Abstract
The flexible and efficient enantioselective synthesis of poison-frog alkaloids has been described using the highly stereoselective conjugate addition reactions as the key step. Several 5,8-disubstituted indolizidines and 1,4-disubstituted quinolizidines have been synthesized according to this strategy. Furthermore, 5,6,8-trisubstituted indolizidne type of poison-frog alkaloid 223A and unique tricyclic poison-frog alkaloid 205B have also been synthesized by sequential use of the above key conjugate addition reaction. Investigations of inhibitory effects of synthetic poison-frog alkaloids on neuronal nicotinic acetylcholine receptors have been conducted, and we found that most of the synthetic compounds showed inhibitory effects on the neuronal nicotinic acetylcholine receptors. Especially, the 5,8-disubstituted indolizidine 235B inhibited the α4 β2-neuronal nicotinic acetylcholine receptors in highly subtype-selective manner. These results suggested that the synthetic alkaloid 235B is a promising lead compound for the drugs designed to treat cholinergic disorders such as autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE).
Keywords: Michael-type conjugate addition, indolizidine, quinolizidine, piperidone synthesis, nicotinic acetylcholine receptors (nAChRs)
Current Chemical Biology
Title: Synthesis of Poison-Frog Alkaloids and Their Pharmacological Effects at Neuronal Nicotinic Acetylcholine Receptors
Volume: 1 Issue: 1
Author(s): Naoki Toyooka, Hiroshi Tsuneki, Soushi Kobayashi, Zhou Dejun, Masashi Kawasaki, Ikuko Kimura, Toshiyasu Sasaoka and Hideo Nemoto
Affiliation:
Keywords: Michael-type conjugate addition, indolizidine, quinolizidine, piperidone synthesis, nicotinic acetylcholine receptors (nAChRs)
Abstract: The flexible and efficient enantioselective synthesis of poison-frog alkaloids has been described using the highly stereoselective conjugate addition reactions as the key step. Several 5,8-disubstituted indolizidines and 1,4-disubstituted quinolizidines have been synthesized according to this strategy. Furthermore, 5,6,8-trisubstituted indolizidne type of poison-frog alkaloid 223A and unique tricyclic poison-frog alkaloid 205B have also been synthesized by sequential use of the above key conjugate addition reaction. Investigations of inhibitory effects of synthetic poison-frog alkaloids on neuronal nicotinic acetylcholine receptors have been conducted, and we found that most of the synthetic compounds showed inhibitory effects on the neuronal nicotinic acetylcholine receptors. Especially, the 5,8-disubstituted indolizidine 235B inhibited the α4 β2-neuronal nicotinic acetylcholine receptors in highly subtype-selective manner. These results suggested that the synthetic alkaloid 235B is a promising lead compound for the drugs designed to treat cholinergic disorders such as autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE).
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Toyooka Naoki, Tsuneki Hiroshi, Kobayashi Soushi, Dejun Zhou, Kawasaki Masashi, Kimura Ikuko, Sasaoka Toshiyasu and Nemoto Hideo, Synthesis of Poison-Frog Alkaloids and Their Pharmacological Effects at Neuronal Nicotinic Acetylcholine Receptors, Current Chemical Biology 2007; 1 (1) . https://dx.doi.org/10.2174/2212796810701010097
DOI https://dx.doi.org/10.2174/2212796810701010097 |
Print ISSN 2212-7968 |
Publisher Name Bentham Science Publisher |
Online ISSN 1872-3136 |
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