|
Effective concentration towards 5-hydroxytryptamine 2C receptors transfected in HEK293 cells was determined by measuring [3H]phosphoinositol release
|
Homo sapiens
|
11.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery and SAR of new benzazepines as potent and selective 5-HT(2C) receptor agonists for the treatment of obesity.
Year : 2005
Volume : 15
Issue : 5
First Page : 1467
Last Page : 1470
Authors : Smith BM, Smith JM, Tsai JH, Schultz JA, Gilson CA, Estrada SA, Chen RR, Park DM, Prieto EB, Gallardo CS, Sengupta D, Thomsen WJ, Saldana HR, Whelan KT, Menzaghi F, Webb RR, Beeley NR.
Abstract : We report on the synthesis, biological evaluation and structure-activity relationships for a series of 3-benzazepine derivatives as 5-HT(2C) receptor agonists. The compounds were evaluated in functional assays measuring [3H] phosphoinositol turnover in HEK-293 cells transiently transfected with h5-HT(2C), h5-HT(2A) or h5-HT(2B) receptors. Several compounds are shown to be potent and selective 5-HT(2C) receptor agonists, which decrease food intake in a rat feeding model.
|
Effective concentration towards 5-hydroxytryptamine 2A receptors transfected in HEK293 cells was determined by measuring [3H]phosphoinositol release
|
Homo sapiens
|
190.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery and SAR of new benzazepines as potent and selective 5-HT(2C) receptor agonists for the treatment of obesity.
Year : 2005
Volume : 15
Issue : 5
First Page : 1467
Last Page : 1470
Authors : Smith BM, Smith JM, Tsai JH, Schultz JA, Gilson CA, Estrada SA, Chen RR, Park DM, Prieto EB, Gallardo CS, Sengupta D, Thomsen WJ, Saldana HR, Whelan KT, Menzaghi F, Webb RR, Beeley NR.
Abstract : We report on the synthesis, biological evaluation and structure-activity relationships for a series of 3-benzazepine derivatives as 5-HT(2C) receptor agonists. The compounds were evaluated in functional assays measuring [3H] phosphoinositol turnover in HEK-293 cells transiently transfected with h5-HT(2C), h5-HT(2A) or h5-HT(2B) receptors. Several compounds are shown to be potent and selective 5-HT(2C) receptor agonists, which decrease food intake in a rat feeding model.
|
Agonist activity at human 5HT2A receptor expressed in HEK293 cells assessed as intracellular IP3 accumulation
|
Homo sapiens
|
158.49
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT2C receptor agonist for the treatment of obesity.
Year : 2008
Volume : 51
Issue : 2
First Page : 305
Last Page : 313
Authors : Smith BM, Smith JM, Tsai JH, Schultz JA, Gilson CA, Estrada SA, Chen RR, Park DM, Prieto EB, Gallardo CS, Sengupta D, Dosa PI, Covel JA, Ren A, Webb RR, Beeley NR, Martin M, Morgan M, Espitia S, Saldana HR, Bjenning C, Whelan KT, Grottick AJ, Menzaghi F, Thomsen WJ.
Abstract : The synthesis and SAR of a novel 3-benzazepine series of 5-HT2C agonists is described. Compound 7d (lorcaserin, APD356) was identified as one of the more potent and selective compounds in vitro (pEC50 values in functional assays measuring [(3)H]phosphoinositol turnover: 5-HT2C = 8.1; 5-HT2A = 6.8; 5-HT2B = 6.1) and was potent in an acute in vivo rat food intake model upon oral administration (ED50 at 6 h = 18 mg/kg). Lorcaserin was further characterized in a single-dose pharmacokinetic study in rat (t1/2 = 3.7 h; F = 86%) and a 28-day model of weight gain in growing Sprague-Dawley rat (8.5% decrease in weight gain observed at 36 mg/kg b.i.d.). Lorcaserin was selected for further evaluation in clinical trials for the treatment of obesity.
|
Agonist activity at human 5HT2C receptor expressed in HEK293 cells assessed as intracellular IP3 accumulation
|
Homo sapiens
|
7.943
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT2C receptor agonist for the treatment of obesity.
Year : 2008
Volume : 51
Issue : 2
First Page : 305
Last Page : 313
Authors : Smith BM, Smith JM, Tsai JH, Schultz JA, Gilson CA, Estrada SA, Chen RR, Park DM, Prieto EB, Gallardo CS, Sengupta D, Dosa PI, Covel JA, Ren A, Webb RR, Beeley NR, Martin M, Morgan M, Espitia S, Saldana HR, Bjenning C, Whelan KT, Grottick AJ, Menzaghi F, Thomsen WJ.
Abstract : The synthesis and SAR of a novel 3-benzazepine series of 5-HT2C agonists is described. Compound 7d (lorcaserin, APD356) was identified as one of the more potent and selective compounds in vitro (pEC50 values in functional assays measuring [(3)H]phosphoinositol turnover: 5-HT2C = 8.1; 5-HT2A = 6.8; 5-HT2B = 6.1) and was potent in an acute in vivo rat food intake model upon oral administration (ED50 at 6 h = 18 mg/kg). Lorcaserin was further characterized in a single-dose pharmacokinetic study in rat (t1/2 = 3.7 h; F = 86%) and a 28-day model of weight gain in growing Sprague-Dawley rat (8.5% decrease in weight gain observed at 36 mg/kg b.i.d.). Lorcaserin was selected for further evaluation in clinical trials for the treatment of obesity.
|
Agonist activity at human 5HT2B receptor expressed in HEK293 cells assessed as intracellular IP3 accumulation
|
Homo sapiens
|
794.33
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT2C receptor agonist for the treatment of obesity.
Year : 2008
Volume : 51
Issue : 2
First Page : 305
Last Page : 313
Authors : Smith BM, Smith JM, Tsai JH, Schultz JA, Gilson CA, Estrada SA, Chen RR, Park DM, Prieto EB, Gallardo CS, Sengupta D, Dosa PI, Covel JA, Ren A, Webb RR, Beeley NR, Martin M, Morgan M, Espitia S, Saldana HR, Bjenning C, Whelan KT, Grottick AJ, Menzaghi F, Thomsen WJ.
Abstract : The synthesis and SAR of a novel 3-benzazepine series of 5-HT2C agonists is described. Compound 7d (lorcaserin, APD356) was identified as one of the more potent and selective compounds in vitro (pEC50 values in functional assays measuring [(3)H]phosphoinositol turnover: 5-HT2C = 8.1; 5-HT2A = 6.8; 5-HT2B = 6.1) and was potent in an acute in vivo rat food intake model upon oral administration (ED50 at 6 h = 18 mg/kg). Lorcaserin was further characterized in a single-dose pharmacokinetic study in rat (t1/2 = 3.7 h; F = 86%) and a 28-day model of weight gain in growing Sprague-Dawley rat (8.5% decrease in weight gain observed at 36 mg/kg b.i.d.). Lorcaserin was selected for further evaluation in clinical trials for the treatment of obesity.
|
Reduction of food intake in Sprague-Dawley rat at 12.5 umol/kg, po after 2 hrs relative to control
|
Rattus norvegicus
|
34.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT2C receptor agonist for the treatment of obesity.
Year : 2008
Volume : 51
Issue : 2
First Page : 305
Last Page : 313
Authors : Smith BM, Smith JM, Tsai JH, Schultz JA, Gilson CA, Estrada SA, Chen RR, Park DM, Prieto EB, Gallardo CS, Sengupta D, Dosa PI, Covel JA, Ren A, Webb RR, Beeley NR, Martin M, Morgan M, Espitia S, Saldana HR, Bjenning C, Whelan KT, Grottick AJ, Menzaghi F, Thomsen WJ.
Abstract : The synthesis and SAR of a novel 3-benzazepine series of 5-HT2C agonists is described. Compound 7d (lorcaserin, APD356) was identified as one of the more potent and selective compounds in vitro (pEC50 values in functional assays measuring [(3)H]phosphoinositol turnover: 5-HT2C = 8.1; 5-HT2A = 6.8; 5-HT2B = 6.1) and was potent in an acute in vivo rat food intake model upon oral administration (ED50 at 6 h = 18 mg/kg). Lorcaserin was further characterized in a single-dose pharmacokinetic study in rat (t1/2 = 3.7 h; F = 86%) and a 28-day model of weight gain in growing Sprague-Dawley rat (8.5% decrease in weight gain observed at 36 mg/kg b.i.d.). Lorcaserin was selected for further evaluation in clinical trials for the treatment of obesity.
|
Reduction of food intake in Sprague-Dawley rat at 25 umol/kg, po after 2 hrs relative to control
|
Rattus norvegicus
|
58.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT2C receptor agonist for the treatment of obesity.
Year : 2008
Volume : 51
Issue : 2
First Page : 305
Last Page : 313
Authors : Smith BM, Smith JM, Tsai JH, Schultz JA, Gilson CA, Estrada SA, Chen RR, Park DM, Prieto EB, Gallardo CS, Sengupta D, Dosa PI, Covel JA, Ren A, Webb RR, Beeley NR, Martin M, Morgan M, Espitia S, Saldana HR, Bjenning C, Whelan KT, Grottick AJ, Menzaghi F, Thomsen WJ.
Abstract : The synthesis and SAR of a novel 3-benzazepine series of 5-HT2C agonists is described. Compound 7d (lorcaserin, APD356) was identified as one of the more potent and selective compounds in vitro (pEC50 values in functional assays measuring [(3)H]phosphoinositol turnover: 5-HT2C = 8.1; 5-HT2A = 6.8; 5-HT2B = 6.1) and was potent in an acute in vivo rat food intake model upon oral administration (ED50 at 6 h = 18 mg/kg). Lorcaserin was further characterized in a single-dose pharmacokinetic study in rat (t1/2 = 3.7 h; F = 86%) and a 28-day model of weight gain in growing Sprague-Dawley rat (8.5% decrease in weight gain observed at 36 mg/kg b.i.d.). Lorcaserin was selected for further evaluation in clinical trials for the treatment of obesity.
|
Reduction of food intake in Sprague-Dawley rat at 50 umol/kg, po after 2 hrs relative to control
|
Rattus norvegicus
|
77.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT2C receptor agonist for the treatment of obesity.
Year : 2008
Volume : 51
Issue : 2
First Page : 305
Last Page : 313
Authors : Smith BM, Smith JM, Tsai JH, Schultz JA, Gilson CA, Estrada SA, Chen RR, Park DM, Prieto EB, Gallardo CS, Sengupta D, Dosa PI, Covel JA, Ren A, Webb RR, Beeley NR, Martin M, Morgan M, Espitia S, Saldana HR, Bjenning C, Whelan KT, Grottick AJ, Menzaghi F, Thomsen WJ.
Abstract : The synthesis and SAR of a novel 3-benzazepine series of 5-HT2C agonists is described. Compound 7d (lorcaserin, APD356) was identified as one of the more potent and selective compounds in vitro (pEC50 values in functional assays measuring [(3)H]phosphoinositol turnover: 5-HT2C = 8.1; 5-HT2A = 6.8; 5-HT2B = 6.1) and was potent in an acute in vivo rat food intake model upon oral administration (ED50 at 6 h = 18 mg/kg). Lorcaserin was further characterized in a single-dose pharmacokinetic study in rat (t1/2 = 3.7 h; F = 86%) and a 28-day model of weight gain in growing Sprague-Dawley rat (8.5% decrease in weight gain observed at 36 mg/kg b.i.d.). Lorcaserin was selected for further evaluation in clinical trials for the treatment of obesity.
|
Reduction of food intake in Sprague-Dawley rat at 100 umol/kg, po after 2 hrs relative to control
|
Rattus norvegicus
|
82.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT2C receptor agonist for the treatment of obesity.
Year : 2008
Volume : 51
Issue : 2
First Page : 305
Last Page : 313
Authors : Smith BM, Smith JM, Tsai JH, Schultz JA, Gilson CA, Estrada SA, Chen RR, Park DM, Prieto EB, Gallardo CS, Sengupta D, Dosa PI, Covel JA, Ren A, Webb RR, Beeley NR, Martin M, Morgan M, Espitia S, Saldana HR, Bjenning C, Whelan KT, Grottick AJ, Menzaghi F, Thomsen WJ.
Abstract : The synthesis and SAR of a novel 3-benzazepine series of 5-HT2C agonists is described. Compound 7d (lorcaserin, APD356) was identified as one of the more potent and selective compounds in vitro (pEC50 values in functional assays measuring [(3)H]phosphoinositol turnover: 5-HT2C = 8.1; 5-HT2A = 6.8; 5-HT2B = 6.1) and was potent in an acute in vivo rat food intake model upon oral administration (ED50 at 6 h = 18 mg/kg). Lorcaserin was further characterized in a single-dose pharmacokinetic study in rat (t1/2 = 3.7 h; F = 86%) and a 28-day model of weight gain in growing Sprague-Dawley rat (8.5% decrease in weight gain observed at 36 mg/kg b.i.d.). Lorcaserin was selected for further evaluation in clinical trials for the treatment of obesity.
|
Agonist activity at human 5HT2A receptor expressed in HEK293 cells assessed as calcium flux by FLIPR assay
|
Homo sapiens
|
616.0
nM
|
|
Journal : J. Med. Chem.
Title : Selective 5-hydroxytryptamine 2C receptor agonists derived from the lead compound tranylcypromine: identification of drugs with antidepressant-like action.
Year : 2009
Volume : 52
Issue : 7
First Page : 1885
Last Page : 1902
Authors : Cho SJ, Jensen NH, Kurome T, Kadari S, Manzano ML, Malberg JE, Caldarone B, Roth BL, Kozikowski AP.
Abstract : We report here the design, synthesis, and pharmacological properties of a series of compounds related to tranylcypromine (9), which itself was discovered as a lead compound in a high-throughput screening campaign. Starting from 9, which shows modest activity as a 5-HT(2C) agonist, a series of 1-aminomethyl-2-phenylcyclopropanes was investigated as 5-HT(2C) agonists through iterative structural modifications. Key pharmacophore feature of this new class of ligands is a 2-aminomethyl-trans-cyclopropyl side chain attached to a substituted benzene ring. Among the tested compounds, several were potent and efficacious 5-HT(2C) receptor agonists with selectivity over both 5-HT(2A) and 5-HT(2B) receptors in functional assays. The most promising compound is 37, with 120- and 14-fold selectivity over 5-HT(2A) and 5-HT(2B), respectively (EC(50) = 585, 65, and 4.8 nM at the 2A, 2B, and 2C subtypes, respectively). In animal studies, compound 37 (10-60 mg/kg) decreased immobility time in the mouse forced swim test.
|
Agonist activity at human 5HT2B receptor expressed in HEK293 cells assessed as calcium flux by FLIPR assay
|
Homo sapiens
|
219.0
nM
|
|
Journal : J. Med. Chem.
Title : Selective 5-hydroxytryptamine 2C receptor agonists derived from the lead compound tranylcypromine: identification of drugs with antidepressant-like action.
Year : 2009
Volume : 52
Issue : 7
First Page : 1885
Last Page : 1902
Authors : Cho SJ, Jensen NH, Kurome T, Kadari S, Manzano ML, Malberg JE, Caldarone B, Roth BL, Kozikowski AP.
Abstract : We report here the design, synthesis, and pharmacological properties of a series of compounds related to tranylcypromine (9), which itself was discovered as a lead compound in a high-throughput screening campaign. Starting from 9, which shows modest activity as a 5-HT(2C) agonist, a series of 1-aminomethyl-2-phenylcyclopropanes was investigated as 5-HT(2C) agonists through iterative structural modifications. Key pharmacophore feature of this new class of ligands is a 2-aminomethyl-trans-cyclopropyl side chain attached to a substituted benzene ring. Among the tested compounds, several were potent and efficacious 5-HT(2C) receptor agonists with selectivity over both 5-HT(2A) and 5-HT(2B) receptors in functional assays. The most promising compound is 37, with 120- and 14-fold selectivity over 5-HT(2A) and 5-HT(2B), respectively (EC(50) = 585, 65, and 4.8 nM at the 2A, 2B, and 2C subtypes, respectively). In animal studies, compound 37 (10-60 mg/kg) decreased immobility time in the mouse forced swim test.
|
Agonist activity at human 5HT2C receptor expressed in HEK293 cells assessed as calcium flux by FLIPR assay
|
Homo sapiens
|
2.7
nM
|
|
Journal : J. Med. Chem.
Title : Selective 5-hydroxytryptamine 2C receptor agonists derived from the lead compound tranylcypromine: identification of drugs with antidepressant-like action.
Year : 2009
Volume : 52
Issue : 7
First Page : 1885
Last Page : 1902
Authors : Cho SJ, Jensen NH, Kurome T, Kadari S, Manzano ML, Malberg JE, Caldarone B, Roth BL, Kozikowski AP.
Abstract : We report here the design, synthesis, and pharmacological properties of a series of compounds related to tranylcypromine (9), which itself was discovered as a lead compound in a high-throughput screening campaign. Starting from 9, which shows modest activity as a 5-HT(2C) agonist, a series of 1-aminomethyl-2-phenylcyclopropanes was investigated as 5-HT(2C) agonists through iterative structural modifications. Key pharmacophore feature of this new class of ligands is a 2-aminomethyl-trans-cyclopropyl side chain attached to a substituted benzene ring. Among the tested compounds, several were potent and efficacious 5-HT(2C) receptor agonists with selectivity over both 5-HT(2A) and 5-HT(2B) receptors in functional assays. The most promising compound is 37, with 120- and 14-fold selectivity over 5-HT(2A) and 5-HT(2B), respectively (EC(50) = 585, 65, and 4.8 nM at the 2A, 2B, and 2C subtypes, respectively). In animal studies, compound 37 (10-60 mg/kg) decreased immobility time in the mouse forced swim test.
|
Displacement of [3H]LSD from human 5HT2B receptor
|
Homo sapiens
|
189.0
nM
|
|
Journal : J. Med. Chem.
Title : Selective 5-hydroxytryptamine 2C receptor agonists derived from the lead compound tranylcypromine: identification of drugs with antidepressant-like action.
Year : 2009
Volume : 52
Issue : 7
First Page : 1885
Last Page : 1902
Authors : Cho SJ, Jensen NH, Kurome T, Kadari S, Manzano ML, Malberg JE, Caldarone B, Roth BL, Kozikowski AP.
Abstract : We report here the design, synthesis, and pharmacological properties of a series of compounds related to tranylcypromine (9), which itself was discovered as a lead compound in a high-throughput screening campaign. Starting from 9, which shows modest activity as a 5-HT(2C) agonist, a series of 1-aminomethyl-2-phenylcyclopropanes was investigated as 5-HT(2C) agonists through iterative structural modifications. Key pharmacophore feature of this new class of ligands is a 2-aminomethyl-trans-cyclopropyl side chain attached to a substituted benzene ring. Among the tested compounds, several were potent and efficacious 5-HT(2C) receptor agonists with selectivity over both 5-HT(2A) and 5-HT(2B) receptors in functional assays. The most promising compound is 37, with 120- and 14-fold selectivity over 5-HT(2A) and 5-HT(2B), respectively (EC(50) = 585, 65, and 4.8 nM at the 2A, 2B, and 2C subtypes, respectively). In animal studies, compound 37 (10-60 mg/kg) decreased immobility time in the mouse forced swim test.
|
Displacement of [3H]mesulergine from 5HT2C receptor
|
None
|
257.0
nM
|
|
Journal : J. Med. Chem.
Title : Selective 5-hydroxytryptamine 2C receptor agonists derived from the lead compound tranylcypromine: identification of drugs with antidepressant-like action.
Year : 2009
Volume : 52
Issue : 7
First Page : 1885
Last Page : 1902
Authors : Cho SJ, Jensen NH, Kurome T, Kadari S, Manzano ML, Malberg JE, Caldarone B, Roth BL, Kozikowski AP.
Abstract : We report here the design, synthesis, and pharmacological properties of a series of compounds related to tranylcypromine (9), which itself was discovered as a lead compound in a high-throughput screening campaign. Starting from 9, which shows modest activity as a 5-HT(2C) agonist, a series of 1-aminomethyl-2-phenylcyclopropanes was investigated as 5-HT(2C) agonists through iterative structural modifications. Key pharmacophore feature of this new class of ligands is a 2-aminomethyl-trans-cyclopropyl side chain attached to a substituted benzene ring. Among the tested compounds, several were potent and efficacious 5-HT(2C) receptor agonists with selectivity over both 5-HT(2A) and 5-HT(2B) receptors in functional assays. The most promising compound is 37, with 120- and 14-fold selectivity over 5-HT(2A) and 5-HT(2B), respectively (EC(50) = 585, 65, and 4.8 nM at the 2A, 2B, and 2C subtypes, respectively). In animal studies, compound 37 (10-60 mg/kg) decreased immobility time in the mouse forced swim test.
|
Agonist activity at human 5HT2C receptor expressed in CHO-K1 cells assessed as increase of fluorescence based calcium mobilization by FLIPR assay
|
Homo sapiens
|
210.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pyrimido[4,5-d]azepines as potent and selective 5-HT2C receptor agonists: design, synthesis, and evaluation of PF-3246799 as a treatment for urinary incontinence.
Year : 2011
Volume : 21
Issue : 9
First Page : 2715
Last Page : 2720
Authors : Andrews MD, Fish PV, Blagg J, Brabham TK, Brennan PE, Bridgeland A, Brown AD, Bungay PJ, Conlon KM, Edmunds NJ, af Forselles K, Gibbons CP, Green MP, Hanton G, Holbrook M, Jessiman AS, McIntosh K, McMurray G, Nichols CL, Root JA, Storer RI, Sutton MR, Ward RV, Westbrook D, Whitlock GA.
Abstract : New pyrimido[4,5-d]azepines 7 are disclosed as potent 5-HT(2C) receptor agonists. A preferred example, 7b had minimal activation at either the 5-HT(2A) or 5-HT(2B) receptors combined with robust efficacy in a preclinical canine model of stress urinary incontinence (SUI) and attractive pharmacokinetic and safety properties. Based on this profile, 7b (PF-3246799) was identified as a candidate for clinical development for the treatment of SUI. In addition, it proved to be critical to build an understanding of the translation between recombinant cell-based systems, native tissue preparations and in vivo preclinical models. This was a significant undertaking and proved to be crucial in compound selection.
|
Displacement of [3H]meselurgine from human 5HT2C receptor expressed in Swiss mouse 3T3 cells by scintillation proximity assay
|
Homo sapiens
|
167.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pyrimido[4,5-d]azepines as potent and selective 5-HT2C receptor agonists: design, synthesis, and evaluation of PF-3246799 as a treatment for urinary incontinence.
Year : 2011
Volume : 21
Issue : 9
First Page : 2715
Last Page : 2720
Authors : Andrews MD, Fish PV, Blagg J, Brabham TK, Brennan PE, Bridgeland A, Brown AD, Bungay PJ, Conlon KM, Edmunds NJ, af Forselles K, Gibbons CP, Green MP, Hanton G, Holbrook M, Jessiman AS, McIntosh K, McMurray G, Nichols CL, Root JA, Storer RI, Sutton MR, Ward RV, Westbrook D, Whitlock GA.
Abstract : New pyrimido[4,5-d]azepines 7 are disclosed as potent 5-HT(2C) receptor agonists. A preferred example, 7b had minimal activation at either the 5-HT(2A) or 5-HT(2B) receptors combined with robust efficacy in a preclinical canine model of stress urinary incontinence (SUI) and attractive pharmacokinetic and safety properties. Based on this profile, 7b (PF-3246799) was identified as a candidate for clinical development for the treatment of SUI. In addition, it proved to be critical to build an understanding of the translation between recombinant cell-based systems, native tissue preparations and in vivo preclinical models. This was a significant undertaking and proved to be crucial in compound selection.
|
Displacement of [125I]DOI from human recombinant 5HT2C receptor expressed in HEK293 cells by scintillation counting
|
Homo sapiens
|
15.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pyrimido[4,5-d]azepines as potent and selective 5-HT2C receptor agonists: design, synthesis, and evaluation of PF-3246799 as a treatment for urinary incontinence.
Year : 2011
Volume : 21
Issue : 9
First Page : 2715
Last Page : 2720
Authors : Andrews MD, Fish PV, Blagg J, Brabham TK, Brennan PE, Bridgeland A, Brown AD, Bungay PJ, Conlon KM, Edmunds NJ, af Forselles K, Gibbons CP, Green MP, Hanton G, Holbrook M, Jessiman AS, McIntosh K, McMurray G, Nichols CL, Root JA, Storer RI, Sutton MR, Ward RV, Westbrook D, Whitlock GA.
Abstract : New pyrimido[4,5-d]azepines 7 are disclosed as potent 5-HT(2C) receptor agonists. A preferred example, 7b had minimal activation at either the 5-HT(2A) or 5-HT(2B) receptors combined with robust efficacy in a preclinical canine model of stress urinary incontinence (SUI) and attractive pharmacokinetic and safety properties. Based on this profile, 7b (PF-3246799) was identified as a candidate for clinical development for the treatment of SUI. In addition, it proved to be critical to build an understanding of the translation between recombinant cell-based systems, native tissue preparations and in vivo preclinical models. This was a significant undertaking and proved to be crucial in compound selection.
|
Agonist activity at human 5HT2C receptor expressed in HEK293 cells by inositol phosphate accumulation assay
|
Homo sapiens
|
9.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pyrimido[4,5-d]azepines as potent and selective 5-HT2C receptor agonists: design, synthesis, and evaluation of PF-3246799 as a treatment for urinary incontinence.
Year : 2011
Volume : 21
Issue : 9
First Page : 2715
Last Page : 2720
Authors : Andrews MD, Fish PV, Blagg J, Brabham TK, Brennan PE, Bridgeland A, Brown AD, Bungay PJ, Conlon KM, Edmunds NJ, af Forselles K, Gibbons CP, Green MP, Hanton G, Holbrook M, Jessiman AS, McIntosh K, McMurray G, Nichols CL, Root JA, Storer RI, Sutton MR, Ward RV, Westbrook D, Whitlock GA.
Abstract : New pyrimido[4,5-d]azepines 7 are disclosed as potent 5-HT(2C) receptor agonists. A preferred example, 7b had minimal activation at either the 5-HT(2A) or 5-HT(2B) receptors combined with robust efficacy in a preclinical canine model of stress urinary incontinence (SUI) and attractive pharmacokinetic and safety properties. Based on this profile, 7b (PF-3246799) was identified as a candidate for clinical development for the treatment of SUI. In addition, it proved to be critical to build an understanding of the translation between recombinant cell-based systems, native tissue preparations and in vivo preclinical models. This was a significant undertaking and proved to be crucial in compound selection.
|
Agonist activity at human 5HT2B receptor expressed in HEK293 cells by inositol phosphate accumulation assay
|
Homo sapiens
|
943.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pyrimido[4,5-d]azepines as potent and selective 5-HT2C receptor agonists: design, synthesis, and evaluation of PF-3246799 as a treatment for urinary incontinence.
Year : 2011
Volume : 21
Issue : 9
First Page : 2715
Last Page : 2720
Authors : Andrews MD, Fish PV, Blagg J, Brabham TK, Brennan PE, Bridgeland A, Brown AD, Bungay PJ, Conlon KM, Edmunds NJ, af Forselles K, Gibbons CP, Green MP, Hanton G, Holbrook M, Jessiman AS, McIntosh K, McMurray G, Nichols CL, Root JA, Storer RI, Sutton MR, Ward RV, Westbrook D, Whitlock GA.
Abstract : New pyrimido[4,5-d]azepines 7 are disclosed as potent 5-HT(2C) receptor agonists. A preferred example, 7b had minimal activation at either the 5-HT(2A) or 5-HT(2B) receptors combined with robust efficacy in a preclinical canine model of stress urinary incontinence (SUI) and attractive pharmacokinetic and safety properties. Based on this profile, 7b (PF-3246799) was identified as a candidate for clinical development for the treatment of SUI. In addition, it proved to be critical to build an understanding of the translation between recombinant cell-based systems, native tissue preparations and in vivo preclinical models. This was a significant undertaking and proved to be crucial in compound selection.
|
Agonist activity at dog 5HT2C receptor
|
Canis lupus familiaris
|
16.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pyrimido[4,5-d]azepines as potent and selective 5-HT2C receptor agonists: design, synthesis, and evaluation of PF-3246799 as a treatment for urinary incontinence.
Year : 2011
Volume : 21
Issue : 9
First Page : 2715
Last Page : 2720
Authors : Andrews MD, Fish PV, Blagg J, Brabham TK, Brennan PE, Bridgeland A, Brown AD, Bungay PJ, Conlon KM, Edmunds NJ, af Forselles K, Gibbons CP, Green MP, Hanton G, Holbrook M, Jessiman AS, McIntosh K, McMurray G, Nichols CL, Root JA, Storer RI, Sutton MR, Ward RV, Westbrook D, Whitlock GA.
Abstract : New pyrimido[4,5-d]azepines 7 are disclosed as potent 5-HT(2C) receptor agonists. A preferred example, 7b had minimal activation at either the 5-HT(2A) or 5-HT(2B) receptors combined with robust efficacy in a preclinical canine model of stress urinary incontinence (SUI) and attractive pharmacokinetic and safety properties. Based on this profile, 7b (PF-3246799) was identified as a candidate for clinical development for the treatment of SUI. In addition, it proved to be critical to build an understanding of the translation between recombinant cell-based systems, native tissue preparations and in vivo preclinical models. This was a significant undertaking and proved to be crucial in compound selection.
|
Agonist activity at 5-HT2B receptor (unknown origin)
|
Homo sapiens
|
1.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and SAR of 2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-ones as 5-HT2C receptor agonists.
Year : 2013
Volume : 23
Issue : 1
First Page : 330
Last Page : 335
Authors : Fevig JM, Feng J, Rossi KA, Miller KJ, Wu G, Hung CP, Ung T, Malmstrom SE, Zhang G, Keim WJ, Cullen MJ, Rohrbach KW, Qu Q, Gan J, Pelleymounter MA, Robl JA.
Abstract : A series of 2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-ones is described, several examples of which exhibit potent 5-HT(2C) agonism with excellent selectivity over the closely related 5-HT(2A) and 5-HT(2B) receptors. Compounds such as 38 and 44 were shown to be effective in reducing food intake in an acute rat feeding model.
|
Agonist activity at 5-HT2A receptor (unknown origin)
|
Homo sapiens
|
1.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and SAR of 2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-ones as 5-HT2C receptor agonists.
Year : 2013
Volume : 23
Issue : 1
First Page : 330
Last Page : 335
Authors : Fevig JM, Feng J, Rossi KA, Miller KJ, Wu G, Hung CP, Ung T, Malmstrom SE, Zhang G, Keim WJ, Cullen MJ, Rohrbach KW, Qu Q, Gan J, Pelleymounter MA, Robl JA.
Abstract : A series of 2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-ones is described, several examples of which exhibit potent 5-HT(2C) agonism with excellent selectivity over the closely related 5-HT(2A) and 5-HT(2B) receptors. Compounds such as 38 and 44 were shown to be effective in reducing food intake in an acute rat feeding model.
|
Agonist activity at 5-HT2C receptor (unknown origin)
|
Homo sapiens
|
9.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and SAR of 2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-ones as 5-HT2C receptor agonists.
Year : 2013
Volume : 23
Issue : 1
First Page : 330
Last Page : 335
Authors : Fevig JM, Feng J, Rossi KA, Miller KJ, Wu G, Hung CP, Ung T, Malmstrom SE, Zhang G, Keim WJ, Cullen MJ, Rohrbach KW, Qu Q, Gan J, Pelleymounter MA, Robl JA.
Abstract : A series of 2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-ones is described, several examples of which exhibit potent 5-HT(2C) agonism with excellent selectivity over the closely related 5-HT(2A) and 5-HT(2B) receptors. Compounds such as 38 and 44 were shown to be effective in reducing food intake in an acute rat feeding model.
|
Binding affinity to 5-HT2C receptor (unknown origin)
|
Homo sapiens
|
15.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : In vitro structure-activity relationships of aplysinopsin analogs and their in vivo evaluation in the chick anxiety-depression model.
Year : 2013
Volume : 21
Issue : 22
First Page : 7083
Last Page : 7090
Authors : Lewellyn K, Bialonska D, Loria MJ, White SW, Sufka KJ, Zjawiony JK.
Abstract : Aplysinopsins are tryptophan-derived natural products that have been isolated from a variety of marine organisms and have been shown to possess a range of biological activities. In vitro receptor binding assays showed that of the 12 serotonin receptor subtypes, analogues showed a high affinity for the 5-HT2B and 5-HT2C receptor subtypes, with selectivity for 5-HT2B over 5-HT2C. While no conclusions could be drawn about the number and position of N-methylations, bromination at C-4 and C-5 of the indole ring resulted in greater binding affinities, with Ki's as low as 35 nM. This data, combined with previous knowledge of the CNS activity of aplysinopsin analogs, suggested that these compounds may have potential as leads for antidepressant drugs. Compounds 3c, 3u, and 3x were evaluated in the chick anxiety-depression model to assess their in vivo efficacy. Compound 3c showed a modest antidepressant effect at a dose of 30 nM/kg in the animal model.
|
Agonist activity at human recombinant 5HT2B receptor expressed in HEK293 cells assessed as [3H]inositol incorporation after 2 hrs by TopCount scintillation counting analysis
|
Homo sapiens
|
943.0
nM
|
|
Journal : J. Med. Chem.
Title : Optimization of 2-phenylcyclopropylmethylamines as selective serotonin 2C receptor agonists and their evaluation as potential antipsychotic agents.
Year : 2015
Volume : 58
Issue : 4
First Page : 1992
Last Page : 2002
Authors : Cheng J, Giguère PM, Onajole OK, Lv W, Gaisin A, Gunosewoyo H, Schmerberg CM, Pogorelov VM, Rodriguiz RM, Vistoli G, Wetsel WC, Roth BL, Kozikowski AP.
Abstract : The discovery of a new series of compounds that are potent, selective 5-HT2C receptor agonists is described herein as we continue our efforts to optimize the 2-phenylcyclopropylmethylamine scaffold. Modifications focused on the alkoxyl substituent present on the aromatic ring led to the identification of improved ligands with better potency at the 5-HT2C receptor and excellent selectivity against the 5-HT2A and 5-HT2B receptors. ADMET studies coupled with a behavioral test using the amphetamine-induced hyperactivity model identified four compounds possessing drug-like profiles and having antipsychotic properties. Compound (+)-16b, which displayed an EC50 of 4.2 nM at 5-HT2C, no activity at 5-HT2B, and an 89-fold selectivity against 5-HT2A, is one of the most potent and selective 5-HT2C agonists reported to date. The likely binding mode of this series of compounds to the 5-HT2C receptor was also investigated in a modeling study, using optimized models incorporating the structures of β2-adrenergic receptor and 5-HT2B receptor.
|
Agonist activity at human 5-HT2C receptor expressed in HEK293 cells assessed as calcium flux by FLIPR assay
|
Homo sapiens
|
3.6
nM
|
|
Journal : J. Med. Chem.
Title : Optimization of 2-phenylcyclopropylmethylamines as selective serotonin 2C receptor agonists and their evaluation as potential antipsychotic agents.
Year : 2015
Volume : 58
Issue : 4
First Page : 1992
Last Page : 2002
Authors : Cheng J, Giguère PM, Onajole OK, Lv W, Gaisin A, Gunosewoyo H, Schmerberg CM, Pogorelov VM, Rodriguiz RM, Vistoli G, Wetsel WC, Roth BL, Kozikowski AP.
Abstract : The discovery of a new series of compounds that are potent, selective 5-HT2C receptor agonists is described herein as we continue our efforts to optimize the 2-phenylcyclopropylmethylamine scaffold. Modifications focused on the alkoxyl substituent present on the aromatic ring led to the identification of improved ligands with better potency at the 5-HT2C receptor and excellent selectivity against the 5-HT2A and 5-HT2B receptors. ADMET studies coupled with a behavioral test using the amphetamine-induced hyperactivity model identified four compounds possessing drug-like profiles and having antipsychotic properties. Compound (+)-16b, which displayed an EC50 of 4.2 nM at 5-HT2C, no activity at 5-HT2B, and an 89-fold selectivity against 5-HT2A, is one of the most potent and selective 5-HT2C agonists reported to date. The likely binding mode of this series of compounds to the 5-HT2C receptor was also investigated in a modeling study, using optimized models incorporating the structures of β2-adrenergic receptor and 5-HT2B receptor.
|
Agonist activity at human 5-HT2B receptor expressed in HEK293 cells assessed as calcium flux by FLIPR assay
|
Homo sapiens
|
478.0
nM
|
|
Journal : J. Med. Chem.
Title : Optimization of 2-phenylcyclopropylmethylamines as selective serotonin 2C receptor agonists and their evaluation as potential antipsychotic agents.
Year : 2015
Volume : 58
Issue : 4
First Page : 1992
Last Page : 2002
Authors : Cheng J, Giguère PM, Onajole OK, Lv W, Gaisin A, Gunosewoyo H, Schmerberg CM, Pogorelov VM, Rodriguiz RM, Vistoli G, Wetsel WC, Roth BL, Kozikowski AP.
Abstract : The discovery of a new series of compounds that are potent, selective 5-HT2C receptor agonists is described herein as we continue our efforts to optimize the 2-phenylcyclopropylmethylamine scaffold. Modifications focused on the alkoxyl substituent present on the aromatic ring led to the identification of improved ligands with better potency at the 5-HT2C receptor and excellent selectivity against the 5-HT2A and 5-HT2B receptors. ADMET studies coupled with a behavioral test using the amphetamine-induced hyperactivity model identified four compounds possessing drug-like profiles and having antipsychotic properties. Compound (+)-16b, which displayed an EC50 of 4.2 nM at 5-HT2C, no activity at 5-HT2B, and an 89-fold selectivity against 5-HT2A, is one of the most potent and selective 5-HT2C agonists reported to date. The likely binding mode of this series of compounds to the 5-HT2C receptor was also investigated in a modeling study, using optimized models incorporating the structures of β2-adrenergic receptor and 5-HT2B receptor.
|
Agonist activity at human 5-HT2A receptor expressed in HEK293 cells assessed as calcium flux by FLIPR assay
|
Homo sapiens
|
302.0
nM
|
|
Journal : J. Med. Chem.
Title : Optimization of 2-phenylcyclopropylmethylamines as selective serotonin 2C receptor agonists and their evaluation as potential antipsychotic agents.
Year : 2015
Volume : 58
Issue : 4
First Page : 1992
Last Page : 2002
Authors : Cheng J, Giguère PM, Onajole OK, Lv W, Gaisin A, Gunosewoyo H, Schmerberg CM, Pogorelov VM, Rodriguiz RM, Vistoli G, Wetsel WC, Roth BL, Kozikowski AP.
Abstract : The discovery of a new series of compounds that are potent, selective 5-HT2C receptor agonists is described herein as we continue our efforts to optimize the 2-phenylcyclopropylmethylamine scaffold. Modifications focused on the alkoxyl substituent present on the aromatic ring led to the identification of improved ligands with better potency at the 5-HT2C receptor and excellent selectivity against the 5-HT2A and 5-HT2B receptors. ADMET studies coupled with a behavioral test using the amphetamine-induced hyperactivity model identified four compounds possessing drug-like profiles and having antipsychotic properties. Compound (+)-16b, which displayed an EC50 of 4.2 nM at 5-HT2C, no activity at 5-HT2B, and an 89-fold selectivity against 5-HT2A, is one of the most potent and selective 5-HT2C agonists reported to date. The likely binding mode of this series of compounds to the 5-HT2C receptor was also investigated in a modeling study, using optimized models incorporating the structures of β2-adrenergic receptor and 5-HT2B receptor.
|
Agonist activity at recombinant human 5HT2C-INI receptor expressed in Flp-In-293 cells assessed as calcium flux by FLIPR assay
|
Homo sapiens
|
2.7
nM
|
|
Agonist activity at recombinant human 5HT2C-INI receptor expressed in Flp-In-293 cells assessed as calcium flux by FLIPR assay
|
Homo sapiens
|
1.82
nM
|
|
Journal : J. Med. Chem.
Title : Further Advances in Optimizing (2-Phenylcyclopropyl)methylamines as Novel Serotonin 2C Agonists: Effects on Hyperlocomotion, Prepulse Inhibition, and Cognition Models.
Year : 2016
Volume : 59
Issue : 2
First Page : 578
Last Page : 591
Authors : Cheng J, Giguere PM, Schmerberg CM, Pogorelov VM, Rodriguiz RM, Huang XP, Zhu H, McCorvy JD, Wetsel WC, Roth BL, Kozikowski AP.
Abstract : A series of novel compounds with two halogen substituents have been designed and synthesized to further optimize the 2-phenylcyclopropylmethylamine scaffold in the quest for drug-like 5-HT2C agonists. Compound (+)-22a was identified as a potent 5-HT2C receptor agonist, with good selectivity against the 5-HT2B and the 5-HT2A receptors. ADMET assays showed that compound (+)-22a possessed desirable properties in terms of its microsomal stability, and CYP and hERG inhibition, along with an excellent brain penetration profile. Evaluation of (+)-22a in animal models of schizophrenia-related behaviors revealed that it had a desirable activity profile, as it reduced d-amphetamine-stimulated hyperlocomotion in the open field test, it restored d-amphetamine-disrupted prepulse inhibition, it induced cognitive improvements in the novel object recognition memory test in NR1-KD animals, and it produced very little catalepsy relative to haloperidol. These data support the further development of (+)-22a as a drug candidate for the treatment of schizophrenia.
|
Agonist activity at recombinant human 5HT2B receptor expressed in Flp-In-293 cells assessed as calcium flux by FLIPR assay
|
Homo sapiens
|
328.0
nM
|
|
Agonist activity at recombinant human 5HT2B receptor expressed in Flp-In-293 cells assessed as calcium flux by FLIPR assay
|
Homo sapiens
|
512.86
nM
|
|
Journal : J. Med. Chem.
Title : Further Advances in Optimizing (2-Phenylcyclopropyl)methylamines as Novel Serotonin 2C Agonists: Effects on Hyperlocomotion, Prepulse Inhibition, and Cognition Models.
Year : 2016
Volume : 59
Issue : 2
First Page : 578
Last Page : 591
Authors : Cheng J, Giguere PM, Schmerberg CM, Pogorelov VM, Rodriguiz RM, Huang XP, Zhu H, McCorvy JD, Wetsel WC, Roth BL, Kozikowski AP.
Abstract : A series of novel compounds with two halogen substituents have been designed and synthesized to further optimize the 2-phenylcyclopropylmethylamine scaffold in the quest for drug-like 5-HT2C agonists. Compound (+)-22a was identified as a potent 5-HT2C receptor agonist, with good selectivity against the 5-HT2B and the 5-HT2A receptors. ADMET assays showed that compound (+)-22a possessed desirable properties in terms of its microsomal stability, and CYP and hERG inhibition, along with an excellent brain penetration profile. Evaluation of (+)-22a in animal models of schizophrenia-related behaviors revealed that it had a desirable activity profile, as it reduced d-amphetamine-stimulated hyperlocomotion in the open field test, it restored d-amphetamine-disrupted prepulse inhibition, it induced cognitive improvements in the novel object recognition memory test in NR1-KD animals, and it produced very little catalepsy relative to haloperidol. These data support the further development of (+)-22a as a drug candidate for the treatment of schizophrenia.
|
Agonist activity at recombinant human 5HT2A receptor expressed in Flp-In-293 cells assessed as calcium flux by FLIPR assay
|
Homo sapiens
|
258.0
nM
|
|
Agonist activity at recombinant human 5HT2A receptor expressed in Flp-In-293 cells assessed as calcium flux by FLIPR assay
|
Homo sapiens
|
165.96
nM
|
|
Journal : J. Med. Chem.
Title : Further Advances in Optimizing (2-Phenylcyclopropyl)methylamines as Novel Serotonin 2C Agonists: Effects on Hyperlocomotion, Prepulse Inhibition, and Cognition Models.
Year : 2016
Volume : 59
Issue : 2
First Page : 578
Last Page : 591
Authors : Cheng J, Giguere PM, Schmerberg CM, Pogorelov VM, Rodriguiz RM, Huang XP, Zhu H, McCorvy JD, Wetsel WC, Roth BL, Kozikowski AP.
Abstract : A series of novel compounds with two halogen substituents have been designed and synthesized to further optimize the 2-phenylcyclopropylmethylamine scaffold in the quest for drug-like 5-HT2C agonists. Compound (+)-22a was identified as a potent 5-HT2C receptor agonist, with good selectivity against the 5-HT2B and the 5-HT2A receptors. ADMET assays showed that compound (+)-22a possessed desirable properties in terms of its microsomal stability, and CYP and hERG inhibition, along with an excellent brain penetration profile. Evaluation of (+)-22a in animal models of schizophrenia-related behaviors revealed that it had a desirable activity profile, as it reduced d-amphetamine-stimulated hyperlocomotion in the open field test, it restored d-amphetamine-disrupted prepulse inhibition, it induced cognitive improvements in the novel object recognition memory test in NR1-KD animals, and it produced very little catalepsy relative to haloperidol. These data support the further development of (+)-22a as a drug candidate for the treatment of schizophrenia.
|
Agonist activity at human 5-HT2C-INI receptor isoform expressed in Flp-IN HEK293 cells assessed as induction of Gq-mediated calcium flux measured every second for 5 mins by Fluo-4 dye based FLIPR assay
|
Homo sapiens
|
2.1
nM
|
|
Agonist activity at human 5-HT2C-INI receptor isoform expressed in Flp-IN HEK293 cells assessed as induction of Gq-mediated calcium flux measured every second for 5 mins by Fluo-4 dye based FLIPR assay
|
Homo sapiens
|
2.63
nM
|
|
Journal : J Med Chem
Title : Discovery of N-Substituted (2-Phenylcyclopropyl)methylamines as Functionally Selective Serotonin 2C Receptor Agonists for Potential Use as Antipsychotic Medications.
Year : 2017
Volume : 60
Issue : 14
First Page : 6273
Last Page : 6288
Authors : Zhang G, Cheng J, McCorvy JD, Lorello PJ, Caldarone BJ, Roth BL, Kozikowski AP.
Abstract : A series of N-substituted (2-phenylcyclopropyl)methylamines were designed and synthesized, with the aim of finding serotonin 2C (5-HT2C)-selective agonists with a preference for Gq signaling. A number of these compounds exhibit 5-HT2C selectivity with a preference for Gq-mediated signaling compared with β-arrestin recruitment. Furthermore, the N-methyl compound (+)-15a, which displayed an EC50 of 23 nM in the calcium flux assay while showing no β-arrestin recruitment activity, is the most functionally selective 5-HT2C agonist reported to date. The N-benzyl compound (+)-19, which showed an EC50 of 24 nM at the 5-HT2C receptor, is fully selective over the 5-HT2B receptor. In an amphetamine-induced hyperactivity model, compound (+)-19 showed significant antipsychotic-drug-like activity. These novel compounds shed light on the role of functional selectivity at the 5-HT2C receptor with respect to antipsychotic activity.
|
Agonist activity at human 5-HT2B receptor expressed in Flp-IN HEK293 cells assessed as induction of calcium flux measured every second for 5 mins by Fluo-4 dye based FLIPR assay
|
Homo sapiens
|
436.52
nM
|
|
Agonist activity at human 5-HT2B receptor expressed in Flp-IN HEK293 cells assessed as induction of calcium flux measured every second for 5 mins by Fluo-4 dye based FLIPR assay
|
Homo sapiens
|
433.0
nM
|
|
Journal : J Med Chem
Title : Discovery of N-Substituted (2-Phenylcyclopropyl)methylamines as Functionally Selective Serotonin 2C Receptor Agonists for Potential Use as Antipsychotic Medications.
Year : 2017
Volume : 60
Issue : 14
First Page : 6273
Last Page : 6288
Authors : Zhang G, Cheng J, McCorvy JD, Lorello PJ, Caldarone BJ, Roth BL, Kozikowski AP.
Abstract : A series of N-substituted (2-phenylcyclopropyl)methylamines were designed and synthesized, with the aim of finding serotonin 2C (5-HT2C)-selective agonists with a preference for Gq signaling. A number of these compounds exhibit 5-HT2C selectivity with a preference for Gq-mediated signaling compared with β-arrestin recruitment. Furthermore, the N-methyl compound (+)-15a, which displayed an EC50 of 23 nM in the calcium flux assay while showing no β-arrestin recruitment activity, is the most functionally selective 5-HT2C agonist reported to date. The N-benzyl compound (+)-19, which showed an EC50 of 24 nM at the 5-HT2C receptor, is fully selective over the 5-HT2B receptor. In an amphetamine-induced hyperactivity model, compound (+)-19 showed significant antipsychotic-drug-like activity. These novel compounds shed light on the role of functional selectivity at the 5-HT2C receptor with respect to antipsychotic activity.
|
Agonist activity at human 5-HT2A receptor expressed in Flp-IN HEK293 cells assessed as induction of calcium flux measured every second for 5 mins by Fluo-4 dye based FLIPR assay
|
Homo sapiens
|
245.47
nM
|
|
Agonist activity at human 5-HT2A receptor expressed in Flp-IN HEK293 cells assessed as induction of calcium flux measured every second for 5 mins by Fluo-4 dye based FLIPR assay
|
Homo sapiens
|
248.0
nM
|
|
Journal : J Med Chem
Title : Discovery of N-Substituted (2-Phenylcyclopropyl)methylamines as Functionally Selective Serotonin 2C Receptor Agonists for Potential Use as Antipsychotic Medications.
Year : 2017
Volume : 60
Issue : 14
First Page : 6273
Last Page : 6288
Authors : Zhang G, Cheng J, McCorvy JD, Lorello PJ, Caldarone BJ, Roth BL, Kozikowski AP.
Abstract : A series of N-substituted (2-phenylcyclopropyl)methylamines were designed and synthesized, with the aim of finding serotonin 2C (5-HT2C)-selective agonists with a preference for Gq signaling. A number of these compounds exhibit 5-HT2C selectivity with a preference for Gq-mediated signaling compared with β-arrestin recruitment. Furthermore, the N-methyl compound (+)-15a, which displayed an EC50 of 23 nM in the calcium flux assay while showing no β-arrestin recruitment activity, is the most functionally selective 5-HT2C agonist reported to date. The N-benzyl compound (+)-19, which showed an EC50 of 24 nM at the 5-HT2C receptor, is fully selective over the 5-HT2B receptor. In an amphetamine-induced hyperactivity model, compound (+)-19 showed significant antipsychotic-drug-like activity. These novel compounds shed light on the role of functional selectivity at the 5-HT2C receptor with respect to antipsychotic activity.
|
Agonist activity at tTA containing TEV cleavage site-fused 5-HT2C-INI receptor isoform (unknown origin) expressed in TEV-fused beta-arrestin2 expressing HEK cells assessed as induction of beta-arrestin2 recruitment after 20 hrs by Tango assay
|
Homo sapiens
|
39.81
nM
|
|
Agonist activity at tTA containing TEV cleavage site-fused 5-HT2C-INI receptor isoform (unknown origin) expressed in TEV-fused beta-arrestin2 expressing HEK cells assessed as induction of beta-arrestin2 recruitment after 20 hrs by Tango assay
|
Homo sapiens
|
40.0
nM
|
|
Journal : J Med Chem
Title : Discovery of N-Substituted (2-Phenylcyclopropyl)methylamines as Functionally Selective Serotonin 2C Receptor Agonists for Potential Use as Antipsychotic Medications.
Year : 2017
Volume : 60
Issue : 14
First Page : 6273
Last Page : 6288
Authors : Zhang G, Cheng J, McCorvy JD, Lorello PJ, Caldarone BJ, Roth BL, Kozikowski AP.
Abstract : A series of N-substituted (2-phenylcyclopropyl)methylamines were designed and synthesized, with the aim of finding serotonin 2C (5-HT2C)-selective agonists with a preference for Gq signaling. A number of these compounds exhibit 5-HT2C selectivity with a preference for Gq-mediated signaling compared with β-arrestin recruitment. Furthermore, the N-methyl compound (+)-15a, which displayed an EC50 of 23 nM in the calcium flux assay while showing no β-arrestin recruitment activity, is the most functionally selective 5-HT2C agonist reported to date. The N-benzyl compound (+)-19, which showed an EC50 of 24 nM at the 5-HT2C receptor, is fully selective over the 5-HT2B receptor. In an amphetamine-induced hyperactivity model, compound (+)-19 showed significant antipsychotic-drug-like activity. These novel compounds shed light on the role of functional selectivity at the 5-HT2C receptor with respect to antipsychotic activity.
|
Agonist activity at 5-HT2CR (unknown origin)
|
Homo sapiens
|
15.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Characterization of 4-Undecylpiperidine-2-carboxamides as Positive Allosteric Modulators of the Serotonin (5-HT) 5-HT2C Receptor.
Year : 2018
Volume : 62
Issue : 1
First Page : 288
Last Page : 305
Authors : Wild CT, Miszkiel JM, Wold EA, Soto CA, Ding C, Hartley RM, White MA, Anastasio NC, Cunningham KA, Zhou J.
Abstract : An impaired signaling capacity of the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) has been implicated in the neurobehavioral processes that promote relapse vulnerability in cocaine use disorder (CUD). Restoration of the diminished 5-HT2CR signaling through positive allosteric modulation presents a novel therapeutic approach. Several new molecules with the 4-alkylpiperidine-2-carboxamide scaffold were designed, synthesized, and pharmacologically evaluated, leading to the discovery of selective 5-HT2CR positive allosteric modulators (PAMs). Compound 16 (CYD-1-79) potentiated 5-HT-evoked intracellular calcium release in cells stably expressing the human 5-HT2CR but not the 5-HT2AR cells. A topographically distinct allosteric site was identified based on the newly solved 5-HT2CR structure. Compound 16 modulated 5-HT2CR-mediated spontaneous ambulation, partially substituted for the training dose of the 5-HT2CR agonist WAY163909, synergized with a low dose of WAY163909 to substitute fully for the stimulus effects of WAY163909, and attenuated relapse vulnerability as assessed in a rodent self-administration model, indicating its therapeutic promise for CUD.
|
Agonist activity at 5-HT2AR (unknown origin)
|
Homo sapiens
|
112.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Characterization of 4-Undecylpiperidine-2-carboxamides as Positive Allosteric Modulators of the Serotonin (5-HT) 5-HT2C Receptor.
Year : 2018
Volume : 62
Issue : 1
First Page : 288
Last Page : 305
Authors : Wild CT, Miszkiel JM, Wold EA, Soto CA, Ding C, Hartley RM, White MA, Anastasio NC, Cunningham KA, Zhou J.
Abstract : An impaired signaling capacity of the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) has been implicated in the neurobehavioral processes that promote relapse vulnerability in cocaine use disorder (CUD). Restoration of the diminished 5-HT2CR signaling through positive allosteric modulation presents a novel therapeutic approach. Several new molecules with the 4-alkylpiperidine-2-carboxamide scaffold were designed, synthesized, and pharmacologically evaluated, leading to the discovery of selective 5-HT2CR positive allosteric modulators (PAMs). Compound 16 (CYD-1-79) potentiated 5-HT-evoked intracellular calcium release in cells stably expressing the human 5-HT2CR but not the 5-HT2AR cells. A topographically distinct allosteric site was identified based on the newly solved 5-HT2CR structure. Compound 16 modulated 5-HT2CR-mediated spontaneous ambulation, partially substituted for the training dose of the 5-HT2CR agonist WAY163909, synergized with a low dose of WAY163909 to substitute fully for the stimulus effects of WAY163909, and attenuated relapse vulnerability as assessed in a rodent self-administration model, indicating its therapeutic promise for CUD.
|
Agonist activity at 5-HT2BR (unknown origin)
|
Homo sapiens
|
174.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Characterization of 4-Undecylpiperidine-2-carboxamides as Positive Allosteric Modulators of the Serotonin (5-HT) 5-HT2C Receptor.
Year : 2018
Volume : 62
Issue : 1
First Page : 288
Last Page : 305
Authors : Wild CT, Miszkiel JM, Wold EA, Soto CA, Ding C, Hartley RM, White MA, Anastasio NC, Cunningham KA, Zhou J.
Abstract : An impaired signaling capacity of the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) has been implicated in the neurobehavioral processes that promote relapse vulnerability in cocaine use disorder (CUD). Restoration of the diminished 5-HT2CR signaling through positive allosteric modulation presents a novel therapeutic approach. Several new molecules with the 4-alkylpiperidine-2-carboxamide scaffold were designed, synthesized, and pharmacologically evaluated, leading to the discovery of selective 5-HT2CR positive allosteric modulators (PAMs). Compound 16 (CYD-1-79) potentiated 5-HT-evoked intracellular calcium release in cells stably expressing the human 5-HT2CR but not the 5-HT2AR cells. A topographically distinct allosteric site was identified based on the newly solved 5-HT2CR structure. Compound 16 modulated 5-HT2CR-mediated spontaneous ambulation, partially substituted for the training dose of the 5-HT2CR agonist WAY163909, synergized with a low dose of WAY163909 to substitute fully for the stimulus effects of WAY163909, and attenuated relapse vulnerability as assessed in a rodent self-administration model, indicating its therapeutic promise for CUD.
|
Agonist activity at recombinant human unedited 5HT2C receptor isoform INI expressed in Flp-In-293 cells assessed as increase in calcium influx measured for 300 secs by Fluo-4 dye based FLIPR assay
|
Homo sapiens
|
4.786
nM
|
|
Agonist activity at recombinant human unedited 5HT2C receptor isoform INI expressed in Flp-In-293 cells assessed as increase in calcium influx measured for 300 secs by Fluo-4 dye based FLIPR assay
|
Homo sapiens
|
4.77
nM
|
|
Journal : Eur J Med Chem
Title : Design of fluorinated cyclopropane derivatives of 2-phenylcyclopropylmethylamine leading to identification of a selective serotonin 2C (5-HT<sub>2C</sub>) receptor agonist without 5-HT<sub>2B</sub> agonism.
Year : 2019
Volume : 182
First Page : 111626
Last Page : 111626
Authors : Zhang G, McCorvy JD, Shen S, Cheng J, Roth BL, Kozikowski AP.
Abstract : A new series of fluorinated 5-HT<sub>2C</sub> agonists were designed and synthesized on the basis of our previous work on 2-phenylcyclopropylmethylamines as a potential approach for the treatment of central nervous system disorders. Key fluorinated cyclopropane moieties were constructed through transition metal catalyzed [2 + 1]-cycloaddition of aromatic vinyl fluorides, and the absolute stereochemistry of the representative compound (-)-21a was established. Functional activity measuring calcium flux at 5-HT<sub>2</sub> receptors reveals high potency for compounds (+)-21a-d. In particular, (+)-21b had no detectable 5-HT<sub>2B</sub> agonism and displayed reasonable selectivity against 5-HT<sub>2A</sub>. Molecular docking studies were further performed to explain the compounds' possible binding poses to the 5-HT<sub>2C</sub> receptor.
|
Agonist activity at recombinant human 5HT2B receptor expressed in Flp-In-293 cells assessed as increase in calcium influx measured for 300 secs by Fluo-4 dye based FLIPR assay
|
Homo sapiens
|
79.43
nM
|
|
Agonist activity at recombinant human 5HT2B receptor expressed in Flp-In-293 cells assessed as increase in calcium influx measured for 300 secs by Fluo-4 dye based FLIPR assay
|
Homo sapiens
|
80.0
nM
|
|
Journal : Eur J Med Chem
Title : Design of fluorinated cyclopropane derivatives of 2-phenylcyclopropylmethylamine leading to identification of a selective serotonin 2C (5-HT<sub>2C</sub>) receptor agonist without 5-HT<sub>2B</sub> agonism.
Year : 2019
Volume : 182
First Page : 111626
Last Page : 111626
Authors : Zhang G, McCorvy JD, Shen S, Cheng J, Roth BL, Kozikowski AP.
Abstract : A new series of fluorinated 5-HT<sub>2C</sub> agonists were designed and synthesized on the basis of our previous work on 2-phenylcyclopropylmethylamines as a potential approach for the treatment of central nervous system disorders. Key fluorinated cyclopropane moieties were constructed through transition metal catalyzed [2 + 1]-cycloaddition of aromatic vinyl fluorides, and the absolute stereochemistry of the representative compound (-)-21a was established. Functional activity measuring calcium flux at 5-HT<sub>2</sub> receptors reveals high potency for compounds (+)-21a-d. In particular, (+)-21b had no detectable 5-HT<sub>2B</sub> agonism and displayed reasonable selectivity against 5-HT<sub>2A</sub>. Molecular docking studies were further performed to explain the compounds' possible binding poses to the 5-HT<sub>2C</sub> receptor.
|
Agonist activity at recombinant human 5HT2A receptor expressed in Flp-In-293 cells assessed as increase in calcium influx measured for 300 secs by Fluo-4 dye based FLIPR assay
|
Homo sapiens
|
32.36
nM
|
|
Agonist activity at recombinant human 5HT2A receptor expressed in Flp-In-293 cells assessed as increase in calcium influx measured for 300 secs by Fluo-4 dye based FLIPR assay
|
Homo sapiens
|
33.0
nM
|
|
Journal : Eur J Med Chem
Title : Design of fluorinated cyclopropane derivatives of 2-phenylcyclopropylmethylamine leading to identification of a selective serotonin 2C (5-HT<sub>2C</sub>) receptor agonist without 5-HT<sub>2B</sub> agonism.
Year : 2019
Volume : 182
First Page : 111626
Last Page : 111626
Authors : Zhang G, McCorvy JD, Shen S, Cheng J, Roth BL, Kozikowski AP.
Abstract : A new series of fluorinated 5-HT<sub>2C</sub> agonists were designed and synthesized on the basis of our previous work on 2-phenylcyclopropylmethylamines as a potential approach for the treatment of central nervous system disorders. Key fluorinated cyclopropane moieties were constructed through transition metal catalyzed [2 + 1]-cycloaddition of aromatic vinyl fluorides, and the absolute stereochemistry of the representative compound (-)-21a was established. Functional activity measuring calcium flux at 5-HT<sub>2</sub> receptors reveals high potency for compounds (+)-21a-d. In particular, (+)-21b had no detectable 5-HT<sub>2B</sub> agonism and displayed reasonable selectivity against 5-HT<sub>2A</sub>. Molecular docking studies were further performed to explain the compounds' possible binding poses to the 5-HT<sub>2C</sub> receptor.
|
Displacement of [3H]DOI from recombinant human 5HT2A receptor expressed in HEK293T cell membranes after 1 hr by beta scintillation counting method
|
Homo sapiens
|
112.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of fluorinated (R)-(-)-aporphine derivatives as potent and selective ligands at serotonin 5-HT2C receptor.
Year : 2019
Volume : 29
Issue : 2
First Page : 230
Last Page : 233
Authors : Xu Y, Sromek AW, Neumeyer JL.
Abstract : A series of novel aporphine derivatives were synthesized for initial screening at the 5-HT2 receptor subtypes. Among them, Compounds 11a and 11b were identified as potent 5-HT2C hit ligands with high selectivity over other 5-HT2 receptor subtypes. Molecular docking study revealed that compounds 11a and 11b formed two key interactions with the binding site of 5-HT2C receptor, including a salt-bridge to D3.32 and a H-bond interaction with N6.55.
|
Displacement of [3H]DOI from recombinant human 5HT2B receptor expressed in HEK293T cell membranes after 1 hr by beta scintillation counting method
|
Homo sapiens
|
174.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of fluorinated (R)-(-)-aporphine derivatives as potent and selective ligands at serotonin 5-HT2C receptor.
Year : 2019
Volume : 29
Issue : 2
First Page : 230
Last Page : 233
Authors : Xu Y, Sromek AW, Neumeyer JL.
Abstract : A series of novel aporphine derivatives were synthesized for initial screening at the 5-HT2 receptor subtypes. Among them, Compounds 11a and 11b were identified as potent 5-HT2C hit ligands with high selectivity over other 5-HT2 receptor subtypes. Molecular docking study revealed that compounds 11a and 11b formed two key interactions with the binding site of 5-HT2C receptor, including a salt-bridge to D3.32 and a H-bond interaction with N6.55.
|
Displacement of [3H]DOI from recombinant human 5HT2C receptor expressed in HEK293T cell membranes after 1 hr by beta scintillation counting method
|
Homo sapiens
|
15.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of fluorinated (R)-(-)-aporphine derivatives as potent and selective ligands at serotonin 5-HT2C receptor.
Year : 2019
Volume : 29
Issue : 2
First Page : 230
Last Page : 233
Authors : Xu Y, Sromek AW, Neumeyer JL.
Abstract : A series of novel aporphine derivatives were synthesized for initial screening at the 5-HT2 receptor subtypes. Among them, Compounds 11a and 11b were identified as potent 5-HT2C hit ligands with high selectivity over other 5-HT2 receptor subtypes. Molecular docking study revealed that compounds 11a and 11b formed two key interactions with the binding site of 5-HT2C receptor, including a salt-bridge to D3.32 and a H-bond interaction with N6.55.
|
Selectivity ratio of Ki for displacement of [3H]DOI from recombinant human 5HT2A receptor expressed in HEK293T cell membranes to Ki for displacement of [3H]DOI from recombinant human 5HT2C receptor expressed in HEK293T cell membranes
|
Homo sapiens
|
7.5
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of fluorinated (R)-(-)-aporphine derivatives as potent and selective ligands at serotonin 5-HT2C receptor.
Year : 2019
Volume : 29
Issue : 2
First Page : 230
Last Page : 233
Authors : Xu Y, Sromek AW, Neumeyer JL.
Abstract : A series of novel aporphine derivatives were synthesized for initial screening at the 5-HT2 receptor subtypes. Among them, Compounds 11a and 11b were identified as potent 5-HT2C hit ligands with high selectivity over other 5-HT2 receptor subtypes. Molecular docking study revealed that compounds 11a and 11b formed two key interactions with the binding site of 5-HT2C receptor, including a salt-bridge to D3.32 and a H-bond interaction with N6.55.
|
Selectivity ratio of Ki for displacement of [3H]DOI from recombinant human 5HT2B receptor expressed in HEK293T cell membranes to Ki for displacement of [3H]DOI from recombinant human 5HT2C receptor expressed in HEK293T cell membranes
|
Homo sapiens
|
12.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of fluorinated (R)-(-)-aporphine derivatives as potent and selective ligands at serotonin 5-HT2C receptor.
Year : 2019
Volume : 29
Issue : 2
First Page : 230
Last Page : 233
Authors : Xu Y, Sromek AW, Neumeyer JL.
Abstract : A series of novel aporphine derivatives were synthesized for initial screening at the 5-HT2 receptor subtypes. Among them, Compounds 11a and 11b were identified as potent 5-HT2C hit ligands with high selectivity over other 5-HT2 receptor subtypes. Molecular docking study revealed that compounds 11a and 11b formed two key interactions with the binding site of 5-HT2C receptor, including a salt-bridge to D3.32 and a H-bond interaction with N6.55.
|
Displacement of [125I]-1,4-Iodanyl-2,5-dimethoxyphenyl)propan-2amine from 5HT2B receptor (unknown origin)
|
Homo sapiens
|
220.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of a lead series of potent benzodiazepine 5-HT<sub>2C</sub> receptor agonists with high selectivity in functional and binding assays.
Year : 2020
Volume : 30
Issue : 5
First Page : 126929
Last Page : 126929
Authors : Ren A, Zhu X, Feichtinger K, Lehman J, Kasem M, Schrader TO, Wong A, Dang H, Le M, Frazer J, Unett DJ, Grottick AJ, Whelan KT, Morgan ME, Sage CR, Semple G.
Abstract : A series of potential new 5-HT<sub>2</sub> receptor scaffolds based on a simplification of the clinically studied, 5-HT<sub>2C</sub>R agonist vabicaserin, were designed. An in vivo feeding assay early in our screening process played an instrumental part in the lead identification process, leading us to focus on a 6,5,7-tricyclic scaffold. A subsequent early SAR investigation provided potent agonists of the 5-HT<sub>2C</sub> receptor that were highly selective in both functional and binding assays, had good rat PK properties and that significantly reduced acute food intake in the rat.
|
Displacement of [125I]-1,4-Iodanyl-2,5-dimethoxyphenyl)propan-2amine from 5HT2A receptor (unknown origin)
|
Homo sapiens
|
98.5
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of a lead series of potent benzodiazepine 5-HT<sub>2C</sub> receptor agonists with high selectivity in functional and binding assays.
Year : 2020
Volume : 30
Issue : 5
First Page : 126929
Last Page : 126929
Authors : Ren A, Zhu X, Feichtinger K, Lehman J, Kasem M, Schrader TO, Wong A, Dang H, Le M, Frazer J, Unett DJ, Grottick AJ, Whelan KT, Morgan ME, Sage CR, Semple G.
Abstract : A series of potential new 5-HT<sub>2</sub> receptor scaffolds based on a simplification of the clinically studied, 5-HT<sub>2C</sub>R agonist vabicaserin, were designed. An in vivo feeding assay early in our screening process played an instrumental part in the lead identification process, leading us to focus on a 6,5,7-tricyclic scaffold. A subsequent early SAR investigation provided potent agonists of the 5-HT<sub>2C</sub> receptor that were highly selective in both functional and binding assays, had good rat PK properties and that significantly reduced acute food intake in the rat.
|
Displacement of [125I]-1,4-Iodanyl-2,5-dimethoxyphenyl)propan-2amine from recombinant human 5HT2C receptor expressed in HEK293 cells measured after 2 hrs by scintillation counter method
|
Homo sapiens
|
15.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of a lead series of potent benzodiazepine 5-HT<sub>2C</sub> receptor agonists with high selectivity in functional and binding assays.
Year : 2020
Volume : 30
Issue : 5
First Page : 126929
Last Page : 126929
Authors : Ren A, Zhu X, Feichtinger K, Lehman J, Kasem M, Schrader TO, Wong A, Dang H, Le M, Frazer J, Unett DJ, Grottick AJ, Whelan KT, Morgan ME, Sage CR, Semple G.
Abstract : A series of potential new 5-HT<sub>2</sub> receptor scaffolds based on a simplification of the clinically studied, 5-HT<sub>2C</sub>R agonist vabicaserin, were designed. An in vivo feeding assay early in our screening process played an instrumental part in the lead identification process, leading us to focus on a 6,5,7-tricyclic scaffold. A subsequent early SAR investigation provided potent agonists of the 5-HT<sub>2C</sub> receptor that were highly selective in both functional and binding assays, had good rat PK properties and that significantly reduced acute food intake in the rat.
|
Agonist activity at recombinant human 5HT2C receptor expressed in HEK293 cells assessed as accumulation of inositol phosphate measured after 2 hrs in presence of [3H]inositol by scintillation counter method
|
Homo sapiens
|
7.6
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of a lead series of potent benzodiazepine 5-HT<sub>2C</sub> receptor agonists with high selectivity in functional and binding assays.
Year : 2020
Volume : 30
Issue : 5
First Page : 126929
Last Page : 126929
Authors : Ren A, Zhu X, Feichtinger K, Lehman J, Kasem M, Schrader TO, Wong A, Dang H, Le M, Frazer J, Unett DJ, Grottick AJ, Whelan KT, Morgan ME, Sage CR, Semple G.
Abstract : A series of potential new 5-HT<sub>2</sub> receptor scaffolds based on a simplification of the clinically studied, 5-HT<sub>2C</sub>R agonist vabicaserin, were designed. An in vivo feeding assay early in our screening process played an instrumental part in the lead identification process, leading us to focus on a 6,5,7-tricyclic scaffold. A subsequent early SAR investigation provided potent agonists of the 5-HT<sub>2C</sub> receptor that were highly selective in both functional and binding assays, had good rat PK properties and that significantly reduced acute food intake in the rat.
|
Agonist activity at human 5-HT2C receptor expressed in human Flp-In-293 cells assessed as induction of calcium flux incubated for 1 hr by Fluo-4 direct dye based FLIPR assay
|
Homo sapiens
|
2.63
nM
|
|
Agonist activity at human 5-HT2C receptor expressed in human Flp-In-293 cells assessed as induction of calcium flux incubated for 1 hr by Fluo-4 direct dye based FLIPR assay
|
Homo sapiens
|
2.64
nM
|
|
Journal : J Med Chem
Title : Design and Discovery of Functionally Selective Serotonin 2C (5-HT) Receptor Agonists.
Year : 2016
Volume : 59
Issue : 21
First Page : 9866
Last Page : 9880
Authors : Cheng J,McCorvy JD,Giguere PM,Zhu H,Kenakin T,Roth BL,Kozikowski AP
Abstract : On the basis of the structural similarity of our previous 5-HT agonists with the melatonin receptor agonist tasimelteon and the putative biological cross-talk between serotonergic and melatonergic systems, a series of new (2,3-dihydro)benzofuran-based compounds were designed and synthesized. The compounds were evaluated for their selectivity toward 5-HT, 5-HT, and 5-HT receptors in the calcium flux assay with the ultimate goal to generate selective 5-HT agonists. Selected compounds were studied for their functional selectivity by comparing their transduction efficiency at the G protein signaling pathway versus β-arrestin recruitment. The most functionally selective compound (+)-7e produced weak β-arrestin recruitment and also demonstrated less receptor desensitization compared to serotonin in both calcium flux and phosphoinositide (PI) hydrolysis assays. We report for the first time that selective 5-HT agonists possessing weak β-arrestin recruitment can produce distinct receptor desensitization properties.
|
Agonist activity at human 5-HT2B receptor expressed in human Flp-In-293 cells assessed as induction of calcium flux incubated for 1 hr by Fluo-4 direct dye based FLIPR assay
|
Homo sapiens
|
436.52
nM
|
|
Agonist activity at human 5-HT2B receptor expressed in human Flp-In-293 cells assessed as induction of calcium flux incubated for 1 hr by Fluo-4 direct dye based FLIPR assay
|
Homo sapiens
|
433.0
nM
|
|
Journal : J Med Chem
Title : Design and Discovery of Functionally Selective Serotonin 2C (5-HT) Receptor Agonists.
Year : 2016
Volume : 59
Issue : 21
First Page : 9866
Last Page : 9880
Authors : Cheng J,McCorvy JD,Giguere PM,Zhu H,Kenakin T,Roth BL,Kozikowski AP
Abstract : On the basis of the structural similarity of our previous 5-HT agonists with the melatonin receptor agonist tasimelteon and the putative biological cross-talk between serotonergic and melatonergic systems, a series of new (2,3-dihydro)benzofuran-based compounds were designed and synthesized. The compounds were evaluated for their selectivity toward 5-HT, 5-HT, and 5-HT receptors in the calcium flux assay with the ultimate goal to generate selective 5-HT agonists. Selected compounds were studied for their functional selectivity by comparing their transduction efficiency at the G protein signaling pathway versus β-arrestin recruitment. The most functionally selective compound (+)-7e produced weak β-arrestin recruitment and also demonstrated less receptor desensitization compared to serotonin in both calcium flux and phosphoinositide (PI) hydrolysis assays. We report for the first time that selective 5-HT agonists possessing weak β-arrestin recruitment can produce distinct receptor desensitization properties.
|
Agonist activity at human 5-HT2A receptor expressed in human Flp-In-293 cells assessed as induction of calcium flux incubated for 1 hr by Fluo-4 direct dye based FLIPR assay
|
Homo sapiens
|
245.47
nM
|
|
Agonist activity at human 5-HT2A receptor expressed in human Flp-In-293 cells assessed as induction of calcium flux incubated for 1 hr by Fluo-4 direct dye based FLIPR assay
|
Homo sapiens
|
248.0
nM
|
|
Journal : J Med Chem
Title : Design and Discovery of Functionally Selective Serotonin 2C (5-HT) Receptor Agonists.
Year : 2016
Volume : 59
Issue : 21
First Page : 9866
Last Page : 9880
Authors : Cheng J,McCorvy JD,Giguere PM,Zhu H,Kenakin T,Roth BL,Kozikowski AP
Abstract : On the basis of the structural similarity of our previous 5-HT agonists with the melatonin receptor agonist tasimelteon and the putative biological cross-talk between serotonergic and melatonergic systems, a series of new (2,3-dihydro)benzofuran-based compounds were designed and synthesized. The compounds were evaluated for their selectivity toward 5-HT, 5-HT, and 5-HT receptors in the calcium flux assay with the ultimate goal to generate selective 5-HT agonists. Selected compounds were studied for their functional selectivity by comparing their transduction efficiency at the G protein signaling pathway versus β-arrestin recruitment. The most functionally selective compound (+)-7e produced weak β-arrestin recruitment and also demonstrated less receptor desensitization compared to serotonin in both calcium flux and phosphoinositide (PI) hydrolysis assays. We report for the first time that selective 5-HT agonists possessing weak β-arrestin recruitment can produce distinct receptor desensitization properties.
|
Agonist activity at human 5-HT2C INI receptor expressed in human Flp-In-293 cells assessed as induction of calcium flux incubated for 1 hr by Fluo-4 direct dye based FLIPR assay
|
Homo sapiens
|
3.467
nM
|
|
Agonist activity at human 5-HT2C INI receptor expressed in human Flp-In-293 cells assessed as induction of calcium flux incubated for 1 hr by Fluo-4 direct dye based FLIPR assay
|
Homo sapiens
|
3.4
nM
|
|
Journal : J Med Chem
Title : Design and Discovery of Functionally Selective Serotonin 2C (5-HT) Receptor Agonists.
Year : 2016
Volume : 59
Issue : 21
First Page : 9866
Last Page : 9880
Authors : Cheng J,McCorvy JD,Giguere PM,Zhu H,Kenakin T,Roth BL,Kozikowski AP
Abstract : On the basis of the structural similarity of our previous 5-HT agonists with the melatonin receptor agonist tasimelteon and the putative biological cross-talk between serotonergic and melatonergic systems, a series of new (2,3-dihydro)benzofuran-based compounds were designed and synthesized. The compounds were evaluated for their selectivity toward 5-HT, 5-HT, and 5-HT receptors in the calcium flux assay with the ultimate goal to generate selective 5-HT agonists. Selected compounds were studied for their functional selectivity by comparing their transduction efficiency at the G protein signaling pathway versus β-arrestin recruitment. The most functionally selective compound (+)-7e produced weak β-arrestin recruitment and also demonstrated less receptor desensitization compared to serotonin in both calcium flux and phosphoinositide (PI) hydrolysis assays. We report for the first time that selective 5-HT agonists possessing weak β-arrestin recruitment can produce distinct receptor desensitization properties.
|
Agonist activity at human 5-HT2C INI receptor expressed in human HEK293 cells assessed as induction of beta-arrestin-2 recruitment incubated for 20 hrs by Tango assay
|
Homo sapiens
|
58.88
nM
|
|
Agonist activity at human 5-HT2C INI receptor expressed in human HEK293 cells assessed as induction of beta-arrestin-2 recruitment incubated for 20 hrs by Tango assay
|
Homo sapiens
|
59.0
nM
|
|
Journal : J Med Chem
Title : Design and Discovery of Functionally Selective Serotonin 2C (5-HT) Receptor Agonists.
Year : 2016
Volume : 59
Issue : 21
First Page : 9866
Last Page : 9880
Authors : Cheng J,McCorvy JD,Giguere PM,Zhu H,Kenakin T,Roth BL,Kozikowski AP
Abstract : On the basis of the structural similarity of our previous 5-HT agonists with the melatonin receptor agonist tasimelteon and the putative biological cross-talk between serotonergic and melatonergic systems, a series of new (2,3-dihydro)benzofuran-based compounds were designed and synthesized. The compounds were evaluated for their selectivity toward 5-HT, 5-HT, and 5-HT receptors in the calcium flux assay with the ultimate goal to generate selective 5-HT agonists. Selected compounds were studied for their functional selectivity by comparing their transduction efficiency at the G protein signaling pathway versus β-arrestin recruitment. The most functionally selective compound (+)-7e produced weak β-arrestin recruitment and also demonstrated less receptor desensitization compared to serotonin in both calcium flux and phosphoinositide (PI) hydrolysis assays. We report for the first time that selective 5-HT agonists possessing weak β-arrestin recruitment can produce distinct receptor desensitization properties.
