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Uli Hacksell - One of the best experts on this subject based on the ideXlab platform.
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3-(2-Benzofuranyl)quinuclidin-2-ene Derivatives: Novel Muscarinic Antagonists†
Journal of medicinal chemistry, 1996Co-Authors: Gunnar Nordvall, Staffan Sundquist, Gary Johansson, Gunilla Glas, Lisbeth Nilvebrant, Uli HacksellAbstract:A series of 26 derivatives of the novel Muscarinic antagonist 3-(2-benzofuranyl)quinuclidin-2-ene (1) has been synthesized and evaluated for Muscarinic and antiMuscarinic properties. The affinity of the compounds was determined by competition experiments in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (−)-[3H]-3-quinuclidinyl benzilate as the radioligand, and the antiMuscarinic potency was determined in a functional assay on isolated guinea pig urinary bladder using carbachol as the agonist. The 5-fluorobenzofuranyl derivative was slightly more potent than 1. The 7-bromo-substituted 8 displayed a 14-fold tissue selectivity ratio for Muscarinic receptors in the cortex versus the parotid gland. Comparative molecular field analysis and quantitative structure−activity relationship models were developed for this series of substituted benzofuranyl derivatives.
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3 heteroaryl substituted quinuclidin 3 ol and quinuclidin 2 ene derivatives as Muscarinic Antagonists synthesis and structure activity relationships
Journal of Medicinal Chemistry, 1995Co-Authors: Bjoern M. Nilsson, Gunnar Nordvall, Staffan Sundquist, Gary Johansson, Gunilla Glas, Lisbeth Nilvebrant, Uli HacksellAbstract:A number of 3-heteroaryl-substituted quinuclidin-3-ol and quinuclidin-2-ene derivatives have been prepared and evaluated for Muscarinic and antiMuscarinic properties. The affinities of the new compounds (13, 14, 16-32, and 36-52a,b) were tested in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[ 3 H]-3-quinuclidinyl benzilate [(-)-[ 3 H]QNB] as the radioligand and in a functional assay using isolated guinea pig urinary bladder. The present compounds behaved as competitive Muscarinic Antagonists in the urinary bladder. The highest receptor binding affinity, K i (cortex) = 9.6 nM, was observed for 3-(2-benzofuranyl)quinuclidin-2-ene (31). The corresponding 3-benzofuranyl (36) and 3-benzothienyl (37) homologues had about 3.5-fold lower affinity for cortical Muscarinic receptors. All quinuclidin-3-ol derivatives (14 and 16-25) had lower binding affinities for the different Muscarinic receptor subtypes than the corresponding quinuclidin-2-ene analogues when examined in the various tissue homogenates. In general, the new compounds showed low subtype selectivity. The structure-affinity relationships are discussed in terms of differences in proton basicity of the azabicyclic nitrogen and differences in geometric, conformational, and/or electronic properties of the compounds. The cortical antiMuscarinic potency is also related to the complementarity of the compounds to the putative binding site of the Muscarinic m1 receptor
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Phenyl-substituted analogues of oxotremorine as Muscarinic Antagonists.
Journal of medicinal chemistry, 1992Co-Authors: Bjoern M. Nilsson, Hugo M. Vargas, Bjoern Ringdahl, Uli HacksellAbstract:A series of phenyl-substituted analogues of the Muscarinic agent oxotremorine (1) have been prepared. The new compounds (3b-11b and 9c) were assayed for antiMuscarinic activity on the isolated guinea pig ileum and in intact mice. They were also evaluated for ability to inhibit the binding of the Muscarinic antagonist (-)-[3H]-N-methylscopolamine to homogenates of the rat cerebral cortex. The phenyl-substituted derivatives were devoid of intrinsic Muscarinic activity. Instead, they behaved as competitive Muscarinic Antagonists in these assays with similar or lower affinity for Muscarinic receptors than the corresponding methyl-substituted analogues. The succinimide (8b) and the pyrrolidone (3b) derivatives of 1 substituted with a phenyl group at position 1 of the butynyl chain showed the highest antiMuscarinic potency with dissociation constants (KD) of 0.10 and 0.20 microM, respectively, in the ileum assay. The phenyl-substituted analogues showed an approximately 10-fold lower in vivo antiMuscarinic potency than their corresponding methyl-substituted positional isomers. A correlation was observed between in vitro and in vivo potency within subsets consisting of methyl- and phenyl-substituted derivatives.
Gunnar Nordvall - One of the best experts on this subject based on the ideXlab platform.
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3-(2-Benzofuranyl)quinuclidin-2-ene Derivatives: Novel Muscarinic Antagonists†
Journal of medicinal chemistry, 1996Co-Authors: Gunnar Nordvall, Staffan Sundquist, Gary Johansson, Gunilla Glas, Lisbeth Nilvebrant, Uli HacksellAbstract:A series of 26 derivatives of the novel Muscarinic antagonist 3-(2-benzofuranyl)quinuclidin-2-ene (1) has been synthesized and evaluated for Muscarinic and antiMuscarinic properties. The affinity of the compounds was determined by competition experiments in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (−)-[3H]-3-quinuclidinyl benzilate as the radioligand, and the antiMuscarinic potency was determined in a functional assay on isolated guinea pig urinary bladder using carbachol as the agonist. The 5-fluorobenzofuranyl derivative was slightly more potent than 1. The 7-bromo-substituted 8 displayed a 14-fold tissue selectivity ratio for Muscarinic receptors in the cortex versus the parotid gland. Comparative molecular field analysis and quantitative structure−activity relationship models were developed for this series of substituted benzofuranyl derivatives.
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3 heteroaryl substituted quinuclidin 3 ol and quinuclidin 2 ene derivatives as Muscarinic Antagonists synthesis and structure activity relationships
Journal of Medicinal Chemistry, 1995Co-Authors: Bjoern M. Nilsson, Gunnar Nordvall, Staffan Sundquist, Gary Johansson, Gunilla Glas, Lisbeth Nilvebrant, Uli HacksellAbstract:A number of 3-heteroaryl-substituted quinuclidin-3-ol and quinuclidin-2-ene derivatives have been prepared and evaluated for Muscarinic and antiMuscarinic properties. The affinities of the new compounds (13, 14, 16-32, and 36-52a,b) were tested in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[ 3 H]-3-quinuclidinyl benzilate [(-)-[ 3 H]QNB] as the radioligand and in a functional assay using isolated guinea pig urinary bladder. The present compounds behaved as competitive Muscarinic Antagonists in the urinary bladder. The highest receptor binding affinity, K i (cortex) = 9.6 nM, was observed for 3-(2-benzofuranyl)quinuclidin-2-ene (31). The corresponding 3-benzofuranyl (36) and 3-benzothienyl (37) homologues had about 3.5-fold lower affinity for cortical Muscarinic receptors. All quinuclidin-3-ol derivatives (14 and 16-25) had lower binding affinities for the different Muscarinic receptor subtypes than the corresponding quinuclidin-2-ene analogues when examined in the various tissue homogenates. In general, the new compounds showed low subtype selectivity. The structure-affinity relationships are discussed in terms of differences in proton basicity of the azabicyclic nitrogen and differences in geometric, conformational, and/or electronic properties of the compounds. The cortical antiMuscarinic potency is also related to the complementarity of the compounds to the putative binding site of the Muscarinic m1 receptor
Bjoern M. Nilsson - One of the best experts on this subject based on the ideXlab platform.
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3 heteroaryl substituted quinuclidin 3 ol and quinuclidin 2 ene derivatives as Muscarinic Antagonists synthesis and structure activity relationships
Journal of Medicinal Chemistry, 1995Co-Authors: Bjoern M. Nilsson, Gunnar Nordvall, Staffan Sundquist, Gary Johansson, Gunilla Glas, Lisbeth Nilvebrant, Uli HacksellAbstract:A number of 3-heteroaryl-substituted quinuclidin-3-ol and quinuclidin-2-ene derivatives have been prepared and evaluated for Muscarinic and antiMuscarinic properties. The affinities of the new compounds (13, 14, 16-32, and 36-52a,b) were tested in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[ 3 H]-3-quinuclidinyl benzilate [(-)-[ 3 H]QNB] as the radioligand and in a functional assay using isolated guinea pig urinary bladder. The present compounds behaved as competitive Muscarinic Antagonists in the urinary bladder. The highest receptor binding affinity, K i (cortex) = 9.6 nM, was observed for 3-(2-benzofuranyl)quinuclidin-2-ene (31). The corresponding 3-benzofuranyl (36) and 3-benzothienyl (37) homologues had about 3.5-fold lower affinity for cortical Muscarinic receptors. All quinuclidin-3-ol derivatives (14 and 16-25) had lower binding affinities for the different Muscarinic receptor subtypes than the corresponding quinuclidin-2-ene analogues when examined in the various tissue homogenates. In general, the new compounds showed low subtype selectivity. The structure-affinity relationships are discussed in terms of differences in proton basicity of the azabicyclic nitrogen and differences in geometric, conformational, and/or electronic properties of the compounds. The cortical antiMuscarinic potency is also related to the complementarity of the compounds to the putative binding site of the Muscarinic m1 receptor
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Phenyl-substituted analogues of oxotremorine as Muscarinic Antagonists.
Journal of medicinal chemistry, 1992Co-Authors: Bjoern M. Nilsson, Hugo M. Vargas, Bjoern Ringdahl, Uli HacksellAbstract:A series of phenyl-substituted analogues of the Muscarinic agent oxotremorine (1) have been prepared. The new compounds (3b-11b and 9c) were assayed for antiMuscarinic activity on the isolated guinea pig ileum and in intact mice. They were also evaluated for ability to inhibit the binding of the Muscarinic antagonist (-)-[3H]-N-methylscopolamine to homogenates of the rat cerebral cortex. The phenyl-substituted derivatives were devoid of intrinsic Muscarinic activity. Instead, they behaved as competitive Muscarinic Antagonists in these assays with similar or lower affinity for Muscarinic receptors than the corresponding methyl-substituted analogues. The succinimide (8b) and the pyrrolidone (3b) derivatives of 1 substituted with a phenyl group at position 1 of the butynyl chain showed the highest antiMuscarinic potency with dissociation constants (KD) of 0.10 and 0.20 microM, respectively, in the ileum assay. The phenyl-substituted analogues showed an approximately 10-fold lower in vivo antiMuscarinic potency than their corresponding methyl-substituted positional isomers. A correlation was observed between in vitro and in vivo potency within subsets consisting of methyl- and phenyl-substituted derivatives.
Lisbeth Nilvebrant - One of the best experts on this subject based on the ideXlab platform.
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3-(2-Benzofuranyl)quinuclidin-2-ene Derivatives: Novel Muscarinic Antagonists†
Journal of medicinal chemistry, 1996Co-Authors: Gunnar Nordvall, Staffan Sundquist, Gary Johansson, Gunilla Glas, Lisbeth Nilvebrant, Uli HacksellAbstract:A series of 26 derivatives of the novel Muscarinic antagonist 3-(2-benzofuranyl)quinuclidin-2-ene (1) has been synthesized and evaluated for Muscarinic and antiMuscarinic properties. The affinity of the compounds was determined by competition experiments in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (−)-[3H]-3-quinuclidinyl benzilate as the radioligand, and the antiMuscarinic potency was determined in a functional assay on isolated guinea pig urinary bladder using carbachol as the agonist. The 5-fluorobenzofuranyl derivative was slightly more potent than 1. The 7-bromo-substituted 8 displayed a 14-fold tissue selectivity ratio for Muscarinic receptors in the cortex versus the parotid gland. Comparative molecular field analysis and quantitative structure−activity relationship models were developed for this series of substituted benzofuranyl derivatives.
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3 heteroaryl substituted quinuclidin 3 ol and quinuclidin 2 ene derivatives as Muscarinic Antagonists synthesis and structure activity relationships
Journal of Medicinal Chemistry, 1995Co-Authors: Bjoern M. Nilsson, Gunnar Nordvall, Staffan Sundquist, Gary Johansson, Gunilla Glas, Lisbeth Nilvebrant, Uli HacksellAbstract:A number of 3-heteroaryl-substituted quinuclidin-3-ol and quinuclidin-2-ene derivatives have been prepared and evaluated for Muscarinic and antiMuscarinic properties. The affinities of the new compounds (13, 14, 16-32, and 36-52a,b) were tested in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[ 3 H]-3-quinuclidinyl benzilate [(-)-[ 3 H]QNB] as the radioligand and in a functional assay using isolated guinea pig urinary bladder. The present compounds behaved as competitive Muscarinic Antagonists in the urinary bladder. The highest receptor binding affinity, K i (cortex) = 9.6 nM, was observed for 3-(2-benzofuranyl)quinuclidin-2-ene (31). The corresponding 3-benzofuranyl (36) and 3-benzothienyl (37) homologues had about 3.5-fold lower affinity for cortical Muscarinic receptors. All quinuclidin-3-ol derivatives (14 and 16-25) had lower binding affinities for the different Muscarinic receptor subtypes than the corresponding quinuclidin-2-ene analogues when examined in the various tissue homogenates. In general, the new compounds showed low subtype selectivity. The structure-affinity relationships are discussed in terms of differences in proton basicity of the azabicyclic nitrogen and differences in geometric, conformational, and/or electronic properties of the compounds. The cortical antiMuscarinic potency is also related to the complementarity of the compounds to the putative binding site of the Muscarinic m1 receptor
Gunilla Glas - One of the best experts on this subject based on the ideXlab platform.
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3-(2-Benzofuranyl)quinuclidin-2-ene Derivatives: Novel Muscarinic Antagonists†
Journal of medicinal chemistry, 1996Co-Authors: Gunnar Nordvall, Staffan Sundquist, Gary Johansson, Gunilla Glas, Lisbeth Nilvebrant, Uli HacksellAbstract:A series of 26 derivatives of the novel Muscarinic antagonist 3-(2-benzofuranyl)quinuclidin-2-ene (1) has been synthesized and evaluated for Muscarinic and antiMuscarinic properties. The affinity of the compounds was determined by competition experiments in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (−)-[3H]-3-quinuclidinyl benzilate as the radioligand, and the antiMuscarinic potency was determined in a functional assay on isolated guinea pig urinary bladder using carbachol as the agonist. The 5-fluorobenzofuranyl derivative was slightly more potent than 1. The 7-bromo-substituted 8 displayed a 14-fold tissue selectivity ratio for Muscarinic receptors in the cortex versus the parotid gland. Comparative molecular field analysis and quantitative structure−activity relationship models were developed for this series of substituted benzofuranyl derivatives.
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3 heteroaryl substituted quinuclidin 3 ol and quinuclidin 2 ene derivatives as Muscarinic Antagonists synthesis and structure activity relationships
Journal of Medicinal Chemistry, 1995Co-Authors: Bjoern M. Nilsson, Gunnar Nordvall, Staffan Sundquist, Gary Johansson, Gunilla Glas, Lisbeth Nilvebrant, Uli HacksellAbstract:A number of 3-heteroaryl-substituted quinuclidin-3-ol and quinuclidin-2-ene derivatives have been prepared and evaluated for Muscarinic and antiMuscarinic properties. The affinities of the new compounds (13, 14, 16-32, and 36-52a,b) were tested in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[ 3 H]-3-quinuclidinyl benzilate [(-)-[ 3 H]QNB] as the radioligand and in a functional assay using isolated guinea pig urinary bladder. The present compounds behaved as competitive Muscarinic Antagonists in the urinary bladder. The highest receptor binding affinity, K i (cortex) = 9.6 nM, was observed for 3-(2-benzofuranyl)quinuclidin-2-ene (31). The corresponding 3-benzofuranyl (36) and 3-benzothienyl (37) homologues had about 3.5-fold lower affinity for cortical Muscarinic receptors. All quinuclidin-3-ol derivatives (14 and 16-25) had lower binding affinities for the different Muscarinic receptor subtypes than the corresponding quinuclidin-2-ene analogues when examined in the various tissue homogenates. In general, the new compounds showed low subtype selectivity. The structure-affinity relationships are discussed in terms of differences in proton basicity of the azabicyclic nitrogen and differences in geometric, conformational, and/or electronic properties of the compounds. The cortical antiMuscarinic potency is also related to the complementarity of the compounds to the putative binding site of the Muscarinic m1 receptor
