()-Cytisine, a natural alkaloid extracted from plants such as Laburnum Anagyroides, behaves mainly as a partial agonist at alpha4beta2 nicotinic acetylcholine receptor subtypes. Moreover, ()-norferruginine, the unnatural nor-analogue of (+)-ferruginine extracted from Darlingia ferruginea, is also more affine for alpha4beta2 neuronal nAChRs. My experimental activity was devoted to the synthesis of a group of derivatives structurally related to Cytisine and Norferruginine. The key step in the preparation of racemates was the 1,3-dipolar cycloaddition of bromonitrile oxide to suitable dipolarophiles, in turn obtained by modifying known reaction sequences. A further investigation of the SAR of cytisine was based on a collaboration with Prof. Gallagher’s research group (University of Bristol, UK). The Gallagher synthesis of cytisine and its analogues involves as a key step a 1,6 addition reaction of a lithium enolate on a pyridone ring. All the compounds have been prepared through palladium catalyzed reactions on the related 4-bromo intermediate (Buchwald-Hartwig, and carbonylation reactions). Another series of compounds has been synthesised taking into account the encouraging results reached by our research group. Based on the structure of ICH3, a selective partial agonist for the alpha7 subtype, I focussed on the evaluation of the relevance of the quinuclidine ring to the biological activity. Applying a molecular simplification strategy, the novel spirocyclic derivatives were prepared via a 1,3-dipolar cycloaddition of nitrile oxides to the suitable olefins. All the compounds were tested for their binding affinity at alpha4beta2 and alpha7 nAChR subtypes.

Design, synthesis and biological evaluation of novel heterocyclic derivatives targeting the neuronal nicotinic receptor subtypes / F. Frigerio ; Tutor: Marco De Amici ; Coordinatore: Carlo De Micheli. - : . DIPARTIMENTO DI SCIENZE FARMACEUTICHE "PIETRO PRATESI", 2009 Dec. ((22. ciclo, Anno Accademico 2008/2009.

Design, synthesis and biological evaluation of novel heterocyclic derivatives targeting the neuronal nicotinic receptor subtypes

F. Frigerio
2009

Abstract

()-Cytisine, a natural alkaloid extracted from plants such as Laburnum Anagyroides, behaves mainly as a partial agonist at alpha4beta2 nicotinic acetylcholine receptor subtypes. Moreover, ()-norferruginine, the unnatural nor-analogue of (+)-ferruginine extracted from Darlingia ferruginea, is also more affine for alpha4beta2 neuronal nAChRs. My experimental activity was devoted to the synthesis of a group of derivatives structurally related to Cytisine and Norferruginine. The key step in the preparation of racemates was the 1,3-dipolar cycloaddition of bromonitrile oxide to suitable dipolarophiles, in turn obtained by modifying known reaction sequences. A further investigation of the SAR of cytisine was based on a collaboration with Prof. Gallagher’s research group (University of Bristol, UK). The Gallagher synthesis of cytisine and its analogues involves as a key step a 1,6 addition reaction of a lithium enolate on a pyridone ring. All the compounds have been prepared through palladium catalyzed reactions on the related 4-bromo intermediate (Buchwald-Hartwig, and carbonylation reactions). Another series of compounds has been synthesised taking into account the encouraging results reached by our research group. Based on the structure of ICH3, a selective partial agonist for the alpha7 subtype, I focussed on the evaluation of the relevance of the quinuclidine ring to the biological activity. Applying a molecular simplification strategy, the novel spirocyclic derivatives were prepared via a 1,3-dipolar cycloaddition of nitrile oxides to the suitable olefins. All the compounds were tested for their binding affinity at alpha4beta2 and alpha7 nAChR subtypes.
DE AMICI, MARCO
DE MICHELI, CARLO
Settore CHIM/08 - Chimica Farmaceutica
Design, synthesis and biological evaluation of novel heterocyclic derivatives targeting the neuronal nicotinic receptor subtypes / F. Frigerio ; Tutor: Marco De Amici ; Coordinatore: Carlo De Micheli. - : . DIPARTIMENTO DI SCIENZE FARMACEUTICHE "PIETRO PRATESI", 2009 Dec. ((22. ciclo, Anno Accademico 2008/2009.
Doctoral Thesis
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/152454
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