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THE SYNTHESIS OF 5-SUBSTITUTED E RING, AND B/E RING ANALOGUES OF METHYLLYCACONITINE (MLA)

by Huang, Junfeng

Abstract (Summary)
Nicotinic acetylcholine receptors (nAChRs), a ligand-gated ion channel, are involved in several important pathologies and linked to many neurodegenerative diseases. Discovery of ligands which can selectively interact with specific nAChR subtypes can help people to better understand physiological processes and pathophysiological conditions involving these receptors. Methyllycaconitine (MLA), a natural alkaloid, is the most potent and nonpeptide competitive ligand which can selectively bind to specific ?7-nAChR subtype. The identification of structure activity relationship of methyllycaconitine (MLA) will help people to better understand the structure of nAChRs and design leading compounds as drug candidates for nAChR disorder or disfunction diseases. Because of the complex structure of MLA, our group is working on the synthesis of simple analogues of MLA. We have synthesized a series of E ring analogues of MLA, but none of them showed desired bioactivities. We tried to introduce more structure restrict to our E-ring analogues and find a competitive ligand to ?7 nAChRs. We synthesized a series of 5-substituted E ring analogues of MLA using Suzuki crossing coupling reaction as a key step. But those compounds also are noncompetitive ligands to nAChRs. We also development two methods – Knoevenagel approach and Baylis-Hillman approach to synthesize highly functionalized cis-decahydroquinoline system, a key structure of BE ring of MLA, and synthesized two BE ring analogues of MLA. The Baylis-Hillman approach also led us to a tricyclic ring system, which can mimic the BEF ring of the MLA. Two tricyclic analogues were synthesized. We hope these rigid structure analogues can bring us some desired bioactivities.
Bibliographical Information:

Advisor:

School:Ohio University

School Location:USA - Ohio

Source Type:Master's Thesis

Keywords:methyllycaconitine 5 substituited e ring be bef cis decahydroquinoline

ISBN:

Date of Publication:01/01/2008

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