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Research paper thumbnail of Discovery of an intrasubunit nicotinic acetylcholine receptor binding site for the positive allosteric modulator Br-PBTC

Journal of Biological Chemistry, 2019

Edited by Mike Shipston Nicotinic acetylcholine receptor (nAChR) ligands that lack agonist activi... more Edited by Mike Shipston Nicotinic acetylcholine receptor (nAChR) ligands that lack agonist activity but enhance activation in the presence of an agonist are called positive allosteric modulators (PAMs). nAChR PAMs have therapeutic potential for the treatment of nicotine addiction and several neuropsychiatric disorders. PAMs need to be selectively targeted toward certain nAChR subtypes to tap this potential. We previously discovered a novel PAM, (R)-7-bromo-N-(piperidin-3-yl)benzo[b]thiophene-2-carboxamide (Br-PBTC), which selectively potentiates the opening of ␣4␤2*, ␣2␤2*, ␣2␤4*, and (␣4␤4) 2 ␣4 nAChRs and reactivates some of these subtypes when desensitized (* indicates the presence of other subunits). We located the Br-PBTC-binding site through mutagenesis and docking in ␣4. The amino acids Glu-282 and Phe-286 near the extracellular domain on the third transmembrane helix were found to be crucial for Br-PBTC's PAM effect. E282Q abolishes Br-PBTC potentiation. Using (␣4 E282Q ␤2) 2 ␣5 nAChRs, we discovered that the trifluoromethylated derivatives of Br-PBTC can potentiate channel opening of ␣5-containing nAChRs. Mutating Tyr-430 in the ␣5 M4 domain changed ␣5-selectivity among Br-PBTC derivatives. There are two kinds of ␣4 subunits in ␣4␤2 nAChRs. Primary ␣4 forms an agonist-binding site with another ␤2 subunit. Accessory ␣4 forms an agonist-binding site with another ␣4 subunit. The pharmacological effect of Br-PBTC depends both on its own and agonists' occupancy of primary and accessory ␣4 subunits. Br-PBTC reactivates desensitized (␣4␤2) 2 ␣4 nAChRs. Its full efficacy requires intact Br-PBTC sites in at least one accessory and one primary ␣4 subunit. PAM potency increases with higher occupancy of the agonist sites. Br-PBTC and its derivatives should prove useful as ␣ subunit-selective nAChR PAMs.

Research paper thumbnail of Discovery of an intrasubunit nicotinic acetylcholine receptor binding site for the positive allosteric modulator Br-PBTC

Journal of Biological Chemistry, 2019

Edited by Mike Shipston Nicotinic acetylcholine receptor (nAChR) ligands that lack agonist activi... more Edited by Mike Shipston Nicotinic acetylcholine receptor (nAChR) ligands that lack agonist activity but enhance activation in the presence of an agonist are called positive allosteric modulators (PAMs). nAChR PAMs have therapeutic potential for the treatment of nicotine addiction and several neuropsychiatric disorders. PAMs need to be selectively targeted toward certain nAChR subtypes to tap this potential. We previously discovered a novel PAM, (R)-7-bromo-N-(piperidin-3-yl)benzo[b]thiophene-2-carboxamide (Br-PBTC), which selectively potentiates the opening of ␣4␤2*, ␣2␤2*, ␣2␤4*, and (␣4␤4) 2 ␣4 nAChRs and reactivates some of these subtypes when desensitized (* indicates the presence of other subunits). We located the Br-PBTC-binding site through mutagenesis and docking in ␣4. The amino acids Glu-282 and Phe-286 near the extracellular domain on the third transmembrane helix were found to be crucial for Br-PBTC's PAM effect. E282Q abolishes Br-PBTC potentiation. Using (␣4 E282Q ␤2) 2 ␣5 nAChRs, we discovered that the trifluoromethylated derivatives of Br-PBTC can potentiate channel opening of ␣5-containing nAChRs. Mutating Tyr-430 in the ␣5 M4 domain changed ␣5-selectivity among Br-PBTC derivatives. There are two kinds of ␣4 subunits in ␣4␤2 nAChRs. Primary ␣4 forms an agonist-binding site with another ␤2 subunit. Accessory ␣4 forms an agonist-binding site with another ␣4 subunit. The pharmacological effect of Br-PBTC depends both on its own and agonists' occupancy of primary and accessory ␣4 subunits. Br-PBTC reactivates desensitized (␣4␤2) 2 ␣4 nAChRs. Its full efficacy requires intact Br-PBTC sites in at least one accessory and one primary ␣4 subunit. PAM potency increases with higher occupancy of the agonist sites. Br-PBTC and its derivatives should prove useful as ␣ subunit-selective nAChR PAMs.

Research paper thumbnail of A Novel α2/α4 Subtype-Selective Positive Allosteric Modulator of Nicotinic Acetylcholine Receptors Acting From the C-tail of an α Subunit

The Journal of biological chemistry, Jan 2, 2015

Positive allosteric modulators (PAMs) of nicotinic acetylcholine receptors (nAChR) are important ... more Positive allosteric modulators (PAMs) of nicotinic acetylcholine receptors (nAChR) are important therapeutic candidates as well as valuable research tools. We identified a novel type II PAM, (R)-7-bromo-N-(piperidin-3-yl)benzo[b]thiophene-2-carboxamide (Br-PBTC), which both increases activation and reactivates desensitized nAChRs. This compound increases acetylcholine-evoked responses of α2* and α4* nAChRs, but is without effect on α3* or α6* nAChRs ('*' indicates presence of other nAChR subunits). Br-BPTC acts from the C-terminal extracellular sequences of α4 subunits, which is also a PAM site for steroid hormone estrogens such as 17β-estradiol. Br-PBTC is much more potent than estrogens. Like 17β-estradiol, the non-steroid Br-PBTC only requires one α4 subunit to potentiate nAChR function, and its potentiation is stronger with more α4 subunits. This feature enables Br-BPTC to potentiate activation of (α4β2)(α6β2)β3 but not (α6β2)2β3 nAChRs. Therefore, this compound is poten...

Research paper thumbnail of Allosteric Potentiation from α4 C-tail A Novel α2/α4 Subtype-Selective Positive Allosteric Modulator of Nicotinic Acetylcholine Receptors Acting from the C-tail of an α Subunit

Background: Nicotinic acetylcholine receptors (nAChRs) are involved in nicotine addiction and som... more Background: Nicotinic acetylcholine receptors (nAChRs) are involved in nicotine addiction and some neurological disorders. Results: A novel positive allosteric modulator potentiates activation through the C-tail of one α4 subunit, but requires two α4 to reactivate desensitized nAChRs. Conclusion: Higher occupancy in allosteric sites promotes nAChR opening and alleviates desensitization. Significance: These α4 modulators may be useful for basic and clinical applications 5 .

Research paper thumbnail of Discovery of an intrasubunit nicotinic acetylcholine receptor binding site for the positive allosteric modulator Br-PBTC

Journal of Biological Chemistry, 2019

Edited by Mike Shipston Nicotinic acetylcholine receptor (nAChR) ligands that lack agonist activi... more Edited by Mike Shipston Nicotinic acetylcholine receptor (nAChR) ligands that lack agonist activity but enhance activation in the presence of an agonist are called positive allosteric modulators (PAMs). nAChR PAMs have therapeutic potential for the treatment of nicotine addiction and several neuropsychiatric disorders. PAMs need to be selectively targeted toward certain nAChR subtypes to tap this potential. We previously discovered a novel PAM, (R)-7-bromo-N-(piperidin-3-yl)benzo[b]thiophene-2-carboxamide (Br-PBTC), which selectively potentiates the opening of ␣4␤2*, ␣2␤2*, ␣2␤4*, and (␣4␤4) 2 ␣4 nAChRs and reactivates some of these subtypes when desensitized (* indicates the presence of other subunits). We located the Br-PBTC-binding site through mutagenesis and docking in ␣4. The amino acids Glu-282 and Phe-286 near the extracellular domain on the third transmembrane helix were found to be crucial for Br-PBTC's PAM effect. E282Q abolishes Br-PBTC potentiation. Using (␣4 E282Q ␤2) 2 ␣5 nAChRs, we discovered that the trifluoromethylated derivatives of Br-PBTC can potentiate channel opening of ␣5-containing nAChRs. Mutating Tyr-430 in the ␣5 M4 domain changed ␣5-selectivity among Br-PBTC derivatives. There are two kinds of ␣4 subunits in ␣4␤2 nAChRs. Primary ␣4 forms an agonist-binding site with another ␤2 subunit. Accessory ␣4 forms an agonist-binding site with another ␣4 subunit. The pharmacological effect of Br-PBTC depends both on its own and agonists' occupancy of primary and accessory ␣4 subunits. Br-PBTC reactivates desensitized (␣4␤2) 2 ␣4 nAChRs. Its full efficacy requires intact Br-PBTC sites in at least one accessory and one primary ␣4 subunit. PAM potency increases with higher occupancy of the agonist sites. Br-PBTC and its derivatives should prove useful as ␣ subunit-selective nAChR PAMs.

Research paper thumbnail of Discovery of an intrasubunit nicotinic acetylcholine receptor binding site for the positive allosteric modulator Br-PBTC

Journal of Biological Chemistry, 2019

Edited by Mike Shipston Nicotinic acetylcholine receptor (nAChR) ligands that lack agonist activi... more Edited by Mike Shipston Nicotinic acetylcholine receptor (nAChR) ligands that lack agonist activity but enhance activation in the presence of an agonist are called positive allosteric modulators (PAMs). nAChR PAMs have therapeutic potential for the treatment of nicotine addiction and several neuropsychiatric disorders. PAMs need to be selectively targeted toward certain nAChR subtypes to tap this potential. We previously discovered a novel PAM, (R)-7-bromo-N-(piperidin-3-yl)benzo[b]thiophene-2-carboxamide (Br-PBTC), which selectively potentiates the opening of ␣4␤2*, ␣2␤2*, ␣2␤4*, and (␣4␤4) 2 ␣4 nAChRs and reactivates some of these subtypes when desensitized (* indicates the presence of other subunits). We located the Br-PBTC-binding site through mutagenesis and docking in ␣4. The amino acids Glu-282 and Phe-286 near the extracellular domain on the third transmembrane helix were found to be crucial for Br-PBTC's PAM effect. E282Q abolishes Br-PBTC potentiation. Using (␣4 E282Q ␤2) 2 ␣5 nAChRs, we discovered that the trifluoromethylated derivatives of Br-PBTC can potentiate channel opening of ␣5-containing nAChRs. Mutating Tyr-430 in the ␣5 M4 domain changed ␣5-selectivity among Br-PBTC derivatives. There are two kinds of ␣4 subunits in ␣4␤2 nAChRs. Primary ␣4 forms an agonist-binding site with another ␤2 subunit. Accessory ␣4 forms an agonist-binding site with another ␣4 subunit. The pharmacological effect of Br-PBTC depends both on its own and agonists' occupancy of primary and accessory ␣4 subunits. Br-PBTC reactivates desensitized (␣4␤2) 2 ␣4 nAChRs. Its full efficacy requires intact Br-PBTC sites in at least one accessory and one primary ␣4 subunit. PAM potency increases with higher occupancy of the agonist sites. Br-PBTC and its derivatives should prove useful as ␣ subunit-selective nAChR PAMs.

Research paper thumbnail of A Novel α2/α4 Subtype-Selective Positive Allosteric Modulator of Nicotinic Acetylcholine Receptors Acting From the C-tail of an α Subunit

The Journal of biological chemistry, Jan 2, 2015

Positive allosteric modulators (PAMs) of nicotinic acetylcholine receptors (nAChR) are important ... more Positive allosteric modulators (PAMs) of nicotinic acetylcholine receptors (nAChR) are important therapeutic candidates as well as valuable research tools. We identified a novel type II PAM, (R)-7-bromo-N-(piperidin-3-yl)benzo[b]thiophene-2-carboxamide (Br-PBTC), which both increases activation and reactivates desensitized nAChRs. This compound increases acetylcholine-evoked responses of α2* and α4* nAChRs, but is without effect on α3* or α6* nAChRs ('*' indicates presence of other nAChR subunits). Br-BPTC acts from the C-terminal extracellular sequences of α4 subunits, which is also a PAM site for steroid hormone estrogens such as 17β-estradiol. Br-PBTC is much more potent than estrogens. Like 17β-estradiol, the non-steroid Br-PBTC only requires one α4 subunit to potentiate nAChR function, and its potentiation is stronger with more α4 subunits. This feature enables Br-BPTC to potentiate activation of (α4β2)(α6β2)β3 but not (α6β2)2β3 nAChRs. Therefore, this compound is poten...

Research paper thumbnail of Allosteric Potentiation from α4 C-tail A Novel α2/α4 Subtype-Selective Positive Allosteric Modulator of Nicotinic Acetylcholine Receptors Acting from the C-tail of an α Subunit

Background: Nicotinic acetylcholine receptors (nAChRs) are involved in nicotine addiction and som... more Background: Nicotinic acetylcholine receptors (nAChRs) are involved in nicotine addiction and some neurological disorders. Results: A novel positive allosteric modulator potentiates activation through the C-tail of one α4 subunit, but requires two α4 to reactivate desensitized nAChRs. Conclusion: Higher occupancy in allosteric sites promotes nAChR opening and alleviates desensitization. Significance: These α4 modulators may be useful for basic and clinical applications 5 .

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