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Kevin R. Criscione - One of the best experts on this subject based on the ideXlab platform.
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inhibitors of phenylethanolamine n methyltransferase that are predicted to penetrate the blood brain barrier design synthesis and evaluation of 3 fluoromethyl 7 n substituted aminosulfonyl 1 2 3 4 Tetrahydroisoquinolines that possess low affinity toward the alpha2 adrenoceptor
Journal of Medicinal Chemistry, 2004Co-Authors: Anthony F Romero, Kevin R. Criscione, Steven M Vodonick, Michael J Mcleish, Gary L. GrunewaldAbstract:(±)-7-Aminosulfonyl-3-fluoromethyl-1,2,3,4-tetrahydroisoquinoline (7) is one of the most potent and selective inhibitors of phenylethanolamine N-methyltransferase (PNMT) reported to date, but a blood−brain barrier (BBB) model indicates that it cannot penetrate the BBB. To increase the lipophilicity of 7 by addition of a nonpolar substituent to the sulfonamide nitrogen, a small library of (±)-3-fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-Tetrahydroisoquinolines was synthesized and evaluated as inhibitors of PNMT and for affinity at the α2-adrenoceptor. In addition, this library probed the PNMT active site surrounding the sulfonamide nitrogen of 7. Bulky substituents on the sulfonamide nitrogen are disfavored at the PNMT active site more so than at the α2-adrenoceptor (thus reducing selectivity). On the other hand, alkyl chains on the sulfonamide nitrogen that contain an electron dense atom, such as a fluorine, are favored in the PNMT active site and possess little α2-adrenoceptor affinity, thereby...
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synthesis and evaluation of 3 trifluoromethyl 7 substituted 1 2 3 4 Tetrahydroisoquinolines as selective inhibitors of phenylethanolamine n methyltransferase versus the α2 adrenoceptor
Journal of Medicinal Chemistry, 1999Co-Authors: Gary L. Grunewald, Timothy M Caldwell, Kevin R. CriscioneAbstract:A series of 3-trifluoromethyl-1,2,3,4-Tetrahydroisoquinolines was synthesized and evaluated as inhibitors of phenylethanolamine N-methyltransferase (PNMT) and as inhibitors of the binding of clonidine at the α2-adrenoceptor. These compounds were found to be selective inhibitors of PNMT due to their decreased affinity for the α2-adrenoceptor, which was attributed to steric bulk intolerance around the 3-position of 1,2,3,4-tetrahydroisoquinoline (THIQ) at the α2-adrenoceptor and to the decreased pKa of the THIQ amine due to the 3-trifluoromethyl moiety. Overall, these compounds displayed less affinity for PNMT compared to previously studied THIQ-type inhibitors, except for 16 which was found to have good affinity for PNMT (PNMT Ki = 0.52 μM). Compounds 14 and 16 proved to be the most selective inhibitors in this small series of compounds and are some of the most selective inhibitors of PNMT known (14, selectivity α2 Ki/PNMT Ki = 700; 16, selectivity α2 Ki/PNMT Ki > 1900). Compounds 14 and 16 are also quite ...
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synthesis and evaluation of 3 trifluoromethyl 7 substituted 1 2 3 4 Tetrahydroisoquinolines as selective inhibitors of phenylethanolamine n methyltransferase versus the alpha 2 adrenoceptor
Journal of Medicinal Chemistry, 1999Co-Authors: Gary L. Grunewald, Timothy M Caldwell, Kevin R. CriscioneAbstract:A series of 3-trifluoromethyl-1,2,3,4-Tetrahydroisoquinolines was synthesized and evaluated as inhibitors of phenylethanolamine N-methyltransferase (PNMT) and as inhibitors of the binding of clonidine at the α2-adrenoceptor. These compounds were found to be selective inhibitors of PNMT due to their decreased affinity for the α2-adrenoceptor, which was attributed to steric bulk intolerance around the 3-position of 1,2,3,4-tetrahydroisoquinoline (THIQ) at the α2-adrenoceptor and to the decreased pKa of the THIQ amine due to the 3-trifluoromethyl moiety. Overall, these compounds displayed less affinity for PNMT compared to previously studied THIQ-type inhibitors, except for 16 which was found to have good affinity for PNMT (PNMT Ki = 0.52 μM). Compounds 14 and 16 proved to be the most selective inhibitors in this small series of compounds and are some of the most selective inhibitors of PNMT known (14, selectivity α2 Ki/PNMT Ki = 700; 16, selectivity α2 Ki/PNMT Ki > 1900). Compounds 14 and 16 are also quite ...
Gary L. Grunewald - One of the best experts on this subject based on the ideXlab platform.
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inhibitors of phenylethanolamine n methyltransferase that are predicted to penetrate the blood brain barrier design synthesis and evaluation of 3 fluoromethyl 7 n substituted aminosulfonyl 1 2 3 4 Tetrahydroisoquinolines that possess low affinity toward the alpha2 adrenoceptor
Journal of Medicinal Chemistry, 2004Co-Authors: Anthony F Romero, Kevin R. Criscione, Steven M Vodonick, Michael J Mcleish, Gary L. GrunewaldAbstract:(±)-7-Aminosulfonyl-3-fluoromethyl-1,2,3,4-tetrahydroisoquinoline (7) is one of the most potent and selective inhibitors of phenylethanolamine N-methyltransferase (PNMT) reported to date, but a blood−brain barrier (BBB) model indicates that it cannot penetrate the BBB. To increase the lipophilicity of 7 by addition of a nonpolar substituent to the sulfonamide nitrogen, a small library of (±)-3-fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-Tetrahydroisoquinolines was synthesized and evaluated as inhibitors of PNMT and for affinity at the α2-adrenoceptor. In addition, this library probed the PNMT active site surrounding the sulfonamide nitrogen of 7. Bulky substituents on the sulfonamide nitrogen are disfavored at the PNMT active site more so than at the α2-adrenoceptor (thus reducing selectivity). On the other hand, alkyl chains on the sulfonamide nitrogen that contain an electron dense atom, such as a fluorine, are favored in the PNMT active site and possess little α2-adrenoceptor affinity, thereby...
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synthesis and evaluation of 3 trifluoromethyl 7 substituted 1 2 3 4 Tetrahydroisoquinolines as selective inhibitors of phenylethanolamine n methyltransferase versus the α2 adrenoceptor
Journal of Medicinal Chemistry, 1999Co-Authors: Gary L. Grunewald, Timothy M Caldwell, Kevin R. CriscioneAbstract:A series of 3-trifluoromethyl-1,2,3,4-Tetrahydroisoquinolines was synthesized and evaluated as inhibitors of phenylethanolamine N-methyltransferase (PNMT) and as inhibitors of the binding of clonidine at the α2-adrenoceptor. These compounds were found to be selective inhibitors of PNMT due to their decreased affinity for the α2-adrenoceptor, which was attributed to steric bulk intolerance around the 3-position of 1,2,3,4-tetrahydroisoquinoline (THIQ) at the α2-adrenoceptor and to the decreased pKa of the THIQ amine due to the 3-trifluoromethyl moiety. Overall, these compounds displayed less affinity for PNMT compared to previously studied THIQ-type inhibitors, except for 16 which was found to have good affinity for PNMT (PNMT Ki = 0.52 μM). Compounds 14 and 16 proved to be the most selective inhibitors in this small series of compounds and are some of the most selective inhibitors of PNMT known (14, selectivity α2 Ki/PNMT Ki = 700; 16, selectivity α2 Ki/PNMT Ki > 1900). Compounds 14 and 16 are also quite ...
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synthesis and evaluation of 3 trifluoromethyl 7 substituted 1 2 3 4 Tetrahydroisoquinolines as selective inhibitors of phenylethanolamine n methyltransferase versus the alpha 2 adrenoceptor
Journal of Medicinal Chemistry, 1999Co-Authors: Gary L. Grunewald, Timothy M Caldwell, Kevin R. CriscioneAbstract:A series of 3-trifluoromethyl-1,2,3,4-Tetrahydroisoquinolines was synthesized and evaluated as inhibitors of phenylethanolamine N-methyltransferase (PNMT) and as inhibitors of the binding of clonidine at the α2-adrenoceptor. These compounds were found to be selective inhibitors of PNMT due to their decreased affinity for the α2-adrenoceptor, which was attributed to steric bulk intolerance around the 3-position of 1,2,3,4-tetrahydroisoquinoline (THIQ) at the α2-adrenoceptor and to the decreased pKa of the THIQ amine due to the 3-trifluoromethyl moiety. Overall, these compounds displayed less affinity for PNMT compared to previously studied THIQ-type inhibitors, except for 16 which was found to have good affinity for PNMT (PNMT Ki = 0.52 μM). Compounds 14 and 16 proved to be the most selective inhibitors in this small series of compounds and are some of the most selective inhibitors of PNMT known (14, selectivity α2 Ki/PNMT Ki = 700; 16, selectivity α2 Ki/PNMT Ki > 1900). Compounds 14 and 16 are also quite ...
Jesper L. Kristensen - One of the best experts on this subject based on the ideXlab platform.
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dual nicotinic acetylcholine receptor α4β2 antagonists α7 agonists synthesis docking studies and pharmacological evaluation of Tetrahydroisoquinolines and tetrahydroisoquinolinium salts
Journal of Medicinal Chemistry, 2018Co-Authors: François Crestey, Anders A. Jensen, Christian Soerensen, Charlotte Busk Magnus, Jesper T. Andreasen, Günther H. J. Peters, Jesper L. KristensenAbstract:We describe the synthesis of Tetrahydroisoquinolines and tetrahydroisoquinolinium salts together with their pharmacological properties at various nicotinic acetylcholine receptors. In general, the compounds were α4β2 nAChR antagonists, with the tetrahydroisoquinolinium salts being more potent than the parent tetrahydroisoquinoline derivatives. The most potent α4β2 antagonist, 6c, exhibited submicromolar binding Ki and functional IC50 values and high selectivity for this receptor over the α4β4 and α3β4 nAChRs. Whereas the (S)-6c enantiomer was essentially inactive at α4β2, (R)-6c was a slightly more potent α4β2 antagonist than the reference β2-nAChR antagonist DHβE. The observation that the α4β2 activity resided exclusively in the (R)-enantiomer was in full agreement with docking studies. Several of tetrahydroisoquinolinium salts also displayed agonist activity at the α7 nAChR. Preliminary in vivo evaluation revealed antidepressant-like effects of both (R)-5c and (R)-6c in the mouse forced swim test, suppo...
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Dual Nicotinic Acetylcholine Receptor α4β2 Antagonists/α7 Agonists: Synthesis, Docking Studies, and Pharmacological Evaluation of Tetrahydroisoquinolines and Tetrahydroisoquinolinium Salts
2018Co-Authors: François Crestey, Anders A. Jensen, Christian Soerensen, Charlotte Busk Magnus, Jesper T. Andreasen, Günther H. J. Peters, Jesper L. KristensenAbstract:We describe the synthesis of Tetrahydroisoquinolines and tetrahydroisoquinolinium salts together with their pharmacological properties at various nicotinic acetylcholine receptors. In general, the compounds were α4β2 nAChR antagonists, with the tetrahydroisoquinolinium salts being more potent than the parent tetrahydroisoquinoline derivatives. The most potent α4β2 antagonist, 6c, exhibited submicromolar binding Ki and functional IC50 values and high selectivity for this receptor over the α4β4 and α3β4 nAChRs. Whereas the (S)-6c enantiomer was essentially inactive at α4β2, (R)-6c was a slightly more potent α4β2 antagonist than the reference β2-nAChR antagonist DHβΕ. The observation that the α4β2 activity resided exclusively in the (R)-enantiomer was in full agreement with docking studies. Several of tetrahydroisoquinolinium salts also displayed agonist activity at the α7 nAChR. Preliminary in vivo evaluation revealed antidepressant-like effects of both (R)-5c and (R)-6c in the mouse forced swim test, supporting the therapeutic potential of α4β2 nAChR antagonists for this indication
Kimihiro Nakano - One of the best experts on this subject based on the ideXlab platform.
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Simple and Direct sp3 C–H Bond Arylation of Tetrahydroisoquinolines and Isochromans via 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone Oxidation under Mild Conditions
2016Co-Authors: Wataru Muramatsu, Kimihiro NakanoAbstract:The 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)-mediated sp3 C–H bond arylation of Tetrahydroisoquinolines and isochromans is described. The corresponding products were facilely synthesized via a simple nucleophilic addition reaction between readily available aryl Grignard reagents and iminium (or oxonium) cations generated in situ by DDQ oxidation of Tetrahydroisoquinolines (or isochromans) under mild conditions
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simple and direct sp3 c h bond arylation of Tetrahydroisoquinolines and isochromans via 2 3 dichloro 5 6 dicyano 1 4 benzoquinone oxidation under mild conditions
ChemInform, 2013Co-Authors: Wataru Muramatsu, Kimihiro NakanoAbstract:DDQ allows the oxidative arylation of activated sp3 C-H bonds of Tetrahydroisoquinolines, isochromanes and structurally related non-cyclic substrates.
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simple and direct sp3 c h bond arylation of Tetrahydroisoquinolines and isochromans via 2 3 dichloro 5 6 dicyano 1 4 benzoquinone oxidation under mild conditions
Organic Letters, 2013Co-Authors: Wataru Muramatsu, Kimihiro NakanoAbstract:The 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)-mediated sp(3) C-H bond arylation of Tetrahydroisoquinolines and isochromans is described. The corresponding products were facilely synthesized via a simple nucleophilic addition reaction between readily available aryl Grignard reagents and iminium (or oxonium) cations generated in situ by DDQ oxidation of Tetrahydroisoquinolines (or isochromans) under mild conditions.
Yun Liang - One of the best experts on this subject based on the ideXlab platform.
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copper catalyzed c sp3 s bond and c sp2 s bond cross coupling of 2 2 iodobenzoyl substituted or 2 2 iodobenzyl substituted 1 2 3 4 Tetrahydroisoquinolines with potassium sulfide synthesis of isoquinoline fused 1 3 benzothiazine scaffolds
Journal of Organic Chemistry, 2017Co-Authors: Pan Dang, Zhilei Zheng, Yun LiangAbstract:The sulfuration reaction of 2-(2-iodobenzoyl) substituted, or 2-(2-iodobenzyl) substituted 1,2,3,4-Tetrahydroisoquinolines with potassium sulfide proceeded in the presence of copper catalysts to give tetrahydroisoquinoline-fused 1,3-benzothiazine scaffolds in moderate to appropriate yields. This protocol provided an efficient and simple strategy to construct the corresponding benzothiazine derivatives via formation of C(sp3)-S bond and C(sp2)-S bond, which the C-S bonds formed via different routes in this reaction (traditional cross-coupling reaction via the cleavage of C-I bond and oxidative cross-coupling reaction via C(sp3)-H bond functionalization).
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Copper-Catalyzed C(sp3)–S Bond and C(sp2)–S Bond Cross-Coupling of 2‑(2-Iodobenzoyl) Substituted or 2‑(2-Iodobenzyl) Substituted 1,2,3,4-Tetrahydroisoquinolines with Potassium Sulfide: Synthesis of Isoquinoline-Fused 1,3-Benzothiazine Scaffolds
2017Co-Authors: Pan Dang, Zhilei Zheng, Yun LiangAbstract:The sulfuration reaction of 2-(2-iodobenzoyl) substituted, or 2-(2-iodobenzyl) substituted 1,2,3,4-Tetrahydroisoquinolines with potassium sulfide proceeded in the presence of copper catalysts to give tetrahydroisoquinoline-fused 1,3-benzothiazine scaffolds in moderate to appropriate yields. This protocol provided an efficient and simple strategy to construct the corresponding benzothiazine derivatives via formation of C(sp3)–S bond and C(sp2)–S bond, which the C–S bonds formed via different routes in this reaction (traditional cross-coupling reaction via the cleavage of C–I bond and oxidative cross-coupling reaction via C(sp3)–H bond functionalization)
