Design, synthesis, structure–activity relationship, and in vivo activity of azabicyclic aryl amides as α7 nicotinic acetylcholine receptor agonists

Walker, Daniel P.; Wishka, Donn G.; Piotrowski, David W.; Jia, Shaojuan; Reitz, Steven C.; Yates, Karen; Myers, Jason K.; Vetman, Tatiana; Margolis, Brandon J.; Jacobsen, E. J.; Acker, Brad A.; Groppi, Vincent E.; Wolfe, Mark L.; Thornburgh, Bruce A.; Tinholt, Paula M.; Cortes-Burgos, Luz A.; Walters, Rodney R.; Hester, Matthew R.; Seest, Eric P.; Dolak, Lester A.; Han, Fusen; Olson, Beth; Fitzgerald, Laura Rydelek; Staton, Brian A.; Raub, Thomas J.; Hajós, Mihály; Hoffmann, William E.; Li, Kai S.; Higdon, Nicole R.; Wall, Theron M.; Hurst, Raymond S; Wong, Erik H. F.; Rogers, Bruce N.

doi:10.1016/j.bmc.2006.09.019

Cited by 91 publications

(51 citation statements)

References 61 publications

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“…PNU-282987 has been thoroughly characterized both in vitro and in vivo, demonstrating the restoration of P50 gating deficits in rodents, and has served as a tool molecule to advance basic research efforts Vicens et al, 2010;McLean et al, 2011). However, a major drawback of this compound was the interaction with the human ether à go-go-related gene (hERG) channel, which could represent a major cardiovascular risk (Walker et al, 2006). Thus, to improve the selectivity and to diminish functional activity at the hERG channel, an analog of PNU-282987 was designed that demonstrated improved absorption, distribution, metabolism, and excretion properties, reduced hERG activity, as well as an adequate therapeutic index.…”

Section: Gts-21mentioning

confidence: 99%

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

et al. 2015

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Section: Gts-21mentioning

confidence: 99%

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

et al. 2015

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“…We selected the quinuclidinyl benzamide, PNU-282987 (Fig. 1B), as the starting point for ligand design because it was reported to cross the blood-brain barrier (20) and to be highly selective for α7 nAChR (21).…”

Section: Several Neuron Manipulation Tools Have Been Derived Frommentioning

confidence: 99%

Chemical and Genetic Engineering of Selective Ion Channel–Ligand Interactions

Magnus

Lee

Atasoy

et al. 2011

Science

268

283

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Ionic flux in defined cell populations mediates essential physiological and behavioral functions. Cell type-specific activators of diverse ionic conductances are needed for probing these relationships. We combined chemistry and protein engineering to enable systematic creation of a toolbox of ligand-gated ion channels (LGICs) with orthogonal pharmacologic selectivity and divergent functional properties. The LGICs and their small molecule effectors can activate a range of ionic conductances in genetically-specified cell types.LGICs constructed for neuronal perturbation can be used to selectively manipulate neuron activity in mammalian brains in vivo.The diversity of ion channel tools accessible from this approach will be useful for examining the relationship between neuronal activity and animal behavior, as well as for cell biological and physiological applications requiring chemical control of ion conductance.Ion channels are complex molecular machines with critical cell biological functions. Ligandgated ion channels (LGICs) provide rapid, remote control over conductances for different ions. In neurons, LGICs can be exploited for stimulation or silencing to examine causal relationships between electrical activity and animal behavior. Several neuron manipulation tools have been derived fromLGICs and G-protein coupled receptors (1-4) that can be genetically targeted and are reported to be orthogonal to endogenous systems. These tools are useful (5-7) but also face limitations such as ligand instability and lack of brain access (2), slow pharmacokinetics (6), the need to knockout endogenous alleles (3), or reliance on complex intracellular signaling pathways (4). Optogenetic tools (8-10) activate conductances with millisecond precision, but optimization of ion conductance properties has been limited and light targeting is invasive.To overcome these limitations, we have developed a strategy to create chimeric LGICs with distinct conductance properties derived from modular combinations of pharmacologicallyselective ligand binding domains (LBDs) and functionally diverse ion pore domains (IPDs). Within the Cys-loop receptor superfamily, the LBD of the α7 nicotinic acetylcholine receptor (nAChR) behaves as an independent actuator module that can be transplanted onto the IPDs of other Cys-loop receptors (11,12). These include at least 43 ion channel subunits in vertebrates (13), and many additional invertebrate (14) and prokaryotic (15) subunits. Distinct IPDs confer selectivity for chloride or calcium as well as nonspecific cations. For example, splicing the α7 nAChR LBD to the IPDs of the serotonin receptor 3a or the glycine receptor produces chimeric channels (α7-5HT3 or α7-GlyR) with α7 nAChR pharmacology and cation or chloride conductance properties, respectively (11,12). This modular property is a strong foundation for tailoring functional characteristics. However, the † To whom correspondence should be addressed. sternsons@janelia.hhmi.org (S.M.S.), HHMI Author ManuscriptHHMI Author Manuscript HHMI Auth...

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“…Both drugs and saline were injected 10 -15 min before HBH or SHBH (in the SHBH group) session. The time of treatment was evaluated from the experimental data [36,37].…”

Section: Experimental Protocolmentioning

confidence: 99%

“…Functional α7 nAChRs have been detected in neurons [9,[29][30][31][32][33] and in cytokine-producing cells of the immune system in both the brain [20,27,29] and other organs [22, 24-26, 34, 35]. In addition, α7 nAChRs of the hippocampus and cortex also play important roles in cognitive function in norm and pathology [29,30,[36][37][38][39], and there is evidence of a relationship between PPI and cognitive disturbances in patients with schizophrenia [9,10,40]. There are also single direct data that α7 nAChRs selectively mediate the stimulating effect of nicotine and other selective agonists on PPI [41,42].…”

Section: Introductionmentioning

confidence: 99%

The Acoustic Sensorimotor Gating Predicts the Efficiency of Hypoxic Preconditioning. Participation of the Cholinergic System in This Phenomenon

Захарова¹,

Сторожева²,

Proshin³

et al. 2018

JBiSE

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Moderate one-off hypobaric hypoxia (HBH) provokes preconditioning and prolongs the resistance (T, the time before apnoea) to severe hypobaric hypoxia (SHBH). Hypoxic preconditioning has therapeutic potential; however, the efficiency of hypoxic preconditioning varies greatly and the methods for its preliminary evaluation are absent in both animals and humans. This rodent study evaluates the dependence of SHBH resistance, initiated by HBH, on the rate of sensorimotor gating estimated in the model of the acoustic startle prepulse inhibition (PPI). A stable negative correlation was found between PPI and T. Low doses of the α7 nicotinic receptor agonist, PNU-282987 (PNU), and more pronouncedly dimethyl sulfoxide (DMSO) (a PNU solvent), inverted the correlation between PPI and T from negative to positive. The DMSO and PNU effects were reversed at PPIs of 0.36 -0.40 (36% -40%). DMSO increased T values by 52.2% ± 9.7% in the region of lower HBH efficiency (PPI ≥ 0.40) and reduced it by 35.2% ± 9.3% in the region of higher HBH efficiency (PPI < 0.40). PNU reduced both DMSO effects. The involvement of the central cholinergic mechanisms was substantiated in both DMSO and PNU influences on HBH. In conclusion, 1) PPI can be used to predict the efficiency of hypoxic preconditioning and to study its mechanisms, 2) two opposite cholinergic PPI-related mechanisms participate in the preconditioning effects of HBH, 3) the sensitivity of rats to DMSO and PNU diverges when the PPI is 0.36 -0.40,

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Design, synthesis, structure–activity relationship, and in vivo activity of azabicyclic aryl amides as α7 nicotinic acetylcholine receptor agonists

Cited by 91 publications

References 61 publications

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

Chemical and Genetic Engineering of Selective Ion Channel–Ligand Interactions

The Acoustic Sensorimotor Gating Predicts the Efficiency of Hypoxic Preconditioning. Participation of the Cholinergic System in This Phenomenon

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