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P Stjernlof - One of the best experts on this subject based on the ideXlab platform.

  • structure activity relationships in the 8 amino 6 7 8 9 tetrahydro 3h benz e indole ring system 2 effect of 8 amino nitrogen substitution on serotonin receptor binding and pharmacology
    Journal of Medicinal Chemistry, 1995
    Co-Authors: P Stjernlof, Robert Louis Hoffman, Nabil B Ghazal, M W Smith, K Svensson, H V Wikstrom, Chiuhong Lin
    Abstract:

    A series of analogs of the potent and selective 5-HT1A agonist 8-(di-n-propylamino)-6,7,8,9-tetrahydro-3H-benz[e]indole-1-carbaldehyde (2b) (OSU191) was prepared in which the dipropylamino group was modified to bear a variety of substituents. These compounds were evaluated for both in vitro and in vivo effects, including the establishment of a receptor binding profile for these analogs at the 5-HT1A, dopamine D-2, dopamine D-3, 5-HT1D alpha, and 5-HT1D beta sites. Several of the analogs were evaluated for their biochemical effects in reserpinized rats, specifically with regard to in vivo changes in brain levels of 5-HTP and DOPA. Nearly all of the compounds prepared for this study were exceedingly potent at the 5-HT1A receptor, although most also displayed significant affinity for the dopamine D-2 receptor. A strong preference for the 5-HT1D alpha, over the 5-HT1D beta receptor was also apparent. An analog bearing a butylglutarimide side chain, S-7k, was extremely selective for the 5-HT1A receptor. Although this compound possessed a K-i of 0.6 nM, it elicited only modest changes in 5-HTP brain levels. However, this compound did not appear as an antagonist when tested in a cyclic-AMP-based intrinsic activity assay.

  • structure activity relationships in the 8 amino 6 7 8 9 tetrahydro 3h benz e indole ring system 1 effects of substituents in the aromatic system on serotonin and dopamine receptor subtypes
    Journal of Medicinal Chemistry, 1995
    Co-Authors: P Stjernlof, Arvid Carlsson, Lars O Hansson, Robert Louis Hoffman, Nabil B Ghazal, S Sundell, M W Smith, K Svensson, H V Wikstrom
    Abstract:

    A series of 1-, 3-, and 4-substituted analogs to the potent 5-HT1A agonist 8-(dipropylamino)-6,7,8,9-tetrahydro-3H-benz[e]indole-1-carbaldehyde (5) were prepared and tested in vitro at 5-HT1A, 5-HT1D alpha, 5-HT1D beta, D-2, and D-3 receptors and in vivo for agonist activity in the 5-HTP and DOPA accumulation assays in reserpine-pretreated rats. Some of the compounds were resolved. The substituents used in the 1-position were chosen from a principal component analysis (PCA) plot constructed from both tabulated variables and variables calculated by semiempirical methods (PM3) and molecular mechanics software (MMX). Among the analogs prepared, some, e.g., compound 21, were equipotent to compound 5 with respect to 5-HT1A effects. All compounds were more or less selective for the 5-HT1A receptor, but-many of the compounds displayed higher affinities for 5-HT1D alpha than for 5-HT1D beta receptors.

  • 6 7 8 9 tetrahydro n n di n propyl 3h benzindol 8 amines derivatives as potent and orally active serotonin 5 ht1a receptor agonists
    Journal of Medicinal Chemistry, 1994
    Co-Authors: P Stjernlof, Thomas Elebring, Jonas Nilsson, Bengt Andersson, Soren Lagerkvist, Kjell Svensson, A Ekman, Arvid Carlsson, Hakan Wikstrom
    Abstract:

    Derivatives and isosteric derivatives of the potent 5-HT1A agonist 8-(di-n-propylamino)-6,7,8,9- tetrahydro-3H-benz[e]indole-1-carbaldehyde (5) were prepared and evaluated in vivo and in vitro for serotonergic and dopaminergic activity. The 1-cyano analog 8 was found to be almost equipotent to 5 and the previously described 2-cyano derivative 6, while a 1-chloro and 1-(1,1,1-trifluoroethyl) substituent (9 and 10, respectively) formed less potent derivatives. The isosteric 6,7,8,9-tetrahydro-1H-benz[g]indoles 4 and 12-15 showed surprisingly low affinity or activity at both serotonergic and dopaminergic systems. The interpretations of these results by means of drug-receptor interactions at the 5-HT1A subtype are discussed. Compounds 6 and 8 were found to have high oral bioavailability in the rat (63% and 54%, respectively).

H V Wikstrom - One of the best experts on this subject based on the ideXlab platform.

  • structure activity relationships in the 8 amino 6 7 8 9 tetrahydro 3h benz e indole ring system 1 effects of substituents in the aromatic system on serotonin and dopamine receptor subtypes
    Journal of Medicinal Chemistry, 1995
    Co-Authors: P Stjernlof, Arvid Carlsson, Lars O Hansson, Robert Louis Hoffman, Nabil B Ghazal, S Sundell, M W Smith, K Svensson, H V Wikstrom
    Abstract:

    A series of 1-, 3-, and 4-substituted analogs to the potent 5-HT1A agonist 8-(dipropylamino)-6,7,8,9-tetrahydro-3H-benz[e]indole-1-carbaldehyde (5) were prepared and tested in vitro at 5-HT1A, 5-HT1D alpha, 5-HT1D beta, D-2, and D-3 receptors and in vivo for agonist activity in the 5-HTP and DOPA accumulation assays in reserpine-pretreated rats. Some of the compounds were resolved. The substituents used in the 1-position were chosen from a principal component analysis (PCA) plot constructed from both tabulated variables and variables calculated by semiempirical methods (PM3) and molecular mechanics software (MMX). Among the analogs prepared, some, e.g., compound 21, were equipotent to compound 5 with respect to 5-HT1A effects. All compounds were more or less selective for the 5-HT1A receptor, but-many of the compounds displayed higher affinities for 5-HT1D alpha than for 5-HT1D beta receptors.

  • structure activity relationships in the 8 amino 6 7 8 9 tetrahydro 3h benz e indole ring system 2 effect of 8 amino nitrogen substitution on serotonin receptor binding and pharmacology
    Journal of Medicinal Chemistry, 1995
    Co-Authors: P Stjernlof, Robert Louis Hoffman, Nabil B Ghazal, M W Smith, K Svensson, H V Wikstrom, Chiuhong Lin
    Abstract:

    A series of analogs of the potent and selective 5-HT1A agonist 8-(di-n-propylamino)-6,7,8,9-tetrahydro-3H-benz[e]indole-1-carbaldehyde (2b) (OSU191) was prepared in which the dipropylamino group was modified to bear a variety of substituents. These compounds were evaluated for both in vitro and in vivo effects, including the establishment of a receptor binding profile for these analogs at the 5-HT1A, dopamine D-2, dopamine D-3, 5-HT1D alpha, and 5-HT1D beta sites. Several of the analogs were evaluated for their biochemical effects in reserpinized rats, specifically with regard to in vivo changes in brain levels of 5-HTP and DOPA. Nearly all of the compounds prepared for this study were exceedingly potent at the 5-HT1A receptor, although most also displayed significant affinity for the dopamine D-2 receptor. A strong preference for the 5-HT1D alpha, over the 5-HT1D beta receptor was also apparent. An analog bearing a butylglutarimide side chain, S-7k, was extremely selective for the 5-HT1A receptor. Although this compound possessed a K-i of 0.6 nM, it elicited only modest changes in 5-HTP brain levels. However, this compound did not appear as an antagonist when tested in a cyclic-AMP-based intrinsic activity assay.

Hakan Wikstrom - One of the best experts on this subject based on the ideXlab platform.

  • 6 7 8 9 tetrahydro n n di n propyl 3h benzindol 8 amines derivatives as potent and orally active serotonin 5 ht1a receptor agonists
    Journal of Medicinal Chemistry, 1994
    Co-Authors: P Stjernlof, Thomas Elebring, Jonas Nilsson, Bengt Andersson, Soren Lagerkvist, Kjell Svensson, A Ekman, Arvid Carlsson, Hakan Wikstrom
    Abstract:

    Derivatives and isosteric derivatives of the potent 5-HT1A agonist 8-(di-n-propylamino)-6,7,8,9- tetrahydro-3H-benz[e]indole-1-carbaldehyde (5) were prepared and evaluated in vivo and in vitro for serotonergic and dopaminergic activity. The 1-cyano analog 8 was found to be almost equipotent to 5 and the previously described 2-cyano derivative 6, while a 1-chloro and 1-(1,1,1-trifluoroethyl) substituent (9 and 10, respectively) formed less potent derivatives. The isosteric 6,7,8,9-tetrahydro-1H-benz[g]indoles 4 and 12-15 showed surprisingly low affinity or activity at both serotonergic and dopaminergic systems. The interpretations of these results by means of drug-receptor interactions at the 5-HT1A subtype are discussed. Compounds 6 and 8 were found to have high oral bioavailability in the rat (63% and 54%, respectively).

Arvid Carlsson - One of the best experts on this subject based on the ideXlab platform.

  • structure activity relationships in the 8 amino 6 7 8 9 tetrahydro 3h benz e indole ring system 1 effects of substituents in the aromatic system on serotonin and dopamine receptor subtypes
    Journal of Medicinal Chemistry, 1995
    Co-Authors: P Stjernlof, Arvid Carlsson, Lars O Hansson, Robert Louis Hoffman, Nabil B Ghazal, S Sundell, M W Smith, K Svensson, H V Wikstrom
    Abstract:

    A series of 1-, 3-, and 4-substituted analogs to the potent 5-HT1A agonist 8-(dipropylamino)-6,7,8,9-tetrahydro-3H-benz[e]indole-1-carbaldehyde (5) were prepared and tested in vitro at 5-HT1A, 5-HT1D alpha, 5-HT1D beta, D-2, and D-3 receptors and in vivo for agonist activity in the 5-HTP and DOPA accumulation assays in reserpine-pretreated rats. Some of the compounds were resolved. The substituents used in the 1-position were chosen from a principal component analysis (PCA) plot constructed from both tabulated variables and variables calculated by semiempirical methods (PM3) and molecular mechanics software (MMX). Among the analogs prepared, some, e.g., compound 21, were equipotent to compound 5 with respect to 5-HT1A effects. All compounds were more or less selective for the 5-HT1A receptor, but-many of the compounds displayed higher affinities for 5-HT1D alpha than for 5-HT1D beta receptors.

  • 6 7 8 9 tetrahydro n n di n propyl 3h benzindol 8 amines derivatives as potent and orally active serotonin 5 ht1a receptor agonists
    Journal of Medicinal Chemistry, 1994
    Co-Authors: P Stjernlof, Thomas Elebring, Jonas Nilsson, Bengt Andersson, Soren Lagerkvist, Kjell Svensson, A Ekman, Arvid Carlsson, Hakan Wikstrom
    Abstract:

    Derivatives and isosteric derivatives of the potent 5-HT1A agonist 8-(di-n-propylamino)-6,7,8,9- tetrahydro-3H-benz[e]indole-1-carbaldehyde (5) were prepared and evaluated in vivo and in vitro for serotonergic and dopaminergic activity. The 1-cyano analog 8 was found to be almost equipotent to 5 and the previously described 2-cyano derivative 6, while a 1-chloro and 1-(1,1,1-trifluoroethyl) substituent (9 and 10, respectively) formed less potent derivatives. The isosteric 6,7,8,9-tetrahydro-1H-benz[g]indoles 4 and 12-15 showed surprisingly low affinity or activity at both serotonergic and dopaminergic systems. The interpretations of these results by means of drug-receptor interactions at the 5-HT1A subtype are discussed. Compounds 6 and 8 were found to have high oral bioavailability in the rat (63% and 54%, respectively).

Robert Louis Hoffman - One of the best experts on this subject based on the ideXlab platform.

  • structure activity relationships in the 8 amino 6 7 8 9 tetrahydro 3h benz e indole ring system 1 effects of substituents in the aromatic system on serotonin and dopamine receptor subtypes
    Journal of Medicinal Chemistry, 1995
    Co-Authors: P Stjernlof, Arvid Carlsson, Lars O Hansson, Robert Louis Hoffman, Nabil B Ghazal, S Sundell, M W Smith, K Svensson, H V Wikstrom
    Abstract:

    A series of 1-, 3-, and 4-substituted analogs to the potent 5-HT1A agonist 8-(dipropylamino)-6,7,8,9-tetrahydro-3H-benz[e]indole-1-carbaldehyde (5) were prepared and tested in vitro at 5-HT1A, 5-HT1D alpha, 5-HT1D beta, D-2, and D-3 receptors and in vivo for agonist activity in the 5-HTP and DOPA accumulation assays in reserpine-pretreated rats. Some of the compounds were resolved. The substituents used in the 1-position were chosen from a principal component analysis (PCA) plot constructed from both tabulated variables and variables calculated by semiempirical methods (PM3) and molecular mechanics software (MMX). Among the analogs prepared, some, e.g., compound 21, were equipotent to compound 5 with respect to 5-HT1A effects. All compounds were more or less selective for the 5-HT1A receptor, but-many of the compounds displayed higher affinities for 5-HT1D alpha than for 5-HT1D beta receptors.

  • structure activity relationships in the 8 amino 6 7 8 9 tetrahydro 3h benz e indole ring system 2 effect of 8 amino nitrogen substitution on serotonin receptor binding and pharmacology
    Journal of Medicinal Chemistry, 1995
    Co-Authors: P Stjernlof, Robert Louis Hoffman, Nabil B Ghazal, M W Smith, K Svensson, H V Wikstrom, Chiuhong Lin
    Abstract:

    A series of analogs of the potent and selective 5-HT1A agonist 8-(di-n-propylamino)-6,7,8,9-tetrahydro-3H-benz[e]indole-1-carbaldehyde (2b) (OSU191) was prepared in which the dipropylamino group was modified to bear a variety of substituents. These compounds were evaluated for both in vitro and in vivo effects, including the establishment of a receptor binding profile for these analogs at the 5-HT1A, dopamine D-2, dopamine D-3, 5-HT1D alpha, and 5-HT1D beta sites. Several of the analogs were evaluated for their biochemical effects in reserpinized rats, specifically with regard to in vivo changes in brain levels of 5-HTP and DOPA. Nearly all of the compounds prepared for this study were exceedingly potent at the 5-HT1A receptor, although most also displayed significant affinity for the dopamine D-2 receptor. A strong preference for the 5-HT1D alpha, over the 5-HT1D beta receptor was also apparent. An analog bearing a butylglutarimide side chain, S-7k, was extremely selective for the 5-HT1A receptor. Although this compound possessed a K-i of 0.6 nM, it elicited only modest changes in 5-HTP brain levels. However, this compound did not appear as an antagonist when tested in a cyclic-AMP-based intrinsic activity assay.