|
Displacement of [3H]-spiperone from human dopamine D2L receptor expressed in CHO cell membranes after 3 hrs by liquid scintillation counting analysis
|
Homo sapiens
|
17.78
nM
|
|
Journal : J. Med. Chem.
Title : A structure-activity analysis of biased agonism at the dopamine D2 receptor.
Year : 2013
Volume : 56
Issue : 22
First Page : 9199
Last Page : 9221
Authors : Shonberg J, Herenbrink CK, López L, Christopoulos A, Scammells PJ, Capuano B, Lane JR.
Abstract : Biased agonism offers an opportunity for the medicinal chemist to discover pathway-selective ligands for GPCRs. A number of studies have suggested that biased agonism at the dopamine D2 receptor (D2R) may be advantageous for the treatment of neuropsychiatric disorders, including schizophrenia. As such, it is of great importance to gain insight into the SAR of biased agonism at this receptor. We have generated SAR based on a novel D2R partial agonist, tert-butyl (trans-4-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)carbamate (4). This ligand shares structural similarity to cariprazine (2), a drug awaiting FDA approval for the treatment of schizophrenia, yet displays a distinct bias toward two different signaling end points. We synthesized a number of derivatives of 4 with subtle structural modifications, including incorporation of cariprazine fragments. By combining pharmacological profiling with analytical methodology to identify and to quantify bias, we have demonstrated that efficacy and biased agonism can be finely tuned by minor structural modifications to the head group containing the tertiary amine, a tail group that extends away from this moiety, and the orientation and length of a spacer region between these two moieties.
|
Displacement of [3H]Spiperone from human dopamine D2 long receptor expressed in CHO cells by competitive binding assay
|
Homo sapiens
|
0.47
nM
|
|
Journal : J. Med. Chem.
Title : Functionally selective dopamine D₂, D₃ receptor partial agonists.
Year : 2014
Volume : 57
Issue : 11
First Page : 4861
Last Page : 4875
Authors : Möller D, Kling RC, Skultety M, Leuner K, Hübner H, Gmeiner P.
Abstract : Dopamine D2 receptor-promoted activation of Gα(o) over Gα(i) may increase synaptic plasticity and thereby might improve negative symptoms of schizophrenia. Heterocyclic dopamine surrogates comprising a pyrazolo[1,5-a]pyridine moiety were synthesized and investigated for their binding properties when low- to subnanomolar K(i) values were determined for D(2L), D(2S), and D3 receptors. Measurement of [(35)S]GTPγS incorporation at D(2S) coexpressed with G-protein subunits indicated significant bias for promotion of Gα(o1) over Gα(i2) coupling for several test compounds. Functionally selective D(2S) activation was most striking for the carbaldoxime 8b (Gα(o1), pEC50 = 8.87, E(max) = 65%; Gα(i2), pEC50 = 6.63, E(max) = 27%). In contrast, the investigated 1,4-disubstituted aromatic piperazines (1,4-DAPs) behaved as antagonists for β-arrestin-2 recruitment, implying significant ligand bias for G-protein activation over β-arrestin-2 recruitment at D(2S) receptors. Ligand efficacy and selectivity between D(2S) and D3 activation were strongly influenced by regiochemistry and the nature of functional groups attached to the pyrazolo[1,5-a]pyridine moiety.
|
Displacement of [3H]Spiperone from human dopamine D2 short receptor expressed in CHO cells by competitive binding assay
|
Homo sapiens
|
0.41
nM
|
|
Journal : J. Med. Chem.
Title : Functionally selective dopamine D₂, D₃ receptor partial agonists.
Year : 2014
Volume : 57
Issue : 11
First Page : 4861
Last Page : 4875
Authors : Möller D, Kling RC, Skultety M, Leuner K, Hübner H, Gmeiner P.
Abstract : Dopamine D2 receptor-promoted activation of Gα(o) over Gα(i) may increase synaptic plasticity and thereby might improve negative symptoms of schizophrenia. Heterocyclic dopamine surrogates comprising a pyrazolo[1,5-a]pyridine moiety were synthesized and investigated for their binding properties when low- to subnanomolar K(i) values were determined for D(2L), D(2S), and D3 receptors. Measurement of [(35)S]GTPγS incorporation at D(2S) coexpressed with G-protein subunits indicated significant bias for promotion of Gα(o1) over Gα(i2) coupling for several test compounds. Functionally selective D(2S) activation was most striking for the carbaldoxime 8b (Gα(o1), pEC50 = 8.87, E(max) = 65%; Gα(i2), pEC50 = 6.63, E(max) = 27%). In contrast, the investigated 1,4-disubstituted aromatic piperazines (1,4-DAPs) behaved as antagonists for β-arrestin-2 recruitment, implying significant ligand bias for G-protein activation over β-arrestin-2 recruitment at D(2S) receptors. Ligand efficacy and selectivity between D(2S) and D3 activation were strongly influenced by regiochemistry and the nature of functional groups attached to the pyrazolo[1,5-a]pyridine moiety.
|
Displacement of [3H]Spiperone from human dopamine D3 receptor expressed in CHO cells by competitive binding assay
|
Homo sapiens
|
0.27
nM
|
|
Journal : J. Med. Chem.
Title : Functionally selective dopamine D₂, D₃ receptor partial agonists.
Year : 2014
Volume : 57
Issue : 11
First Page : 4861
Last Page : 4875
Authors : Möller D, Kling RC, Skultety M, Leuner K, Hübner H, Gmeiner P.
Abstract : Dopamine D2 receptor-promoted activation of Gα(o) over Gα(i) may increase synaptic plasticity and thereby might improve negative symptoms of schizophrenia. Heterocyclic dopamine surrogates comprising a pyrazolo[1,5-a]pyridine moiety were synthesized and investigated for their binding properties when low- to subnanomolar K(i) values were determined for D(2L), D(2S), and D3 receptors. Measurement of [(35)S]GTPγS incorporation at D(2S) coexpressed with G-protein subunits indicated significant bias for promotion of Gα(o1) over Gα(i2) coupling for several test compounds. Functionally selective D(2S) activation was most striking for the carbaldoxime 8b (Gα(o1), pEC50 = 8.87, E(max) = 65%; Gα(i2), pEC50 = 6.63, E(max) = 27%). In contrast, the investigated 1,4-disubstituted aromatic piperazines (1,4-DAPs) behaved as antagonists for β-arrestin-2 recruitment, implying significant ligand bias for G-protein activation over β-arrestin-2 recruitment at D(2S) receptors. Ligand efficacy and selectivity between D(2S) and D3 activation were strongly influenced by regiochemistry and the nature of functional groups attached to the pyrazolo[1,5-a]pyridine moiety.
|
Displacement of [3H]Spiperone from human dopamine D4.4 receptor expressed in CHO cells by competitive binding assay
|
Homo sapiens
|
110.0
nM
|
|
Journal : J. Med. Chem.
Title : Functionally selective dopamine D₂, D₃ receptor partial agonists.
Year : 2014
Volume : 57
Issue : 11
First Page : 4861
Last Page : 4875
Authors : Möller D, Kling RC, Skultety M, Leuner K, Hübner H, Gmeiner P.
Abstract : Dopamine D2 receptor-promoted activation of Gα(o) over Gα(i) may increase synaptic plasticity and thereby might improve negative symptoms of schizophrenia. Heterocyclic dopamine surrogates comprising a pyrazolo[1,5-a]pyridine moiety were synthesized and investigated for their binding properties when low- to subnanomolar K(i) values were determined for D(2L), D(2S), and D3 receptors. Measurement of [(35)S]GTPγS incorporation at D(2S) coexpressed with G-protein subunits indicated significant bias for promotion of Gα(o1) over Gα(i2) coupling for several test compounds. Functionally selective D(2S) activation was most striking for the carbaldoxime 8b (Gα(o1), pEC50 = 8.87, E(max) = 65%; Gα(i2), pEC50 = 6.63, E(max) = 27%). In contrast, the investigated 1,4-disubstituted aromatic piperazines (1,4-DAPs) behaved as antagonists for β-arrestin-2 recruitment, implying significant ligand bias for G-protein activation over β-arrestin-2 recruitment at D(2S) receptors. Ligand efficacy and selectivity between D(2S) and D3 activation were strongly influenced by regiochemistry and the nature of functional groups attached to the pyrazolo[1,5-a]pyridine moiety.
|
Displacement of [3H]WAY-100635 from 5-HT1A receptor in pig cerebral cortex homogenates by competitive binding assay
|
Sus scrofa
|
0.49
nM
|
|
Journal : J. Med. Chem.
Title : Functionally selective dopamine D₂, D₃ receptor partial agonists.
Year : 2014
Volume : 57
Issue : 11
First Page : 4861
Last Page : 4875
Authors : Möller D, Kling RC, Skultety M, Leuner K, Hübner H, Gmeiner P.
Abstract : Dopamine D2 receptor-promoted activation of Gα(o) over Gα(i) may increase synaptic plasticity and thereby might improve negative symptoms of schizophrenia. Heterocyclic dopamine surrogates comprising a pyrazolo[1,5-a]pyridine moiety were synthesized and investigated for their binding properties when low- to subnanomolar K(i) values were determined for D(2L), D(2S), and D3 receptors. Measurement of [(35)S]GTPγS incorporation at D(2S) coexpressed with G-protein subunits indicated significant bias for promotion of Gα(o1) over Gα(i2) coupling for several test compounds. Functionally selective D(2S) activation was most striking for the carbaldoxime 8b (Gα(o1), pEC50 = 8.87, E(max) = 65%; Gα(i2), pEC50 = 6.63, E(max) = 27%). In contrast, the investigated 1,4-disubstituted aromatic piperazines (1,4-DAPs) behaved as antagonists for β-arrestin-2 recruitment, implying significant ligand bias for G-protein activation over β-arrestin-2 recruitment at D(2S) receptors. Ligand efficacy and selectivity between D(2S) and D3 activation were strongly influenced by regiochemistry and the nature of functional groups attached to the pyrazolo[1,5-a]pyridine moiety.
|
Displacement of [3H]-ketanserin from human 5HT2A receptor expressed in HEK293 cells by competitive binding assay
|
Homo sapiens
|
22.0
nM
|
|
Journal : J. Med. Chem.
Title : Functionally selective dopamine D₂, D₃ receptor partial agonists.
Year : 2014
Volume : 57
Issue : 11
First Page : 4861
Last Page : 4875
Authors : Möller D, Kling RC, Skultety M, Leuner K, Hübner H, Gmeiner P.
Abstract : Dopamine D2 receptor-promoted activation of Gα(o) over Gα(i) may increase synaptic plasticity and thereby might improve negative symptoms of schizophrenia. Heterocyclic dopamine surrogates comprising a pyrazolo[1,5-a]pyridine moiety were synthesized and investigated for their binding properties when low- to subnanomolar K(i) values were determined for D(2L), D(2S), and D3 receptors. Measurement of [(35)S]GTPγS incorporation at D(2S) coexpressed with G-protein subunits indicated significant bias for promotion of Gα(o1) over Gα(i2) coupling for several test compounds. Functionally selective D(2S) activation was most striking for the carbaldoxime 8b (Gα(o1), pEC50 = 8.87, E(max) = 65%; Gα(i2), pEC50 = 6.63, E(max) = 27%). In contrast, the investigated 1,4-disubstituted aromatic piperazines (1,4-DAPs) behaved as antagonists for β-arrestin-2 recruitment, implying significant ligand bias for G-protein activation over β-arrestin-2 recruitment at D(2S) receptors. Ligand efficacy and selectivity between D(2S) and D3 activation were strongly influenced by regiochemistry and the nature of functional groups attached to the pyrazolo[1,5-a]pyridine moiety.
|
Displacement of [3Hprazosin from adrenergic alpha1 receptor in pig cerebral cortex homogenates by competitive binding assay
|
Sus scrofa
|
70.0
nM
|
|
Displacement of [3Hprazosin from adrenergic alpha1 receptor in pig cerebral cortex homogenates by competitive binding assay
|
Sus scrofa
|
3.09
nM
|
|
Displacement of [3Hprazosin from adrenergic alpha1 receptor in pig cerebral cortex homogenates by competitive binding assay
|
Sus scrofa
|
3.1
nM
|
|
Journal : J. Med. Chem.
Title : Functionally selective dopamine D₂, D₃ receptor partial agonists.
Year : 2014
Volume : 57
Issue : 11
First Page : 4861
Last Page : 4875
Authors : Möller D, Kling RC, Skultety M, Leuner K, Hübner H, Gmeiner P.
Abstract : Dopamine D2 receptor-promoted activation of Gα(o) over Gα(i) may increase synaptic plasticity and thereby might improve negative symptoms of schizophrenia. Heterocyclic dopamine surrogates comprising a pyrazolo[1,5-a]pyridine moiety were synthesized and investigated for their binding properties when low- to subnanomolar K(i) values were determined for D(2L), D(2S), and D3 receptors. Measurement of [(35)S]GTPγS incorporation at D(2S) coexpressed with G-protein subunits indicated significant bias for promotion of Gα(o1) over Gα(i2) coupling for several test compounds. Functionally selective D(2S) activation was most striking for the carbaldoxime 8b (Gα(o1), pEC50 = 8.87, E(max) = 65%; Gα(i2), pEC50 = 6.63, E(max) = 27%). In contrast, the investigated 1,4-disubstituted aromatic piperazines (1,4-DAPs) behaved as antagonists for β-arrestin-2 recruitment, implying significant ligand bias for G-protein activation over β-arrestin-2 recruitment at D(2S) receptors. Ligand efficacy and selectivity between D(2S) and D3 activation were strongly influenced by regiochemistry and the nature of functional groups attached to the pyrazolo[1,5-a]pyridine moiety.
|
Agonist activity at human dopamine D2 short receptor transiently expressed in HEK293 cells co-expressing Galphai2 after 30 mins by [35S]GTPgammaS binding assay
|
Homo sapiens
|
112.2
nM
|
|
Agonist activity at human dopamine D2 short receptor transiently expressed in HEK293 cells co-expressing Galphai2 after 30 mins by [35S]GTPgammaS binding assay
|
Homo sapiens
|
110.0
nM
|
|
Journal : J. Med. Chem.
Title : Functionally selective dopamine D₂, D₃ receptor partial agonists.
Year : 2014
Volume : 57
Issue : 11
First Page : 4861
Last Page : 4875
Authors : Möller D, Kling RC, Skultety M, Leuner K, Hübner H, Gmeiner P.
Abstract : Dopamine D2 receptor-promoted activation of Gα(o) over Gα(i) may increase synaptic plasticity and thereby might improve negative symptoms of schizophrenia. Heterocyclic dopamine surrogates comprising a pyrazolo[1,5-a]pyridine moiety were synthesized and investigated for their binding properties when low- to subnanomolar K(i) values were determined for D(2L), D(2S), and D3 receptors. Measurement of [(35)S]GTPγS incorporation at D(2S) coexpressed with G-protein subunits indicated significant bias for promotion of Gα(o1) over Gα(i2) coupling for several test compounds. Functionally selective D(2S) activation was most striking for the carbaldoxime 8b (Gα(o1), pEC50 = 8.87, E(max) = 65%; Gα(i2), pEC50 = 6.63, E(max) = 27%). In contrast, the investigated 1,4-disubstituted aromatic piperazines (1,4-DAPs) behaved as antagonists for β-arrestin-2 recruitment, implying significant ligand bias for G-protein activation over β-arrestin-2 recruitment at D(2S) receptors. Ligand efficacy and selectivity between D(2S) and D3 activation were strongly influenced by regiochemistry and the nature of functional groups attached to the pyrazolo[1,5-a]pyridine moiety.
|
Agonist activity at human dopamine D3 receptor transiently expressed in HEK293 cells co-expressing Galphao1 after 30 mins by [35S]GTPgammaS binding assay
|
Homo sapiens
|
5.754
nM
|
|
Agonist activity at human dopamine D3 receptor transiently expressed in HEK293 cells co-expressing Galphao1 after 30 mins by [35S]GTPgammaS binding assay
|
Homo sapiens
|
5.8
nM
|
|
Journal : J. Med. Chem.
Title : Functionally selective dopamine D₂, D₃ receptor partial agonists.
Year : 2014
Volume : 57
Issue : 11
First Page : 4861
Last Page : 4875
Authors : Möller D, Kling RC, Skultety M, Leuner K, Hübner H, Gmeiner P.
Abstract : Dopamine D2 receptor-promoted activation of Gα(o) over Gα(i) may increase synaptic plasticity and thereby might improve negative symptoms of schizophrenia. Heterocyclic dopamine surrogates comprising a pyrazolo[1,5-a]pyridine moiety were synthesized and investigated for their binding properties when low- to subnanomolar K(i) values were determined for D(2L), D(2S), and D3 receptors. Measurement of [(35)S]GTPγS incorporation at D(2S) coexpressed with G-protein subunits indicated significant bias for promotion of Gα(o1) over Gα(i2) coupling for several test compounds. Functionally selective D(2S) activation was most striking for the carbaldoxime 8b (Gα(o1), pEC50 = 8.87, E(max) = 65%; Gα(i2), pEC50 = 6.63, E(max) = 27%). In contrast, the investigated 1,4-disubstituted aromatic piperazines (1,4-DAPs) behaved as antagonists for β-arrestin-2 recruitment, implying significant ligand bias for G-protein activation over β-arrestin-2 recruitment at D(2S) receptors. Ligand efficacy and selectivity between D(2S) and D3 activation were strongly influenced by regiochemistry and the nature of functional groups attached to the pyrazolo[1,5-a]pyridine moiety.
|
Antagonist activity at human dopamine D2 short receptor transiently expressed in HEK293 cells assessed as inhibition of beta-arrestin recruitment after 6 hrs by chemiluminescence assay
|
Homo sapiens
|
1.66
nM
|
|
Antagonist activity at human dopamine D2 short receptor transiently expressed in HEK293 cells assessed as inhibition of beta-arrestin recruitment after 6 hrs by chemiluminescence assay
|
Homo sapiens
|
1.7
nM
|
|
Journal : J. Med. Chem.
Title : Functionally selective dopamine D₂, D₃ receptor partial agonists.
Year : 2014
Volume : 57
Issue : 11
First Page : 4861
Last Page : 4875
Authors : Möller D, Kling RC, Skultety M, Leuner K, Hübner H, Gmeiner P.
Abstract : Dopamine D2 receptor-promoted activation of Gα(o) over Gα(i) may increase synaptic plasticity and thereby might improve negative symptoms of schizophrenia. Heterocyclic dopamine surrogates comprising a pyrazolo[1,5-a]pyridine moiety were synthesized and investigated for their binding properties when low- to subnanomolar K(i) values were determined for D(2L), D(2S), and D3 receptors. Measurement of [(35)S]GTPγS incorporation at D(2S) coexpressed with G-protein subunits indicated significant bias for promotion of Gα(o1) over Gα(i2) coupling for several test compounds. Functionally selective D(2S) activation was most striking for the carbaldoxime 8b (Gα(o1), pEC50 = 8.87, E(max) = 65%; Gα(i2), pEC50 = 6.63, E(max) = 27%). In contrast, the investigated 1,4-disubstituted aromatic piperazines (1,4-DAPs) behaved as antagonists for β-arrestin-2 recruitment, implying significant ligand bias for G-protein activation over β-arrestin-2 recruitment at D(2S) receptors. Ligand efficacy and selectivity between D(2S) and D3 activation were strongly influenced by regiochemistry and the nature of functional groups attached to the pyrazolo[1,5-a]pyridine moiety.
|
Partial agonist activity at human dopamine D2 short receptor transiently expressed in HEK293 cells assessed as inhibition of beta-arrestin recruitment after 6 hrs by chemiluminescence assay
|
Homo sapiens
|
3.467
nM
|
|
Journal : J. Med. Chem.
Title : Functionally selective dopamine D₂, D₃ receptor partial agonists.
Year : 2014
Volume : 57
Issue : 11
First Page : 4861
Last Page : 4875
Authors : Möller D, Kling RC, Skultety M, Leuner K, Hübner H, Gmeiner P.
Abstract : Dopamine D2 receptor-promoted activation of Gα(o) over Gα(i) may increase synaptic plasticity and thereby might improve negative symptoms of schizophrenia. Heterocyclic dopamine surrogates comprising a pyrazolo[1,5-a]pyridine moiety were synthesized and investigated for their binding properties when low- to subnanomolar K(i) values were determined for D(2L), D(2S), and D3 receptors. Measurement of [(35)S]GTPγS incorporation at D(2S) coexpressed with G-protein subunits indicated significant bias for promotion of Gα(o1) over Gα(i2) coupling for several test compounds. Functionally selective D(2S) activation was most striking for the carbaldoxime 8b (Gα(o1), pEC50 = 8.87, E(max) = 65%; Gα(i2), pEC50 = 6.63, E(max) = 27%). In contrast, the investigated 1,4-disubstituted aromatic piperazines (1,4-DAPs) behaved as antagonists for β-arrestin-2 recruitment, implying significant ligand bias for G-protein activation over β-arrestin-2 recruitment at D(2S) receptors. Ligand efficacy and selectivity between D(2S) and D3 activation were strongly influenced by regiochemistry and the nature of functional groups attached to the pyrazolo[1,5-a]pyridine moiety.
|
Displacement of [3H]spiperone from recombinant human D2L receptor expressed in CHO cell membranes after 60 mins by scintillation counting method
|
Homo sapiens
|
1.3
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and pharmacological characterization of novel N-(trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)amides as potential multireceptor atypical antipsychotics.
Year : 2016
Volume : 123
First Page : 332
Last Page : 353
Authors : Chen XW, Sun YY, Fu L, Li JQ.
Abstract : A series of novel benzisothiazolylpiperazine derivatives combining potent dopamine D2 and D3, and serotonin 5-HT1A and 5-HT2A receptor properties were synthesized and evaluated for their potential antipsychotic properties. The most-promising derivative was 9j. The unique pharmacological features of 9j were a high affinity for D2, D3, 5-HT1A, and 5-HT2A receptors, together with a 20-fold selectivity for the D3 versus D2 subtype, and a low affinity for muscarinic M1 (reducing the risk of anticholinergic side effects), and for hERG channels (reducing incidence of QT interval prolongation). In animal behavioral models, 9j inhibited the locomotor-stimulating effects of phencyclidine, blocked conditioned avoidance response, and improved the cognitive deficit in the novel object recognition tests in rats. 9j exhibited a low potential for catalepsy, consistent with results with risperidone. In addition, favorable brain penetration of 9j in rats was detected. These studies have demonstrated that 9j is a potential atypical antipsychotic candidate.
|
Displacement of [3H]methyl-spiperone from recombinant human D3 receptor expressed in CHO cell membranes after 60 mins by scintillation counting method
|
Homo sapiens
|
0.096
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and pharmacological characterization of novel N-(trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)amides as potential multireceptor atypical antipsychotics.
Year : 2016
Volume : 123
First Page : 332
Last Page : 353
Authors : Chen XW, Sun YY, Fu L, Li JQ.
Abstract : A series of novel benzisothiazolylpiperazine derivatives combining potent dopamine D2 and D3, and serotonin 5-HT1A and 5-HT2A receptor properties were synthesized and evaluated for their potential antipsychotic properties. The most-promising derivative was 9j. The unique pharmacological features of 9j were a high affinity for D2, D3, 5-HT1A, and 5-HT2A receptors, together with a 20-fold selectivity for the D3 versus D2 subtype, and a low affinity for muscarinic M1 (reducing the risk of anticholinergic side effects), and for hERG channels (reducing incidence of QT interval prolongation). In animal behavioral models, 9j inhibited the locomotor-stimulating effects of phencyclidine, blocked conditioned avoidance response, and improved the cognitive deficit in the novel object recognition tests in rats. 9j exhibited a low potential for catalepsy, consistent with results with risperidone. In addition, favorable brain penetration of 9j in rats was detected. These studies have demonstrated that 9j is a potential atypical antipsychotic candidate.
|
Displacement of [3H]8-OH-DPAT from recombinant human 5-HT1A receptor expressed in HEK293 cell membranes after 60 mins by scintillation counting method
|
Homo sapiens
|
3.1
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and pharmacological characterization of novel N-(trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)amides as potential multireceptor atypical antipsychotics.
Year : 2016
Volume : 123
First Page : 332
Last Page : 353
Authors : Chen XW, Sun YY, Fu L, Li JQ.
Abstract : A series of novel benzisothiazolylpiperazine derivatives combining potent dopamine D2 and D3, and serotonin 5-HT1A and 5-HT2A receptor properties were synthesized and evaluated for their potential antipsychotic properties. The most-promising derivative was 9j. The unique pharmacological features of 9j were a high affinity for D2, D3, 5-HT1A, and 5-HT2A receptors, together with a 20-fold selectivity for the D3 versus D2 subtype, and a low affinity for muscarinic M1 (reducing the risk of anticholinergic side effects), and for hERG channels (reducing incidence of QT interval prolongation). In animal behavioral models, 9j inhibited the locomotor-stimulating effects of phencyclidine, blocked conditioned avoidance response, and improved the cognitive deficit in the novel object recognition tests in rats. 9j exhibited a low potential for catalepsy, consistent with results with risperidone. In addition, favorable brain penetration of 9j in rats was detected. These studies have demonstrated that 9j is a potential atypical antipsychotic candidate.
|
Displacement of [3H]ketanserin from recombinant human 5-HT2A receptor expressed in HEK293 cell membranes after 60 mins by scintillation counting method
|
Homo sapiens
|
23.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and pharmacological characterization of novel N-(trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)amides as potential multireceptor atypical antipsychotics.
Year : 2016
Volume : 123
First Page : 332
Last Page : 353
Authors : Chen XW, Sun YY, Fu L, Li JQ.
Abstract : A series of novel benzisothiazolylpiperazine derivatives combining potent dopamine D2 and D3, and serotonin 5-HT1A and 5-HT2A receptor properties were synthesized and evaluated for their potential antipsychotic properties. The most-promising derivative was 9j. The unique pharmacological features of 9j were a high affinity for D2, D3, 5-HT1A, and 5-HT2A receptors, together with a 20-fold selectivity for the D3 versus D2 subtype, and a low affinity for muscarinic M1 (reducing the risk of anticholinergic side effects), and for hERG channels (reducing incidence of QT interval prolongation). In animal behavioral models, 9j inhibited the locomotor-stimulating effects of phencyclidine, blocked conditioned avoidance response, and improved the cognitive deficit in the novel object recognition tests in rats. 9j exhibited a low potential for catalepsy, consistent with results with risperidone. In addition, favorable brain penetration of 9j in rats was detected. These studies have demonstrated that 9j is a potential atypical antipsychotic candidate.
|
Displacement of [3H]pirenzepine from recombinant human M1 receptor expressed in CHO cell membranes at 1 uM after 60 mins by scintillation counting method relative to control
|
Homo sapiens
|
20.0
%
|
|
Journal : Eur J Med Chem
Title : Synthesis and pharmacological characterization of novel N-(trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)amides as potential multireceptor atypical antipsychotics.
Year : 2016
Volume : 123
First Page : 332
Last Page : 353
Authors : Chen XW, Sun YY, Fu L, Li JQ.
Abstract : A series of novel benzisothiazolylpiperazine derivatives combining potent dopamine D2 and D3, and serotonin 5-HT1A and 5-HT2A receptor properties were synthesized and evaluated for their potential antipsychotic properties. The most-promising derivative was 9j. The unique pharmacological features of 9j were a high affinity for D2, D3, 5-HT1A, and 5-HT2A receptors, together with a 20-fold selectivity for the D3 versus D2 subtype, and a low affinity for muscarinic M1 (reducing the risk of anticholinergic side effects), and for hERG channels (reducing incidence of QT interval prolongation). In animal behavioral models, 9j inhibited the locomotor-stimulating effects of phencyclidine, blocked conditioned avoidance response, and improved the cognitive deficit in the novel object recognition tests in rats. 9j exhibited a low potential for catalepsy, consistent with results with risperidone. In addition, favorable brain penetration of 9j in rats was detected. These studies have demonstrated that 9j is a potential atypical antipsychotic candidate.
|
Displacement of [3H]Spiperone from dopamine D3 receptor (unknown origin)
|
Homo sapiens
|
0.085
nM
|
|
Journal : J Med Chem
Title : Synthetic Approaches to the New Drugs Approved During 2015.
Year : 2017
Volume : 60
Issue : 15
First Page : 6480
Last Page : 6515
Authors : Flick AC, Ding HX, Leverett CA, Kyne RE, Liu KK, Fink SJ, O'Donnell CJ.
Abstract : New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition while serving as leads for designing future new drugs. This annual review describes the most likely process-scale synthetic approaches to 29 new chemical entities (NCEs) that were approved for the first time in 2015.
|
Displacement of [3H]Spiperone from human dopamine D2L receptor expressed in CHO cells
|
Homo sapiens
|
0.49
nM
|
|
Journal : J Med Chem
Title : Synthetic Approaches to the New Drugs Approved During 2015.
Year : 2017
Volume : 60
Issue : 15
First Page : 6480
Last Page : 6515
Authors : Flick AC, Ding HX, Leverett CA, Kyne RE, Liu KK, Fink SJ, O'Donnell CJ.
Abstract : New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition while serving as leads for designing future new drugs. This annual review describes the most likely process-scale synthetic approaches to 29 new chemical entities (NCEs) that were approved for the first time in 2015.
|
Displacement of [3H]Spiperone from human D2S receptor expressed in CHO cells
|
Homo sapiens
|
0.69
nM
|
|
Journal : J Med Chem
Title : Synthetic Approaches to the New Drugs Approved During 2015.
Year : 2017
Volume : 60
Issue : 15
First Page : 6480
Last Page : 6515
Authors : Flick AC, Ding HX, Leverett CA, Kyne RE, Liu KK, Fink SJ, O'Donnell CJ.
Abstract : New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition while serving as leads for designing future new drugs. This annual review describes the most likely process-scale synthetic approaches to 29 new chemical entities (NCEs) that were approved for the first time in 2015.
|
Displacement of [3H]spiperone from human D2-long receptor expressed in CHO cell membranes
|
Homo sapiens
|
0.47
nM
|
|
Journal : Bioorg Med Chem
Title : Development of molecular tools based on the dopamine D3 receptor ligand FAUC 329 showing inhibiting effects on drug and food maintained behavior.
Year : 2017
Volume : 25
Issue : 13
First Page : 3491
Last Page : 3499
Authors : Stößel A, Brox R, Purkayastha N, Hübner H, Hocke C, Prante O, Gmeiner P.
Abstract : Dopamine D3 receptor-mediated networks have been associated with a wide range of neuropsychiatric diseases, drug addiction and food maintained behavior, which makes D3 a highly promising biological target. The previously described dopamine D3 receptor ligand FAUC 329 (1) showed protective effects against dopamine depletion in a MPTP mouse model of Parkinson's disease. We used the radioligand [18F]2, a [18F]fluoroethoxy substituted analog of the lead compound 1 as a molecular tool for visualization of D3-rich brain regions including the islands of Calleja. Furthermore, structural modifications are reported leading to the pyrimidylpiperazine derivatives 3 and 9 displaying superior subtype selectivity and preference over serotonergic receptors. Evaluation of the lead compound 1 on cocaine-seeking behavior in non-human primates showed a substantial reduction in cocaine self-administration behavior and food intake.
|
Displacement of [3H]spiperone from human D2-short receptor expressed in CHO cell membranes
|
Homo sapiens
|
0.41
nM
|
|
Journal : Bioorg Med Chem
Title : Development of molecular tools based on the dopamine D3 receptor ligand FAUC 329 showing inhibiting effects on drug and food maintained behavior.
Year : 2017
Volume : 25
Issue : 13
First Page : 3491
Last Page : 3499
Authors : Stößel A, Brox R, Purkayastha N, Hübner H, Hocke C, Prante O, Gmeiner P.
Abstract : Dopamine D3 receptor-mediated networks have been associated with a wide range of neuropsychiatric diseases, drug addiction and food maintained behavior, which makes D3 a highly promising biological target. The previously described dopamine D3 receptor ligand FAUC 329 (1) showed protective effects against dopamine depletion in a MPTP mouse model of Parkinson's disease. We used the radioligand [18F]2, a [18F]fluoroethoxy substituted analog of the lead compound 1 as a molecular tool for visualization of D3-rich brain regions including the islands of Calleja. Furthermore, structural modifications are reported leading to the pyrimidylpiperazine derivatives 3 and 9 displaying superior subtype selectivity and preference over serotonergic receptors. Evaluation of the lead compound 1 on cocaine-seeking behavior in non-human primates showed a substantial reduction in cocaine self-administration behavior and food intake.
|
Displacement of [3H]spiperone from human D3 receptor expressed in CHO cell membranes
|
Homo sapiens
|
0.27
nM
|
|
Journal : Bioorg Med Chem
Title : Development of molecular tools based on the dopamine D3 receptor ligand FAUC 329 showing inhibiting effects on drug and food maintained behavior.
Year : 2017
Volume : 25
Issue : 13
First Page : 3491
Last Page : 3499
Authors : Stößel A, Brox R, Purkayastha N, Hübner H, Hocke C, Prante O, Gmeiner P.
Abstract : Dopamine D3 receptor-mediated networks have been associated with a wide range of neuropsychiatric diseases, drug addiction and food maintained behavior, which makes D3 a highly promising biological target. The previously described dopamine D3 receptor ligand FAUC 329 (1) showed protective effects against dopamine depletion in a MPTP mouse model of Parkinson's disease. We used the radioligand [18F]2, a [18F]fluoroethoxy substituted analog of the lead compound 1 as a molecular tool for visualization of D3-rich brain regions including the islands of Calleja. Furthermore, structural modifications are reported leading to the pyrimidylpiperazine derivatives 3 and 9 displaying superior subtype selectivity and preference over serotonergic receptors. Evaluation of the lead compound 1 on cocaine-seeking behavior in non-human primates showed a substantial reduction in cocaine self-administration behavior and food intake.
|
Displacement of [3H]spiperone from human D4 receptor expressed in CHO cell membranes
|
Homo sapiens
|
110.0
nM
|
|
Journal : Bioorg Med Chem
Title : Development of molecular tools based on the dopamine D3 receptor ligand FAUC 329 showing inhibiting effects on drug and food maintained behavior.
Year : 2017
Volume : 25
Issue : 13
First Page : 3491
Last Page : 3499
Authors : Stößel A, Brox R, Purkayastha N, Hübner H, Hocke C, Prante O, Gmeiner P.
Abstract : Dopamine D3 receptor-mediated networks have been associated with a wide range of neuropsychiatric diseases, drug addiction and food maintained behavior, which makes D3 a highly promising biological target. The previously described dopamine D3 receptor ligand FAUC 329 (1) showed protective effects against dopamine depletion in a MPTP mouse model of Parkinson's disease. We used the radioligand [18F]2, a [18F]fluoroethoxy substituted analog of the lead compound 1 as a molecular tool for visualization of D3-rich brain regions including the islands of Calleja. Furthermore, structural modifications are reported leading to the pyrimidylpiperazine derivatives 3 and 9 displaying superior subtype selectivity and preference over serotonergic receptors. Evaluation of the lead compound 1 on cocaine-seeking behavior in non-human primates showed a substantial reduction in cocaine self-administration behavior and food intake.
|
Displacement of [3H]WAY600135 from porcine cerebral cortex 5-HT1A receptor
|
Sus scrofa
|
0.49
nM
|
|
Journal : Bioorg Med Chem
Title : Development of molecular tools based on the dopamine D3 receptor ligand FAUC 329 showing inhibiting effects on drug and food maintained behavior.
Year : 2017
Volume : 25
Issue : 13
First Page : 3491
Last Page : 3499
Authors : Stößel A, Brox R, Purkayastha N, Hübner H, Hocke C, Prante O, Gmeiner P.
Abstract : Dopamine D3 receptor-mediated networks have been associated with a wide range of neuropsychiatric diseases, drug addiction and food maintained behavior, which makes D3 a highly promising biological target. The previously described dopamine D3 receptor ligand FAUC 329 (1) showed protective effects against dopamine depletion in a MPTP mouse model of Parkinson's disease. We used the radioligand [18F]2, a [18F]fluoroethoxy substituted analog of the lead compound 1 as a molecular tool for visualization of D3-rich brain regions including the islands of Calleja. Furthermore, structural modifications are reported leading to the pyrimidylpiperazine derivatives 3 and 9 displaying superior subtype selectivity and preference over serotonergic receptors. Evaluation of the lead compound 1 on cocaine-seeking behavior in non-human primates showed a substantial reduction in cocaine self-administration behavior and food intake.
|
Displacement of [3H]ketanserin from human 5-HT2A receptor expressed in HEK293T cell membranes
|
Homo sapiens
|
22.0
nM
|
|
Journal : Bioorg Med Chem
Title : Development of molecular tools based on the dopamine D3 receptor ligand FAUC 329 showing inhibiting effects on drug and food maintained behavior.
Year : 2017
Volume : 25
Issue : 13
First Page : 3491
Last Page : 3499
Authors : Stößel A, Brox R, Purkayastha N, Hübner H, Hocke C, Prante O, Gmeiner P.
Abstract : Dopamine D3 receptor-mediated networks have been associated with a wide range of neuropsychiatric diseases, drug addiction and food maintained behavior, which makes D3 a highly promising biological target. The previously described dopamine D3 receptor ligand FAUC 329 (1) showed protective effects against dopamine depletion in a MPTP mouse model of Parkinson's disease. We used the radioligand [18F]2, a [18F]fluoroethoxy substituted analog of the lead compound 1 as a molecular tool for visualization of D3-rich brain regions including the islands of Calleja. Furthermore, structural modifications are reported leading to the pyrimidylpiperazine derivatives 3 and 9 displaying superior subtype selectivity and preference over serotonergic receptors. Evaluation of the lead compound 1 on cocaine-seeking behavior in non-human primates showed a substantial reduction in cocaine self-administration behavior and food intake.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
5.46
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Displacement of [3H]-8-OH-DPAT from human 5HT1A receptor expressed in CHO-K1 cell membranes incubated for 60 mins by microbeta scintillation counting analysis
|
Homo sapiens
|
2.6
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of new multi-target 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives with potential antidepressant effect.
Year : 2019
Volume : 183
First Page : 111736
Last Page : 111736
Authors : Wróbel MZ, Chodkowski A, Herold F, Marciniak M, Dawidowski M, Siwek A, Starowicz G, Stachowicz K, Szewczyk B, Nowak G, Belka M, Bączek T, Satała G, Bojarski AJ, Turło J.
Abstract : A series of novel 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives were synthesised and evaluated for their 5-HT<sub>1A</sub>/D<sub>2</sub>/5-HT<sub>2A</sub>/5-HT<sub>6</sub>/5-HT<sub>7</sub> receptor affinity and serotonin reuptake inhibition. Most of the evaluated compounds displayed high affinities for 5-HT<sub>1A</sub> receptors (e.g., 4cK<sub>i</sub> = 2.3 nM, 4lK<sub>i</sub> = 3.2 nM). The antidepressant activity of the selected compounds was screened in vivo using the forced swim test (FST). The results indicate that compound MW005 (agonist of the pre- and postsynaptic 5-HT<sub>1A</sub> receptor) exhibited promising affinities for the 5-HT<sub>1A</sub>/SERT/D<sub>2</sub>/5-HT<sub>6</sub>/5-HT<sub>7</sub> receptors and showed an antidepressant-like activity in the FST model.
|
Displacement of [3H]-Ketanserin from human 5-HT2A receptor expressed in rat cortex tissue incubated for 30 mins by liquid scintillation counting method
|
Homo sapiens
|
18.8
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of new multi-target 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives with potential antidepressant effect.
Year : 2019
Volume : 183
First Page : 111736
Last Page : 111736
Authors : Wróbel MZ, Chodkowski A, Herold F, Marciniak M, Dawidowski M, Siwek A, Starowicz G, Stachowicz K, Szewczyk B, Nowak G, Belka M, Bączek T, Satała G, Bojarski AJ, Turło J.
Abstract : A series of novel 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives were synthesised and evaluated for their 5-HT<sub>1A</sub>/D<sub>2</sub>/5-HT<sub>2A</sub>/5-HT<sub>6</sub>/5-HT<sub>7</sub> receptor affinity and serotonin reuptake inhibition. Most of the evaluated compounds displayed high affinities for 5-HT<sub>1A</sub> receptors (e.g., 4cK<sub>i</sub> = 2.3 nM, 4lK<sub>i</sub> = 3.2 nM). The antidepressant activity of the selected compounds was screened in vivo using the forced swim test (FST). The results indicate that compound MW005 (agonist of the pre- and postsynaptic 5-HT<sub>1A</sub> receptor) exhibited promising affinities for the 5-HT<sub>1A</sub>/SERT/D<sub>2</sub>/5-HT<sub>6</sub>/5-HT<sub>7</sub> receptors and showed an antidepressant-like activity in the FST model.
|
Displacement of [3H]-raclopride from human D2L receptor expressed in HEK293 cells incubated for 1 hr by liquid scintillation counting method
|
Homo sapiens
|
0.49
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of new multi-target 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives with potential antidepressant effect.
Year : 2019
Volume : 183
First Page : 111736
Last Page : 111736
Authors : Wróbel MZ, Chodkowski A, Herold F, Marciniak M, Dawidowski M, Siwek A, Starowicz G, Stachowicz K, Szewczyk B, Nowak G, Belka M, Bączek T, Satała G, Bojarski AJ, Turło J.
Abstract : A series of novel 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives were synthesised and evaluated for their 5-HT<sub>1A</sub>/D<sub>2</sub>/5-HT<sub>2A</sub>/5-HT<sub>6</sub>/5-HT<sub>7</sub> receptor affinity and serotonin reuptake inhibition. Most of the evaluated compounds displayed high affinities for 5-HT<sub>1A</sub> receptors (e.g., 4cK<sub>i</sub> = 2.3 nM, 4lK<sub>i</sub> = 3.2 nM). The antidepressant activity of the selected compounds was screened in vivo using the forced swim test (FST). The results indicate that compound MW005 (agonist of the pre- and postsynaptic 5-HT<sub>1A</sub> receptor) exhibited promising affinities for the 5-HT<sub>1A</sub>/SERT/D<sub>2</sub>/5-HT<sub>6</sub>/5-HT<sub>7</sub> receptors and showed an antidepressant-like activity in the FST model.
|
Displacement of [3H]-5-CT from human 5HT7 receptor expressed in HEK293 cells incubated for 1 hr by liquid scintillation counting method
|
Homo sapiens
|
111.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of new multi-target 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives with potential antidepressant effect.
Year : 2019
Volume : 183
First Page : 111736
Last Page : 111736
Authors : Wróbel MZ, Chodkowski A, Herold F, Marciniak M, Dawidowski M, Siwek A, Starowicz G, Stachowicz K, Szewczyk B, Nowak G, Belka M, Bączek T, Satała G, Bojarski AJ, Turło J.
Abstract : A series of novel 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives were synthesised and evaluated for their 5-HT<sub>1A</sub>/D<sub>2</sub>/5-HT<sub>2A</sub>/5-HT<sub>6</sub>/5-HT<sub>7</sub> receptor affinity and serotonin reuptake inhibition. Most of the evaluated compounds displayed high affinities for 5-HT<sub>1A</sub> receptors (e.g., 4cK<sub>i</sub> = 2.3 nM, 4lK<sub>i</sub> = 3.2 nM). The antidepressant activity of the selected compounds was screened in vivo using the forced swim test (FST). The results indicate that compound MW005 (agonist of the pre- and postsynaptic 5-HT<sub>1A</sub> receptor) exhibited promising affinities for the 5-HT<sub>1A</sub>/SERT/D<sub>2</sub>/5-HT<sub>6</sub>/5-HT<sub>7</sub> receptors and showed an antidepressant-like activity in the FST model.
|
Partial agonist activity at human Gi/o-coupled D2R expressed in HEK293T cells assessed as inhibition of isoproterenol-induced cAMP accumulation preincubated for 15 mins followed by isoproterenol-stimulation and measured by Glosensor-based luminescence assay
|
Homo sapiens
|
0.4
nM
|
|
Partial agonist activity at human Gi/o-coupled D2R expressed in HEK293T cells assessed as inhibition of isoproterenol-induced cAMP accumulation preincubated for 15 mins followed by isoproterenol-stimulation and measured by Glosensor-based luminescence assay
|
Homo sapiens
|
0.4467
nM
|
|
Journal : J Med Chem
Title : D<sub>2</sub> Dopamine Receptor G Protein-Biased Partial Agonists Based on Cariprazine.
Year : 2019
Volume : 62
Issue : 9
First Page : 4755
Last Page : 4771
Authors : Shen Y, McCorvy JD, Martini ML, Rodriguiz RM, Pogorelov VM, Ward KM, Wetsel WC, Liu J, Roth BL, Jin J.
Abstract : Functionally selective G protein-coupled receptor ligands are valuable tools for deciphering the roles of downstream signaling pathways that potentially contribute to therapeutic effects versus side effects. Recently, we discovered both G<sub>i/o</sub>-biased and β-arrestin2-biased D<sub>2</sub> receptor agonists based on the Food and Drug Administration (FDA)-approved drug aripiprazole. In this work, based on another FDA-approved drug, cariprazine, we conducted a structure-functional selectivity relationship study and discovered compound 38 (MS1768) as a potent partial agonist that selectively activates the G<sub>i/o</sub> pathway over β-arrestin2. Unlike the dual D<sub>2</sub>R/D<sub>3</sub>R partial agonist cariprazine, compound 38 showed selective agonist activity for D<sub>2</sub>R over D<sub>3</sub>R. In fact, compound 38 exhibited potent antagonism of dopamine-stimulated β-arrestin2 recruitment. In our docking studies, compound 38 directly interacts with S193<sup>5.42</sup> on TM5 but has no interactions with extracellular loop 2, which appears to be in contrast to the binding poses of D<sub>2</sub>R β-arrestin2-biased ligands. In in vivo studies, compound 38 showed high D<sub>2</sub>R receptor occupancy in mice and effectively inhibited phencyclidine-induced hyperlocomotion.
|
Partial agonist activity at D2L receptor (unknown origin) expressed in human HTLA cells assessed as beta-arrestin2 recruitment after 20 to 22 hrs by brightglo-luciferase reporter gene assay
|
Homo sapiens
|
0.6
nM
|
|
Partial agonist activity at D2L receptor (unknown origin) expressed in human HTLA cells assessed as beta-arrestin2 recruitment after 20 to 22 hrs by brightglo-luciferase reporter gene assay
|
Homo sapiens
|
0.631
nM
|
|
Journal : J Med Chem
Title : D<sub>2</sub> Dopamine Receptor G Protein-Biased Partial Agonists Based on Cariprazine.
Year : 2019
Volume : 62
Issue : 9
First Page : 4755
Last Page : 4771
Authors : Shen Y, McCorvy JD, Martini ML, Rodriguiz RM, Pogorelov VM, Ward KM, Wetsel WC, Liu J, Roth BL, Jin J.
Abstract : Functionally selective G protein-coupled receptor ligands are valuable tools for deciphering the roles of downstream signaling pathways that potentially contribute to therapeutic effects versus side effects. Recently, we discovered both G<sub>i/o</sub>-biased and β-arrestin2-biased D<sub>2</sub> receptor agonists based on the Food and Drug Administration (FDA)-approved drug aripiprazole. In this work, based on another FDA-approved drug, cariprazine, we conducted a structure-functional selectivity relationship study and discovered compound 38 (MS1768) as a potent partial agonist that selectively activates the G<sub>i/o</sub> pathway over β-arrestin2. Unlike the dual D<sub>2</sub>R/D<sub>3</sub>R partial agonist cariprazine, compound 38 showed selective agonist activity for D<sub>2</sub>R over D<sub>3</sub>R. In fact, compound 38 exhibited potent antagonism of dopamine-stimulated β-arrestin2 recruitment. In our docking studies, compound 38 directly interacts with S193<sup>5.42</sup> on TM5 but has no interactions with extracellular loop 2, which appears to be in contrast to the binding poses of D<sub>2</sub>R β-arrestin2-biased ligands. In in vivo studies, compound 38 showed high D<sub>2</sub>R receptor occupancy in mice and effectively inhibited phencyclidine-induced hyperlocomotion.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
14.63
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
9.203
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.06
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.22
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.22
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.06
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Displacement of [3H]ketanserin from recombinant human 5-HT2A receptor expressed in human HEK293 cells
|
Homo sapiens
|
18.8
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and biological evaluation of novel antipsychotic trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives targeting dopamine/serotonin receptor subtypes.
Year : 2021
Volume : 31
First Page : 127681
Last Page : 127681
Authors : Xu JW,Qi YL,Wu JW,Yuan RX,Chen XW,Li JQ
Abstract : In this study, a series of trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives as potential antipsychotics were synthesized and biologically evaluated to discover potential antipsychotics with good drug target selectivity. The preliminary structure-activity relationship was discussed, and optimal compound 12a showed both nanomolar affinity for D/D/5-HT/5-HT receptors and weak α and H receptor binding affinity. In addition, 12a was metabolically stable in vitro, displayed micromolar affinity for the hERG channel, and exhibited antipsychotic efficacy in the animal model of locomotor-stimulating effects of phencyclidine.
|
Displacement of [3H]OH-DPAT from recombinant human 5-HT1A receptor expressed in human HEK293 cells
|
Homo sapiens
|
2.6
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and biological evaluation of novel antipsychotic trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives targeting dopamine/serotonin receptor subtypes.
Year : 2021
Volume : 31
First Page : 127681
Last Page : 127681
Authors : Xu JW,Qi YL,Wu JW,Yuan RX,Chen XW,Li JQ
Abstract : In this study, a series of trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives as potential antipsychotics were synthesized and biologically evaluated to discover potential antipsychotics with good drug target selectivity. The preliminary structure-activity relationship was discussed, and optimal compound 12a showed both nanomolar affinity for D/D/5-HT/5-HT receptors and weak α and H receptor binding affinity. In addition, 12a was metabolically stable in vitro, displayed micromolar affinity for the hERG channel, and exhibited antipsychotic efficacy in the animal model of locomotor-stimulating effects of phencyclidine.
|
Displacement of [3H]methyl-spiperone from recombinant human D3 receptor expressed in CHO cells
|
Homo sapiens
|
0.085
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and biological evaluation of novel antipsychotic trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives targeting dopamine/serotonin receptor subtypes.
Year : 2021
Volume : 31
First Page : 127681
Last Page : 127681
Authors : Xu JW,Qi YL,Wu JW,Yuan RX,Chen XW,Li JQ
Abstract : In this study, a series of trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives as potential antipsychotics were synthesized and biologically evaluated to discover potential antipsychotics with good drug target selectivity. The preliminary structure-activity relationship was discussed, and optimal compound 12a showed both nanomolar affinity for D/D/5-HT/5-HT receptors and weak α and H receptor binding affinity. In addition, 12a was metabolically stable in vitro, displayed micromolar affinity for the hERG channel, and exhibited antipsychotic efficacy in the animal model of locomotor-stimulating effects of phencyclidine.
|
Displacement of [3H]-pyrilamine from human H1 histamine receptor expressed in human HEK293 cells
|
Homo sapiens
|
23.2
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and biological evaluation of novel antipsychotic trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives targeting dopamine/serotonin receptor subtypes.
Year : 2021
Volume : 31
First Page : 127681
Last Page : 127681
Authors : Xu JW,Qi YL,Wu JW,Yuan RX,Chen XW,Li JQ
Abstract : In this study, a series of trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives as potential antipsychotics were synthesized and biologically evaluated to discover potential antipsychotics with good drug target selectivity. The preliminary structure-activity relationship was discussed, and optimal compound 12a showed both nanomolar affinity for D/D/5-HT/5-HT receptors and weak α and H receptor binding affinity. In addition, 12a was metabolically stable in vitro, displayed micromolar affinity for the hERG channel, and exhibited antipsychotic efficacy in the animal model of locomotor-stimulating effects of phencyclidine.
|
Displacement of [3H]-spiperone from recombinant human D2L receptor expressed in CHO cells
|
Homo sapiens
|
0.49
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and biological evaluation of novel antipsychotic trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives targeting dopamine/serotonin receptor subtypes.
Year : 2021
Volume : 31
First Page : 127681
Last Page : 127681
Authors : Xu JW,Qi YL,Wu JW,Yuan RX,Chen XW,Li JQ
Abstract : In this study, a series of trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives as potential antipsychotics were synthesized and biologically evaluated to discover potential antipsychotics with good drug target selectivity. The preliminary structure-activity relationship was discussed, and optimal compound 12a showed both nanomolar affinity for D/D/5-HT/5-HT receptors and weak α and H receptor binding affinity. In addition, 12a was metabolically stable in vitro, displayed micromolar affinity for the hERG channel, and exhibited antipsychotic efficacy in the animal model of locomotor-stimulating effects of phencyclidine.
|
Displacement of [3H]-prazosin from adrenergic alpha1 in rat cerebral cortex
|
Rattus norvegicus
|
155.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and biological evaluation of novel antipsychotic trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives targeting dopamine/serotonin receptor subtypes.
Year : 2021
Volume : 31
First Page : 127681
Last Page : 127681
Authors : Xu JW,Qi YL,Wu JW,Yuan RX,Chen XW,Li JQ
Abstract : In this study, a series of trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives as potential antipsychotics were synthesized and biologically evaluated to discover potential antipsychotics with good drug target selectivity. The preliminary structure-activity relationship was discussed, and optimal compound 12a showed both nanomolar affinity for D/D/5-HT/5-HT receptors and weak α and H receptor binding affinity. In addition, 12a was metabolically stable in vitro, displayed micromolar affinity for the hERG channel, and exhibited antipsychotic efficacy in the animal model of locomotor-stimulating effects of phencyclidine.
|
Displacement of [3H]-N-methylspiperone from D2 receptor (unknown origin) expressed in HEK293T cell membranes measured after 2 hrs by microbeta scintillation counting method
|
Homo sapiens
|
1.45
nM
|
|
Displacement of [3H]-N-methylspiperone from D2 receptor (unknown origin) expressed in HEK293T cell membranes measured after 2 hrs by microbeta scintillation counting method
|
Homo sapiens
|
1.445
nM
|
|
|
Partial agonist activity at D2 receptor (unknown origin) expressed in HEK293T cells co-expressing Rluc8-tagged Galpahi1 assessed as Galphai1 dissociation preincubated for 2 mins with coelenterazine followed by compound addition and measured after 2 mins by BRET assay
|
Homo sapiens
|
1.02
nM
|
|
Partial agonist activity at D2 receptor (unknown origin) expressed in HEK293T cells co-expressing Rluc8-tagged Galpahi1 assessed as Galphai1 dissociation preincubated for 2 mins with coelenterazine followed by compound addition and measured after 2 mins by BRET assay
|
Homo sapiens
|
1.023
nM
|
|
|
Partial agonist activity at D2 receptor (unknown origin) expressed in HEK293T cells co-expressing GFP2-beta-arrestin2 assessed as beta-arrestin2 recruitment preincubated for 2 mins with coelenterazine followed by compound addition and measured after 2 mins by BRET assay
|
Homo sapiens
|
2.37
nM
|
|
Partial agonist activity at D2 receptor (unknown origin) expressed in HEK293T cells co-expressing GFP2-beta-arrestin2 assessed as beta-arrestin2 recruitment preincubated for 2 mins with coelenterazine followed by compound addition and measured after 2 mins by BRET assay
|
Homo sapiens
|
2.344
nM
|
|
|
Displacement of [3H]-SCH23390 from D3 receptor (unknown origin) expressed in HEK293T cell membranes measured after 2 hrs by microbeta scintillation counting method
|
Homo sapiens
|
0.27
nM
|
|
Displacement of [3H]-SCH23390 from D3 receptor (unknown origin) expressed in HEK293T cell membranes measured after 2 hrs by microbeta scintillation counting method
|
Homo sapiens
|
0.2692
nM
|
|
|
Displacement of [3H]-LSD from 5HT1A receptor (unknown origin) expressed in HEK293T cell membranes measured after 2 hrs by microbeta scintillation counting method
|
Homo sapiens
|
4.01
nM
|
|
Displacement of [3H]-LSD from 5HT1A receptor (unknown origin) expressed in HEK293T cell membranes measured after 2 hrs by microbeta scintillation counting method
|
Homo sapiens
|
3.981
nM
|
|
|
Displacement of [3H]-LSD from 5HT2A receptor (unknown origin) expressed in HEK293T cell membranes measured after 2 hrs by microbeta scintillation counting method
|
Homo sapiens
|
219.4
nM
|
|
Displacement of [3H]-LSD from 5HT2A receptor (unknown origin) expressed in HEK293T cell membranes measured after 2 hrs by microbeta scintillation counting method
|
Homo sapiens
|
218.78
nM
|
|
|
Displacement of [3H]-LSD from 5HT2C receptor (unknown origin) expressed in HEK293T cell membranes measured after 2 hrs by microbeta scintillation counting method
|
Homo sapiens
|
198.2
nM
|
|
Displacement of [3H]-LSD from 5HT2C receptor (unknown origin) expressed in HEK293T cell membranes measured after 2 hrs by microbeta scintillation counting method
|
Homo sapiens
|
199.53
nM
|
|
|
Displacement of [3H]-SCH23390 from D4 receptor (unknown origin) expressed in HEK293T cell membranes measured after 2 hrs by microbeta scintillation counting method
|
Homo sapiens
|
507.0
nM
|
|
Displacement of [3H]-SCH23390 from D4 receptor (unknown origin) expressed in HEK293T cell membranes measured after 2 hrs by microbeta scintillation counting method
|
Homo sapiens
|
501.19
nM
|
|
