Effects at a distance in α7 nAChR selective agonists: benzylidene substitutions that regulate potency and efficacy

Papke, Roger L.; Meyer, Edwin M.; Lavieri, Sophie; Bollampally, Sirisha R.; Papke, Thaddeus; Horenstein, Nicole A.; Itoh, Yoshitsugu; Papke, Julia Kay Porter

doi:10.1016/j.neuropharm.2004.01.005

Cited by 32 publications

(43 citation statements)

References 29 publications

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“…The OpusXpress system is an integrated work station that allows electrophysiological recordings to be made from up to eight oocytes simultaneously. This system has been used previously to examine the function of ion channels, including nicotinic acetylcholine and serotonin 5HT3 receptors as well as CFTR (23)(24)(25). Oocyte impalement is automated, and compound delivery is performed by a computer-controlled fluid handler; compounds are removed from 96-well plates using disposable pipette tips and applied to individual oocytes.…”

Section: Methodsmentioning

confidence: 99%

Small Molecule Activator of the Human Epithelial Sodium Channel

Lü¹,

Echeverri²,

Kalabat³

et al. 2008

Journal of Biological Chemistry

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The epithelial sodium channel (ENaC), a heterotrimeric complex composed of ␣, ␤, and ␥ subunits, belongs to the ENaC/ degenerin family of ion channels and forms the principal route for apical Na ؉ entry in many reabsorbing epithelia. Although high affinity ENaC blockers, including amiloride and derivatives, have been described, potent and specific small molecule ENaC activators have not been reported. Here we describe compound S3969 that fully and reversibly activates human ENaC (hENaC) in an amiloride-sensitive and dose-dependent manner in heterologous cells. Mechanistically, S3969 increases hENaC open probability through interactions requiring the extracellular domain of the ␤ subunit. hENaC activation by S3969 did not require cleavage by the furin protease, indicating that nonproteolyzed channels can be opened. Function of ␣␤G37S␥ hENaC, a channel defective in gating that leads to the salt-wasting disease pseudohypoaldosteronism type I, was rescued by S3969. Small molecule activation of hENaC may find application in alleviating human disease, including pseudohypoaldosteronism type I, hypotension, and neonatal respiratory distress syndrome, when improved Na ؉ flux across epithelial membranes is clinically desirable.

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Section: Methodsmentioning

confidence: 99%

Small Molecule Activator of the Human Epithelial Sodium Channel

Lü¹,

Echeverri²,

Kalabat³

et al. 2008

Journal of Biological Chemistry

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“…Although the active component in cigarette smoke is not yet known, accumulating evidence points to a role for nicotine as a contributor to this apparent neuroprotective effect (O'Neill et al, 2002;Quik, 2004). Support for this possibility stems from studies showing that exposure of cultured cells to nicotine attenuates cellular degeneration (Jin et al, 2004;Papke et al, 2004;Zhou et al, 2004), including damage induced by neurotoxins that selectively destroy dopamine neurons (Jeyarasasingam et al, 2002). In vivo studies also indicate that nicotine protects against nigrostriatal damage, although inconsistencies have been observed in rodent models that may relate to the specific experimental paradigms used, species, or other factors (Janson et al, 1992;Hadjiconstantinou et al, 1994;Costa et al, 2001;Ryan et al, 2001;O'Neill et al, 2002;Parain et al, 2003;Quik, 2004).…”

Section: Introductionmentioning

confidence: 99%

Chronic Oral Nicotine Normalizes Dopaminergic Function and Synaptic Plasticity in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Lesioned Primates

Quik

Chen²,

Parameswaran³

et al. 2006

J. Neurosci.

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Our recent studies show that chronic oral nicotine partially protects against striatal damage in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated nonhuman primates. To identify the cellular changes associated with this protective action, we investigated the effects of nicotine treatment on stimulus-evoked dopamine release, dopamine turnover, and synaptic plasticity in striatum from lesioned and unlesioned animals. Monkeys were chronically (6 months) treated with nicotine in the drinking water and subsequently lesioned with the dopaminergic neurotoxin MPTP (6 months) while nicotine was continued. Nigrostriatal damage increased nicotinic acetylcholine receptor (nAChR)-mediated fractional dopamine release from residual terminals, primarily through changes in ␣3*/␣6* nAChRs. In contrast, fractional receptor-evoked dopamine release was similar to control in unlesioned and lesioned animals with chronic oral nicotine. Long-term nicotine administration also attenuated the enhanced K ϩ -evoked fractional dopamine release from synaptosomes of MPTP-lesioned animals, suggesting that nicotine treatment had a generalized effect on dopaminergic function. This premise was further supported by experiments showing that nicotine dosing decreased the elevated dopamine turnover that occurs after nigrostriatal damage. We next investigated changes in synaptic plasticity with lesioning and nicotine treatment. Nicotine treatment alone enhanced synaptic plasticity by lowering the threshold for long-term depression (LTD) in the corticostriatal pathway. MPTP lesioning led to a loss of LTD, a measure of short-term synaptic plasticity. In contrast, LTD was preserved in nicotine-treated lesioned animals. Thus, the present data show that the disruptions in striatal dopaminergic function after nigrostriatal damage were attenuated with chronic nicotine administration. These cellular alterations may underlie the ability of nicotine to maintain/restore normal function with nigrostriatal damage.

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Section: Introductionmentioning

confidence: 99%

“…[4][5][6] While the benzylidene derivation of anabaseine is sufficient to produce selective agonist activity for the a7 receptor subtype, 4-substitutions on the benzylidene ring modulate both the agonist and antagonist properties. 6) We have previously reported that a series of 3-benzylideneanabaseine (BA) analogues and 6Ј-chloro-3-benzylideneanabaseine (CBA) analogues, which have a chlorine atom at the 6Ј-position of the pyridine ring, display high affinity for nAChRs of the American cockroach (Periplaneta americana L.). 7,8) Structureactivity studies suggested that both the electronic and steric properties of the para-substituent of the phenyl group affect the potency of CBA analogues; the greater the electron-donating ability and the smaller the minimum width of the substituents, the higher the potency of these analogues.…”

Section: Introductionmentioning

confidence: 99%

Affinity of 3-benzylidene- and 3-cinnamylidenemyosmine analogues for Periplaneta americana nicotinic acetylcholine receptors

et al. 2006

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3-Benzylidenemyosmine analogues with substituents at the ortho-, meta-, and para-positions of the phenyl ring and 3-cinnamylidenemyosmine analogues with substituents at a para-position of the phenyl ring were synthesized. The affinity of the synthesized compounds for nicotinic acetylcholine receptors (nAChRs) in the nerve cord of the American cockroach (Periplaneta americana L.) was determined by radioligand binding assay using [ 3 H]epibatidine. Of the compounds tested, 3-(2,4-dihydroxybenzylidene)myosmine 3 and 3-(4-hydroxybenzylidene)-myosmine 4 displayed the highest potency, with IC 50 values of 0.120 and 0.310 mM, respectively. 3-(4-Dimethylaminobenzylidene)myosmine 15 with a para-dimethylamino group on the benzylidene moiety displayed moderate affinity (IC 50 ϭ5.49 mM). On the other hand, cinnamylidene analogues, 3-(4-dimethylaminocinnamylidene)myosmine 16 and 3-cinnamylidenemyosmine 17, displayed moderate affinity, with IC 50 values of 2.07 and 3.52 mM, respectively.

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Effects at a distance in α7 nAChR selective agonists: benzylidene substitutions that regulate potency and efficacy

Cited by 32 publications

References 29 publications

Small Molecule Activator of the Human Epithelial Sodium Channel

Small Molecule Activator of the Human Epithelial Sodium Channel

Chronic Oral Nicotine Normalizes Dopaminergic Function and Synaptic Plasticity in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Lesioned Primates

Affinity of 3-benzylidene- and 3-cinnamylidenemyosmine analogues for Periplaneta americana nicotinic acetylcholine receptors

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