1 receptor. Thus, blockage of the presynaptic muscarinic receptor of M_2 subtype leads to an elevation of the synaptic levels of acetylcholine, possibly offsetting some of the losses in the cholinergic system that occurs in Alzheimer's disease. Therefore, much interests have been paid on 1 from the viewpoint of medicinal and/or synthetic organic chemistry. With an aim to disclose novel aspects of the structure-activity relationships of 1, and moreover, to explore the promising himbacine congeners which may show more improved M_2 antagonistic activity and subtype selectivity, we embarked on the synthetic studies on 1. Our novel total synthesis of 1 was completed in 1999 by employing highly stereoselective intermolecular Diels-Alder reaction of the tetrahydrofuran 2 with the chiral furan-2(5H)-one 3 as a key step. Successful application of the explored synthetic route to the synthesis of ent-1 realized its efficiency and directness. Binding affinity assay of ent-1 against the muscarinic receptor of M_2 subtype uncovered that the absolute configuration of 1 was obviously correlated with its activity. In order to explore further novel aspects of the structure-activity relationships of 1, we continued the synthetic studies on various structural types of himbacine congeners. These studies resulted in the successful preparations of 4-epi-himbacine 8, the compounds 10 carrying olefin bioisosteres and aromatic or aliphatic amines in place of an (E)-double bond and a 2,6-disubstituted piperidine, 2',6'-diepi-himbacine 12 and its enantiomer ent-12, 3-norhimbacine 20 and its enantiomer ent-20, 4-epi-3-norhimbacine 21 and its enantiomer ent-21, 11-methylhimbacine 27, and 3-epi-himbacine 29. Synthesis of 10, 12, and ent-12 was achieved starting with the synthetic intermediates 6, 7, 9 and ent-6, 7, 9 for 1 and ent-1, respectively. The 3-norhimbacine derivatives 20, ent-20, 21, and ent-21 were prepared from 2 and achiral furan-2(5H)-one 13 following the same synthetic route as that for 1 and ent-1 and separating four diastereomeric intermediates by CHIRALCEL OD. Preparation of 27 was carried out using (S)-5-ethylfuran-2(5H)-one 23 in place of 3. Direct epimerization of the C_<3α>-methyl group for the synthetic intermediate of 1 afforded 29. All the synthesized congeners were subjected to binding affinity assay against the muscarinic receptor of M_2 subtype. It appeared evident that, while its subtype selectivity is similar to that of 1, 3-norhimbacine 20 shows more potent binding affinity than 1 and that binding affinity of all other congeners is clearly inferior to that of 1. In summary, we have succeeded in preparing various structural types of himbacine congeners by employing the synthetic route previously explored to prepare 1. Binding affinity assay of all the synthesized congeners explored novel aspects of the structure-activity relationships for 1, leading to find 3-norhimbacine 20 which shows more potent binding affinity than 1.