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Der Pharmacia Sinica
ISSN: 0976-8688
Eurosc i con Conference on
Medicinal Chemistry
and Biosimilars
M a r c h 2 5 - 2 6 , 2 0 1 9
B u d a p e s t , H u n g a r y
Medicinal Chemistry & Biosimilars 2019
T
his talk will cover the synthesis of new ligands that are specific for key neuronal nicotinic acetylcholine receptor (nAChR)
subtypes. This, in turn, links to an ability to target, for example, the high affinity nicotine receptor in brain (the 4, 2 nAChR) and
that has implications for treating tobacco addiction and smoking cessation. It is important to understand the society and health
challenge that tobacco addiction presents, so there will be some coverage of this and current therapeutic approaches and that
touches on the business drivers that are also (inevitably) involved. The talk will also discuss the synthetic chemistry explored and
developed around cytisine, a naturally occurring nicotinic partial agonist that was the inspiration for a current smoking cessation
agent (varencline) but that is also used widely in its own right. Total synthesis had been used to access a number of interesting
ligands but this has been superseded by an approach based on direct and highly effective C-H activation of cytisine itself. The
outcomes of that chemistry will be described as well as the associated pharmacology that characterised the selectivity profiles
observed. Computational studies have also played a central role both to elucidate the mode of action of a ligand’s interaction
with the receptor protein associated with the immediate region of the binding site but also at a full receptor scale, to understand
how ligand binding and subsequent protein perturbation leads to activation (opening) of ion channel. This, in turn, has led to
development of a general mechanism for signal transduction within the therapeutically-important Cys-loop family of receptors.
t.gallagher@bristol.ac.ukUnlocking nicotinic selectivity: direct C‒H
functionalisation of (‒) cytisine
Timothy Gallagher
1
, Hugo Rego Campello
1
, Silvia Garcia Del
Villar
2
, Aurelien Honraedt
1
Teresa Minguez Vinas
2
, A Sofia F
Oliveira
1, 3
, Kara E Ranaghan
1
, Deborah K Shoemark
3
,
Isabel Bermudez
2
, Cecilia Gotti
4
, Richard B Sessions
3
,
Adrian J Mulholland
1
and Susan Wonnacott
5
1
University of Bristol, UK
2
Oxford Brookes University, UK
3
University of Bristol, UK
4
University of Milan, Italy
5
University of Bath, UK
Der Pharmacia Sinica 2019, Volume:10
DOI: 10.21767/0976-8688-C1-003