Abstract
Several pharmacophore models were previously formulated to account for the actions of nicotinic acetylcholinergic (nACh) agents. Most of these models were developed without express consideration of specific radioligand binding data because such data were not available at the time the models were described. In this review, the ability of these models to account for the binding of nicotinic agents at α4β2 nACh receptors (or rat brain receptors for which α4β2 receptors are the major component) is assessed. It seems that none of the early models can adequately explain the binding of these agents as a group. Furthermore, different series of nicotinic agents behave differently depending upon the nature of terminal amine substituents and the spacer that separates the amine from the pyridine ring. A region of bulk tolerance has been identified that accommodates substituents on some nicotinic ligands, but not the same substituents at seemingly corresponding locations of others. The concept of multiple modes of binding has been previously raised and, clearly, cannot yet be discarded. Nevertheless, new vector models seemingly provide a better picture of nACh receptor binding and account for many of the shortcomings associated with the earlier models.
Keywords: Nicotinic Acetylcholine, pyridine ring
Current Topics in Medicinal Chemistry
Title: Musings on α4β2 Nicotinic Acetylcholine (nACh) Receptor Pharmacophore Models
Volume: 4 Issue: 6
Author(s): Richard A. Glennon, Malgorzata Dukat and Liang Liao
Affiliation:
Keywords: Nicotinic Acetylcholine, pyridine ring
Abstract: Several pharmacophore models were previously formulated to account for the actions of nicotinic acetylcholinergic (nACh) agents. Most of these models were developed without express consideration of specific radioligand binding data because such data were not available at the time the models were described. In this review, the ability of these models to account for the binding of nicotinic agents at α4β2 nACh receptors (or rat brain receptors for which α4β2 receptors are the major component) is assessed. It seems that none of the early models can adequately explain the binding of these agents as a group. Furthermore, different series of nicotinic agents behave differently depending upon the nature of terminal amine substituents and the spacer that separates the amine from the pyridine ring. A region of bulk tolerance has been identified that accommodates substituents on some nicotinic ligands, but not the same substituents at seemingly corresponding locations of others. The concept of multiple modes of binding has been previously raised and, clearly, cannot yet be discarded. Nevertheless, new vector models seemingly provide a better picture of nACh receptor binding and account for many of the shortcomings associated with the earlier models.
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Glennon A. Richard, Dukat Malgorzata and Liao Liang, Musings on α4β2 Nicotinic Acetylcholine (nACh) Receptor Pharmacophore Models, Current Topics in Medicinal Chemistry 2004; 4 (6) . https://dx.doi.org/10.2174/1568026043451122
DOI https://dx.doi.org/10.2174/1568026043451122 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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