Discovery and Development of α7 Nicotinic Acetylcholine Receptor Modulators

Mazurov, A. A.; Speake, Jason D.; Yohannes, Daniel

doi:10.1021/jm2007672

Cited by 54 publications

(50 citation statements)

References 81 publications

(118 reference statements)

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“…A number of previous reviews have discussed the structural diversity of nAChR allosteric modulators, including many compounds that have been described in patent applications [36][37][38][39][40]. In addition, previous reviews have discussed the possible therapeutic uses of nAChRs allosteric modulators [27, [41][42][43] for example in the treatment of cognitive deficits [44]; depression [35]; pain [45,46] and cancer [47].…”

Section: Allosteric Modulation Of Nachrsmentioning

confidence: 99%

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Allosteric modulation of nicotinic acetylcholine receptors

Chatzidaki

Millar

2015

Biochemical Pharmacology

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Section: Allosteric Modulation Of Nachrsmentioning

confidence: 99%

“…Much of the recent work concerning nAChR PAMs has focussed on the homomeric α7 receptor [36,37,40,48], one of the main nAChR subtypes expressed in the mammalian brain.…”

Section: Homomeric α7 Nachrsmentioning

confidence: 99%

Allosteric modulation of nicotinic acetylcholine receptors

Chatzidaki

Millar

2015

Biochemical Pharmacology

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“…It has attracted considerable interest as a therapeutic target for Alzheimer's disease, schizophrenia, and inflammation (Martin et al, 2004;de Jonge and Ulloa, 2007;Hernandez and Dineley, 2012), and a number of a7-directed compounds are currently in the clinic (Mazurov et al, 2011). A wide range of structural types activates the receptor (Horenstein et al, 2008), making drug development a serious challenge.…”

Section: Introductionmentioning

confidence: 99%

An Unusual Pattern of Ligand-Receptor Interactions for theα7 Nicotinic Acetylcholine Receptor, with Implications for the Binding of Varenicline

et al. 2013

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The a7 nicotinic acetylcholine receptor shows broad pharmacology, complicating the development of subtype-specific nicotinic receptor agonists. Here we use unnatural amino acid mutagenesis to characterize binding to a7 by the smoking cessation drug varenicline (Chantix; Pfizer, Groton, CT), an a4b2-targeted agonist that shows full efficacy and modest potency at the a7 receptor. We find that unlike binding to its target receptor, varenicline does not form a cation-p interaction with TrpB, further supporting a unique binding mode for the cationic amine of nicotinic agonists at the a7 receptor. We also evaluate binding to the complementary face of the receptor's binding site by varenicline, the endogenous agonist acetylcholine, and the potent nicotine analog epibatidine. Interestingly, we find no evidence for functionally important interactions involving backbone NH and CO groups thought to bind the canonical agonist hydrogen bond acceptor of the nicotinic pharmacophore, perhaps reflecting a lesser importance of this pharmacophore element for a7 binding. We also show that the Trp55 and Leu119 side chains of the binding site's complementary face are important for the binding of the larger agonists epibatidine and varenicline, but dispensable for binding of the smaller, endogenous agonist acetylcholine.

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“…Among them, the neuronal α7 receptor subtype (α7 nAChRs) has attracted considerable interest as a potential target for therapeutic intervention in schizophrenia, Alzheimer's disease and different pain conditions [4,5]. Most of the compounds described as modulators of these channels are competitive agonists or antagonists that interact at the orthosteric binding site of the endogenous ligand, acetylcholine [2,6].…”

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confidence: 99%