The characterization of a novel rigid nicotine analog with α7-selective nAChR agonist activity and modulation of agonist properties by boron inclusion

Papke, Roger L.; Zheng, Guangrong; Horenstein, Nicole A.; Dwoskin, Linda P.; Crooks, Peter A.

doi:10.1016/j.bmcl.2005.05.118

Cited by 15 publications

(14 citation statements)

References 21 publications

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“…1) may provide an indication that the benzylidene selectivity filter could “start” as close as 3.7 Å from the charged nitrogen. In ACME, which is α7-selective, the ethyl chain, which constrains the pyridine ring from free rotation, is approximately in the same location as the benzylic carbon in compounds like benzylidene anabaseine and BQNE (Papke et al, 2005b). …”

Section: Resultsmentioning

confidence: 99%

“…1 have very large hydrophobic groups, and many may be grouped into common classes based on the size and position of the groups. However, we have reported previously that the size of the hydrophobic element(s) need not be large (Papke et al, 2004b, 2005a,b). The data of the present study support the hypothesis that a hydrophobic element as small as a single methyl group can provide selective activation of α7 nAChR.…”

Section: Discussionmentioning

confidence: 98%

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Multiple Pharmacophores for the Selective Activation of Nicotinic α7-Type Acetylcholine Receptors

Horenstein¹,

Leonik²,

Papke³

2008

Mol Pharmacol

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The activation of heteromeric and homomeric nicotinic acetylcholine receptors was studied in Xenopus laevis oocytes to identify key structures of putative agonist molecules associated with the selective activation of homomeric ␣7 receptors. We observed that selectivity between ␣7 and ␣4␤2 was more readily obtained than selectivity between ␣7 and ␣3␤4. Based on structural comparisons of previously characterized selective and nonselective agonists, we hypothesize at least three chemical motifs exist that, when present in molecules containing an appropriate cationic center, could be associated with the selective activation of ␣7 receptors. We identify the three distinct structural motifs based on prototypical drugs as the choline motif, the tropane motif, and the benzylidene motif. The choline motif involves the location of an oxygen-containing polar group such as a hydroxyl or carbonyl separated by two carbons from the charged nitrogen. The tropane motif provides ␣7-selectivity based on the addition of multiple small hydrophobic groups positioned away from the cationic center in specific orientations. We show that this motif can convert the nonselective agonists quinuclidine and ethyltrimethyl-ammonium to the ␣7-selective analogs methyl-quinuclidine and diethyldimethyl-ammonium, respectively. We have shown previously that the benzylidene group of 3-2,4, dimethoxy-benzylidene anabaseine (GTS-21) converts anabaseine into an ␣7-selective agonist. The benzylidene motif was also applied to quinuclidine to generate another distinct family of ␣7-selective agonists. Our results provide insight for the further development of nicotinic therapeutics and will be useful to direct future experiments with protein structure-based modeling and site-directed mutagenesis.The nicotinic acetylcholine receptors of the brain can be broadly divided into two classes: heteromeric ␤-subunit-containing receptors, and homomeric ␣7-type receptors. Homomeric ␣7-type receptors have emerged as an exciting potential therapeutic target for several indications, and this has encouraged the development of ␣7-selective agonists. This path of drug development relies on the consideration of both features that distinguish the heteromeric receptors from the homomeric receptors and features that distinguish selective agonists from nonselective agonists.Both heteromeric, ␤-subunit-containing receptors and homomeric ␣7-type receptors are pentameric. The heteromeric neuronal nAChR contain at least one or more ␣ subunits (␣2-␣6) and additional ␤ subunits (␤2-␤4), with two agonist binding sites located at the interface between ␣ and ␤ subunits (Dani, 2001). Neuronal nicotinic receptor ␣ subunits are classified as such based on sequence homology to the ␣ subunits of muscle-type receptors (Heinemann et al., 1990), and essential conserved aspects of muscle and neuronal ␣ subunits provide specialized subdomains that contribute to the primary face of an asymmetrical binding site for acetylcholine and other agonists. In contrast, there is structural homology b...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

Multiple Pharmacophores for the Selective Activation of Nicotinic α7-Type Acetylcholine Receptors

Horenstein¹,

Leonik²,

Papke³

2008

Mol Pharmacol

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“…The N-conjugation of (S)-nicotine with cyanoborane decreased efficacy for a3b4 and a4b2 receptors, as well as for a7 nAChR. [109] Antagonists Whereas considerable efforts have been directed toward the development of nicotinic agonists because of their interesting therapeutic potential, the search for nicotinic antagonists has so far attracted less attention. It was shown in the previous section that structural changes on the lead compound can shift the activity from agonist to antagonist, but only in few instances have the structural requirements for such transformation been elucidated.…”

Section: Rbmentioning

confidence: 99%

Central Nicotinic Receptors: Structure, Function, Ligands, and Therapeutic Potential

et al. 2007

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The growing interest in nicotinic receptors, because of their wide expression in neuronal and non-neuronal tissues and their involvement in several important CNS pathologies, has stimulated the synthesis of a high number of ligands able to modulate their function. These membrane proteins appear to be highly heterogeneous, and still only incomplete information is available on their structure, subunit composition, and stoichiometry. This is due to the lack of selective ligands to study the role of nAChR under physiological or pathological conditions; so far, only compounds showing selectivity between alpha4beta2 and alpha7 receptors have been obtained. The nicotinic receptor ligands have been designed starting from lead compounds from natural sources such as nicotine, cytisine, or epibatidine, and, more recently, through the high-throughput screening of chemical libraries. This review focuses on the structure of the new agonists, antagonists, and allosteric ligands of nicotinic receptors, it highlights the current knowledge on the binding site models as a molecular modeling approach to design new compounds, and it discusses the nAChR modulators which have entered clinical trials.

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“…[1][2][3][4][5] Heterocyclic compounds with two different heteroatoms particularly are the object of growing research interest of chemists. In particular, compounds bearing the thiazole ring in the molecular structure, such as isothiazolidines or isothiazolines, have antitumor, anti-allergic, anti-diabetic, anti-inflammatory, anthelmintic and anti-HIV activity.…”

Section: Introductionmentioning

confidence: 99%

A DFT computational study on the [3+2] cycloaddition between parent thionitrone and nitroethene

Kula¹,

Łapczuk-Krygier²

2018

10.5267/j.ccl

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The characterization of a novel rigid nicotine analog with α7-selective nAChR agonist activity and modulation of agonist properties by boron inclusion

Cited by 15 publications

References 21 publications

Multiple Pharmacophores for the Selective Activation of Nicotinic α7-Type Acetylcholine Receptors

Multiple Pharmacophores for the Selective Activation of Nicotinic α7-Type Acetylcholine Receptors

Central Nicotinic Receptors: Structure, Function, Ligands, and Therapeutic Potential

A DFT computational study on the [3+2] cycloaddition between parent thionitrone and nitroethene

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