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Preface [Hot topic: Nicotinic Acetylcholine Receptors: Ligand Design Issues (Guest Editor: Jeffrey D. Schmitt)]

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Nicotinic Acetylcholine Receptors: Ligand Design Issues

Nearly 100 years have passed since Langley suggested the existence of nicotinic acetylcholine receptors (nAChRs) [1]. Only in the past decade has enough evidence accumulated to demonstrate, beyond the anecdotal, the potential of nAChR-based therapeutics to address significant unmet medical need. Areas of intense academic and pharmaceutical industry focus include neurodegenerative diseases and neuropsychiatric disorders. Not only do nAChRs continue to provide challenging research opportunities at the molecular and pharmacological level, but they have also become an emerging theme in therapeutics where modulation of complex temporal phenomena takes precedence over indiscriminate activation or inhibition sought by traditional pharmacotherapies.

In this special section, S. Breining reviews recent publications describing synthesis of nAChR ligands based on variants of natural products and / or first-principles design. As expected, this review highlights recent focus on the synthesis of ligands containing the aza[2.2.1]bicycloheptane system of epibatidine. Other highlights include numerous stereospecific routes, nicotinoid synthesis using the Hamaguchi-Ibata reaction and intramolecular Heck arylation.

R. Glennon and coworkers, discuss current thinking in nAChR molecular recognition in light of established pharmacophore models and emerging SAR. Vector pharmacophore models proposed by T√łnder (essentially pharmacophore models that include site points) are envisaged to hold great promise in explaining many of the contradictions in nicotinic SARs. Glennon suggests that the vector pharmacophore could be refined by structure-affinity data from different structural series.

A contribution by T. Grutter encapsulates contributions of the Changeux group in using the Molluskan acetylcholine binding protein structure for developing nAChR binding-domain models. Results of docking experiments may explain why different allosteric states exhibit distinct ligand affinities; this work also indicates that a specific E-loop residue is critical in determining subtype specificity in the desensitized state. So-called ‘gain of function’ and ‘loss of function’ mutants are also discussed as tools for a new generation of research on the biophysical mechanisms of allosterism.

In closing, I would like to express my appreciation for the authors that contributed to this issue. Their contributions exemplify what an exciting time it is in the world of nicotinic acetylcholine receptor research and its role in health and disease.


[1] Langley, J.N. J. Physiol. 1905, 33, 374.
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Document Type: Book Review

Affiliations: Molecular Design Group Targacept Inc. 200 East First Street Suite 300, Winston-Salem NC 27101 USA

Publication date: 01 February 2004

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