|
Binding affinity of compound measured using [3H]-spiperone for the cloned human dopamine receptor D2 long (high/low affinity is given as 27/5400)
|
None
|
27.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Fused azaindole derivatives: molecular design, synthesis and in vitro pharmacology leading to the preferential dopamine D3 receptor agonist FAUC 725.
Year : 2002
Volume : 12
Issue : 17
First Page : 2377
Last Page : 2380
Authors : Löber S, Hübner H, Gmeiner P.
Abstract : Computational studies based on the similarity of molecular electrostatic potential maps initiated the synthesis of the tricyclic target compounds 1 (FAUC 725) and 2. Receptor binding studies at the dopamine receptor subtypes D1, D2(long), D2(short), D3 and D4 showed that the azaindole 1 revealed D3 affinity (K(i)=0.54 nM) comparable to the lead pramipexole and enhanced selectivity over D2 and D4. Mitogenesis experiments indicated substantial intrinsic activity for the D3 selective dipropylamine 1. Based on the structure of (S)-3-PPP, bioisosteric replacement and conformational restriction leading to the test compound 2 was not fruitful.
|
Effective concentration required for agonistic activity against rat D2 long receptor
|
None
|
9.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Fused azaindole derivatives: molecular design, synthesis and in vitro pharmacology leading to the preferential dopamine D3 receptor agonist FAUC 725.
Year : 2002
Volume : 12
Issue : 17
First Page : 2377
Last Page : 2380
Authors : Löber S, Hübner H, Gmeiner P.
Abstract : Computational studies based on the similarity of molecular electrostatic potential maps initiated the synthesis of the tricyclic target compounds 1 (FAUC 725) and 2. Receptor binding studies at the dopamine receptor subtypes D1, D2(long), D2(short), D3 and D4 showed that the azaindole 1 revealed D3 affinity (K(i)=0.54 nM) comparable to the lead pramipexole and enhanced selectivity over D2 and D4. Mitogenesis experiments indicated substantial intrinsic activity for the D3 selective dipropylamine 1. Based on the structure of (S)-3-PPP, bioisosteric replacement and conformational restriction leading to the test compound 2 was not fruitful.
|
Binding affinity of compound measured using [3H]spiperone for the cloned human dopamine receptor D2 short (high/low affinity is given as 40/3600)
|
None
|
40.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Fused azaindole derivatives: molecular design, synthesis and in vitro pharmacology leading to the preferential dopamine D3 receptor agonist FAUC 725.
Year : 2002
Volume : 12
Issue : 17
First Page : 2377
Last Page : 2380
Authors : Löber S, Hübner H, Gmeiner P.
Abstract : Computational studies based on the similarity of molecular electrostatic potential maps initiated the synthesis of the tricyclic target compounds 1 (FAUC 725) and 2. Receptor binding studies at the dopamine receptor subtypes D1, D2(long), D2(short), D3 and D4 showed that the azaindole 1 revealed D3 affinity (K(i)=0.54 nM) comparable to the lead pramipexole and enhanced selectivity over D2 and D4. Mitogenesis experiments indicated substantial intrinsic activity for the D3 selective dipropylamine 1. Based on the structure of (S)-3-PPP, bioisosteric replacement and conformational restriction leading to the test compound 2 was not fruitful.
|
Effective concentration required for agonistic activity against rat D2 short receptor
|
None
|
12.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Fused azaindole derivatives: molecular design, synthesis and in vitro pharmacology leading to the preferential dopamine D3 receptor agonist FAUC 725.
Year : 2002
Volume : 12
Issue : 17
First Page : 2377
Last Page : 2380
Authors : Löber S, Hübner H, Gmeiner P.
Abstract : Computational studies based on the similarity of molecular electrostatic potential maps initiated the synthesis of the tricyclic target compounds 1 (FAUC 725) and 2. Receptor binding studies at the dopamine receptor subtypes D1, D2(long), D2(short), D3 and D4 showed that the azaindole 1 revealed D3 affinity (K(i)=0.54 nM) comparable to the lead pramipexole and enhanced selectivity over D2 and D4. Mitogenesis experiments indicated substantial intrinsic activity for the D3 selective dipropylamine 1. Based on the structure of (S)-3-PPP, bioisosteric replacement and conformational restriction leading to the test compound 2 was not fruitful.
|
Effective concentration required for agonistic activity against human D4.2 receptor
|
None
|
15.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Fused azaindole derivatives: molecular design, synthesis and in vitro pharmacology leading to the preferential dopamine D3 receptor agonist FAUC 725.
Year : 2002
Volume : 12
Issue : 17
First Page : 2377
Last Page : 2380
Authors : Löber S, Hübner H, Gmeiner P.
Abstract : Computational studies based on the similarity of molecular electrostatic potential maps initiated the synthesis of the tricyclic target compounds 1 (FAUC 725) and 2. Receptor binding studies at the dopamine receptor subtypes D1, D2(long), D2(short), D3 and D4 showed that the azaindole 1 revealed D3 affinity (K(i)=0.54 nM) comparable to the lead pramipexole and enhanced selectivity over D2 and D4. Mitogenesis experiments indicated substantial intrinsic activity for the D3 selective dipropylamine 1. Based on the structure of (S)-3-PPP, bioisosteric replacement and conformational restriction leading to the test compound 2 was not fruitful.
|
Binding affinity of compound measured using [3H]spiperone for the cloned human dopamine receptor D4.4 (high/low affinity is given as 8.5/130)
|
None
|
8.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Fused azaindole derivatives: molecular design, synthesis and in vitro pharmacology leading to the preferential dopamine D3 receptor agonist FAUC 725.
Year : 2002
Volume : 12
Issue : 17
First Page : 2377
Last Page : 2380
Authors : Löber S, Hübner H, Gmeiner P.
Abstract : Computational studies based on the similarity of molecular electrostatic potential maps initiated the synthesis of the tricyclic target compounds 1 (FAUC 725) and 2. Receptor binding studies at the dopamine receptor subtypes D1, D2(long), D2(short), D3 and D4 showed that the azaindole 1 revealed D3 affinity (K(i)=0.54 nM) comparable to the lead pramipexole and enhanced selectivity over D2 and D4. Mitogenesis experiments indicated substantial intrinsic activity for the D3 selective dipropylamine 1. Based on the structure of (S)-3-PPP, bioisosteric replacement and conformational restriction leading to the test compound 2 was not fruitful.
|
Binding affinity of compound against Dopamine receptor D2 was measured using [3H]pramipexole in Bovine striatal membranes
|
None
|
1.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Fused azaindole derivatives: molecular design, synthesis and in vitro pharmacology leading to the preferential dopamine D3 receptor agonist FAUC 725.
Year : 2002
Volume : 12
Issue : 17
First Page : 2377
Last Page : 2380
Authors : Löber S, Hübner H, Gmeiner P.
Abstract : Computational studies based on the similarity of molecular electrostatic potential maps initiated the synthesis of the tricyclic target compounds 1 (FAUC 725) and 2. Receptor binding studies at the dopamine receptor subtypes D1, D2(long), D2(short), D3 and D4 showed that the azaindole 1 revealed D3 affinity (K(i)=0.54 nM) comparable to the lead pramipexole and enhanced selectivity over D2 and D4. Mitogenesis experiments indicated substantial intrinsic activity for the D3 selective dipropylamine 1. Based on the structure of (S)-3-PPP, bioisosteric replacement and conformational restriction leading to the test compound 2 was not fruitful.
|
in vitro high binding affinity was determined on human Dopamine receptor D4 expressed in chinese hamster ovary(CHO) K-1 cells using [3H]spiperone as radioligand.
|
None
|
2.07
nM
|
|
in vitro high binding affinity was determined on human Dopamine receptor D4 expressed in chinese hamster ovary(CHO) K-1 cells using [3H]spiperone as radioligand.
|
None
|
0.49
nM
|
|
in vitro high binding affinity was determined on human Dopamine receptor D4 expressed in chinese hamster ovary(CHO) K-1 cells using [3H]spiperone as radioligand.
|
None
|
2.76
nM
|
|
Journal : J. Med. Chem.
Title : Thiazoloindans and thiazolobenzopyrans: a novel class of orally active central dopamine (partial) agonists.
Year : 2000
Volume : 43
Issue : 19
First Page : 3549
Last Page : 3557
Authors : van Vliet LA, Rodenhuis N, Wikström H, Pugsley TA, Serpa KA, Meltzer LT, Heffner TG, Wise LD, Lajiness ME, Huff RM, Svensson K, Haenen GR, Bast A.
Abstract : The 2-aminothiazole moiety has proven its value in medicinal chemistry as a stable and lipophilic bioisosteric replacement of a phenol group. This approach has provided dopamine (DA) agonists with good oral availability. To further explore its use in the development of DA agonists, we have combined the 2-aminothiazole moiety with 2-aminoindans and 3-aminobenzopyrans, which are known templates for DA agonists. In this study we have synthesized 6-amino-3-(N,N-di-n-propylamino)-3,4-dihydro-2H-thiazolo[5, 4-f]-[1]benzopyran (12) and 6-amino-2-(N, N-di-n-propylamino)thiazolo[4,5-f]indan (20) and several analogues (13, 17, and 21). The affinity of the thiazolobenzopyrans and thiazoloindans for DA receptors was evaluated, which revealed compound 20 to have high affinity for DA D(3) receptors. In addition, the compounds were screened for their potential to inhibit lipid peroxidation, to determine their radical scavenging properties. Compounds 12, 20, and 21 were subjected to further pharmacological evaluation in a functional assay to determine intrinsic activity. Compound 20 was also studied with microdialysis (to determine effects on DA turnover in striatum) and in unilaterally 6-OH-DA lesioned rats (to determine their potential as DA agonists). These studies selected compound 20 (GMC 1111) as particularly interesting. Compound 20 caused a rotation activation in unilaterally 6-OH-DA lesioned rats and an increase in DA turnover in rat striatum. This dual agonist/antagonist action is best accounted for by its partial agonism at striatal DA D(2) receptors. Interestingly, 20 displayed long-lasting activity and excellent oral availability in 6-OH-DA lesioned rats, making this compound potentially useful for the treatment of Parkinson's disease.
|
in vitro low binding affinity was determined on human Dopamine receptor D4 expressed in chinese hamster ovary(CHO) K-1 cells using [3H]spiperone as radioligand.
|
None
|
138.0
nM
|
|
Journal : J. Med. Chem.
Title : Thiazoloindans and thiazolobenzopyrans: a novel class of orally active central dopamine (partial) agonists.
Year : 2000
Volume : 43
Issue : 19
First Page : 3549
Last Page : 3557
Authors : van Vliet LA, Rodenhuis N, Wikström H, Pugsley TA, Serpa KA, Meltzer LT, Heffner TG, Wise LD, Lajiness ME, Huff RM, Svensson K, Haenen GR, Bast A.
Abstract : The 2-aminothiazole moiety has proven its value in medicinal chemistry as a stable and lipophilic bioisosteric replacement of a phenol group. This approach has provided dopamine (DA) agonists with good oral availability. To further explore its use in the development of DA agonists, we have combined the 2-aminothiazole moiety with 2-aminoindans and 3-aminobenzopyrans, which are known templates for DA agonists. In this study we have synthesized 6-amino-3-(N,N-di-n-propylamino)-3,4-dihydro-2H-thiazolo[5, 4-f]-[1]benzopyran (12) and 6-amino-2-(N, N-di-n-propylamino)thiazolo[4,5-f]indan (20) and several analogues (13, 17, and 21). The affinity of the thiazolobenzopyrans and thiazoloindans for DA receptors was evaluated, which revealed compound 20 to have high affinity for DA D(3) receptors. In addition, the compounds were screened for their potential to inhibit lipid peroxidation, to determine their radical scavenging properties. Compounds 12, 20, and 21 were subjected to further pharmacological evaluation in a functional assay to determine intrinsic activity. Compound 20 was also studied with microdialysis (to determine effects on DA turnover in striatum) and in unilaterally 6-OH-DA lesioned rats (to determine their potential as DA agonists). These studies selected compound 20 (GMC 1111) as particularly interesting. Compound 20 caused a rotation activation in unilaterally 6-OH-DA lesioned rats and an increase in DA turnover in rat striatum. This dual agonist/antagonist action is best accounted for by its partial agonism at striatal DA D(2) receptors. Interestingly, 20 displayed long-lasting activity and excellent oral availability in 6-OH-DA lesioned rats, making this compound potentially useful for the treatment of Parkinson's disease.
|
in vitro low binding affinity was determined on human Dopamine receptor D2L expressed in chinese hamster ovary(CHO) K-1 cells using [3H]-spiperone as radioligand.
|
None
|
139.0
nM
|
|
Journal : J. Med. Chem.
Title : Thiazoloindans and thiazolobenzopyrans: a novel class of orally active central dopamine (partial) agonists.
Year : 2000
Volume : 43
Issue : 19
First Page : 3549
Last Page : 3557
Authors : van Vliet LA, Rodenhuis N, Wikström H, Pugsley TA, Serpa KA, Meltzer LT, Heffner TG, Wise LD, Lajiness ME, Huff RM, Svensson K, Haenen GR, Bast A.
Abstract : The 2-aminothiazole moiety has proven its value in medicinal chemistry as a stable and lipophilic bioisosteric replacement of a phenol group. This approach has provided dopamine (DA) agonists with good oral availability. To further explore its use in the development of DA agonists, we have combined the 2-aminothiazole moiety with 2-aminoindans and 3-aminobenzopyrans, which are known templates for DA agonists. In this study we have synthesized 6-amino-3-(N,N-di-n-propylamino)-3,4-dihydro-2H-thiazolo[5, 4-f]-[1]benzopyran (12) and 6-amino-2-(N, N-di-n-propylamino)thiazolo[4,5-f]indan (20) and several analogues (13, 17, and 21). The affinity of the thiazolobenzopyrans and thiazoloindans for DA receptors was evaluated, which revealed compound 20 to have high affinity for DA D(3) receptors. In addition, the compounds were screened for their potential to inhibit lipid peroxidation, to determine their radical scavenging properties. Compounds 12, 20, and 21 were subjected to further pharmacological evaluation in a functional assay to determine intrinsic activity. Compound 20 was also studied with microdialysis (to determine effects on DA turnover in striatum) and in unilaterally 6-OH-DA lesioned rats (to determine their potential as DA agonists). These studies selected compound 20 (GMC 1111) as particularly interesting. Compound 20 caused a rotation activation in unilaterally 6-OH-DA lesioned rats and an increase in DA turnover in rat striatum. This dual agonist/antagonist action is best accounted for by its partial agonism at striatal DA D(2) receptors. Interestingly, 20 displayed long-lasting activity and excellent oral availability in 6-OH-DA lesioned rats, making this compound potentially useful for the treatment of Parkinson's disease.
|
Effective concentration was determined as thymidine uptake in CHO-L6 cells transfected with the rat Dopamine receptor D2L by mitogenesis assay
|
None
|
1.7
nM
|
|
Journal : J. Med. Chem.
Title : Thiazoloindans and thiazolobenzopyrans: a novel class of orally active central dopamine (partial) agonists.
Year : 2000
Volume : 43
Issue : 19
First Page : 3549
Last Page : 3557
Authors : van Vliet LA, Rodenhuis N, Wikström H, Pugsley TA, Serpa KA, Meltzer LT, Heffner TG, Wise LD, Lajiness ME, Huff RM, Svensson K, Haenen GR, Bast A.
Abstract : The 2-aminothiazole moiety has proven its value in medicinal chemistry as a stable and lipophilic bioisosteric replacement of a phenol group. This approach has provided dopamine (DA) agonists with good oral availability. To further explore its use in the development of DA agonists, we have combined the 2-aminothiazole moiety with 2-aminoindans and 3-aminobenzopyrans, which are known templates for DA agonists. In this study we have synthesized 6-amino-3-(N,N-di-n-propylamino)-3,4-dihydro-2H-thiazolo[5, 4-f]-[1]benzopyran (12) and 6-amino-2-(N, N-di-n-propylamino)thiazolo[4,5-f]indan (20) and several analogues (13, 17, and 21). The affinity of the thiazolobenzopyrans and thiazoloindans for DA receptors was evaluated, which revealed compound 20 to have high affinity for DA D(3) receptors. In addition, the compounds were screened for their potential to inhibit lipid peroxidation, to determine their radical scavenging properties. Compounds 12, 20, and 21 were subjected to further pharmacological evaluation in a functional assay to determine intrinsic activity. Compound 20 was also studied with microdialysis (to determine effects on DA turnover in striatum) and in unilaterally 6-OH-DA lesioned rats (to determine their potential as DA agonists). These studies selected compound 20 (GMC 1111) as particularly interesting. Compound 20 caused a rotation activation in unilaterally 6-OH-DA lesioned rats and an increase in DA turnover in rat striatum. This dual agonist/antagonist action is best accounted for by its partial agonism at striatal DA D(2) receptors. Interestingly, 20 displayed long-lasting activity and excellent oral availability in 6-OH-DA lesioned rats, making this compound potentially useful for the treatment of Parkinson's disease.
|
Effective concentration required for agonistic activity against human D3 receptor
|
None
|
1.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Fused azaindole derivatives: molecular design, synthesis and in vitro pharmacology leading to the preferential dopamine D3 receptor agonist FAUC 725.
Year : 2002
Volume : 12
Issue : 17
First Page : 2377
Last Page : 2380
Authors : Löber S, Hübner H, Gmeiner P.
Abstract : Computational studies based on the similarity of molecular electrostatic potential maps initiated the synthesis of the tricyclic target compounds 1 (FAUC 725) and 2. Receptor binding studies at the dopamine receptor subtypes D1, D2(long), D2(short), D3 and D4 showed that the azaindole 1 revealed D3 affinity (K(i)=0.54 nM) comparable to the lead pramipexole and enhanced selectivity over D2 and D4. Mitogenesis experiments indicated substantial intrinsic activity for the D3 selective dipropylamine 1. Based on the structure of (S)-3-PPP, bioisosteric replacement and conformational restriction leading to the test compound 2 was not fruitful.
|
Binding affinity of compound measured using [3H]-spiperone for the cloned human Dopamine receptor D3 (high/low affinity is given as 0.87/44)
|
None
|
0.87
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Fused azaindole derivatives: molecular design, synthesis and in vitro pharmacology leading to the preferential dopamine D3 receptor agonist FAUC 725.
Year : 2002
Volume : 12
Issue : 17
First Page : 2377
Last Page : 2380
Authors : Löber S, Hübner H, Gmeiner P.
Abstract : Computational studies based on the similarity of molecular electrostatic potential maps initiated the synthesis of the tricyclic target compounds 1 (FAUC 725) and 2. Receptor binding studies at the dopamine receptor subtypes D1, D2(long), D2(short), D3 and D4 showed that the azaindole 1 revealed D3 affinity (K(i)=0.54 nM) comparable to the lead pramipexole and enhanced selectivity over D2 and D4. Mitogenesis experiments indicated substantial intrinsic activity for the D3 selective dipropylamine 1. Based on the structure of (S)-3-PPP, bioisosteric replacement and conformational restriction leading to the test compound 2 was not fruitful.
|
in vitro low binding affinity was determined on human Dopamine receptor D3 expressed in chinese hamster ovary(CHO) K-1 cells using [3H]spiperone as radioligand.
|
None
|
2.78
nM
|
|
Journal : J. Med. Chem.
Title : Thiazoloindans and thiazolobenzopyrans: a novel class of orally active central dopamine (partial) agonists.
Year : 2000
Volume : 43
Issue : 19
First Page : 3549
Last Page : 3557
Authors : van Vliet LA, Rodenhuis N, Wikström H, Pugsley TA, Serpa KA, Meltzer LT, Heffner TG, Wise LD, Lajiness ME, Huff RM, Svensson K, Haenen GR, Bast A.
Abstract : The 2-aminothiazole moiety has proven its value in medicinal chemistry as a stable and lipophilic bioisosteric replacement of a phenol group. This approach has provided dopamine (DA) agonists with good oral availability. To further explore its use in the development of DA agonists, we have combined the 2-aminothiazole moiety with 2-aminoindans and 3-aminobenzopyrans, which are known templates for DA agonists. In this study we have synthesized 6-amino-3-(N,N-di-n-propylamino)-3,4-dihydro-2H-thiazolo[5, 4-f]-[1]benzopyran (12) and 6-amino-2-(N, N-di-n-propylamino)thiazolo[4,5-f]indan (20) and several analogues (13, 17, and 21). The affinity of the thiazolobenzopyrans and thiazoloindans for DA receptors was evaluated, which revealed compound 20 to have high affinity for DA D(3) receptors. In addition, the compounds were screened for their potential to inhibit lipid peroxidation, to determine their radical scavenging properties. Compounds 12, 20, and 21 were subjected to further pharmacological evaluation in a functional assay to determine intrinsic activity. Compound 20 was also studied with microdialysis (to determine effects on DA turnover in striatum) and in unilaterally 6-OH-DA lesioned rats (to determine their potential as DA agonists). These studies selected compound 20 (GMC 1111) as particularly interesting. Compound 20 caused a rotation activation in unilaterally 6-OH-DA lesioned rats and an increase in DA turnover in rat striatum. This dual agonist/antagonist action is best accounted for by its partial agonism at striatal DA D(2) receptors. Interestingly, 20 displayed long-lasting activity and excellent oral availability in 6-OH-DA lesioned rats, making this compound potentially useful for the treatment of Parkinson's disease.
|
Effective concentration was determined as thymidine uptake in CHO-L6 cells transfected with the rat Dopamine receptor D3 by mitogenesis assay
|
None
|
0.21
nM
|
|
Journal : J. Med. Chem.
Title : Thiazoloindans and thiazolobenzopyrans: a novel class of orally active central dopamine (partial) agonists.
Year : 2000
Volume : 43
Issue : 19
First Page : 3549
Last Page : 3557
Authors : van Vliet LA, Rodenhuis N, Wikström H, Pugsley TA, Serpa KA, Meltzer LT, Heffner TG, Wise LD, Lajiness ME, Huff RM, Svensson K, Haenen GR, Bast A.
Abstract : The 2-aminothiazole moiety has proven its value in medicinal chemistry as a stable and lipophilic bioisosteric replacement of a phenol group. This approach has provided dopamine (DA) agonists with good oral availability. To further explore its use in the development of DA agonists, we have combined the 2-aminothiazole moiety with 2-aminoindans and 3-aminobenzopyrans, which are known templates for DA agonists. In this study we have synthesized 6-amino-3-(N,N-di-n-propylamino)-3,4-dihydro-2H-thiazolo[5, 4-f]-[1]benzopyran (12) and 6-amino-2-(N, N-di-n-propylamino)thiazolo[4,5-f]indan (20) and several analogues (13, 17, and 21). The affinity of the thiazolobenzopyrans and thiazoloindans for DA receptors was evaluated, which revealed compound 20 to have high affinity for DA D(3) receptors. In addition, the compounds were screened for their potential to inhibit lipid peroxidation, to determine their radical scavenging properties. Compounds 12, 20, and 21 were subjected to further pharmacological evaluation in a functional assay to determine intrinsic activity. Compound 20 was also studied with microdialysis (to determine effects on DA turnover in striatum) and in unilaterally 6-OH-DA lesioned rats (to determine their potential as DA agonists). These studies selected compound 20 (GMC 1111) as particularly interesting. Compound 20 caused a rotation activation in unilaterally 6-OH-DA lesioned rats and an increase in DA turnover in rat striatum. This dual agonist/antagonist action is best accounted for by its partial agonism at striatal DA D(2) receptors. Interestingly, 20 displayed long-lasting activity and excellent oral availability in 6-OH-DA lesioned rats, making this compound potentially useful for the treatment of Parkinson's disease.
|
Low inhibition constant against [3H]spiperone binding to human Dopamine receptor D3 expressed in CHO cells
|
Homo sapiens
|
38.0
nM
|
|
Journal : J. Med. Chem.
Title : CoMFA and CoMSIA investigations revealing novel insights into the binding modes of dopamine D3 receptor agonists.
Year : 2005
Volume : 48
Issue : 7
First Page : 2493
Last Page : 2508
Authors : Boeckler F, Ohnmacht U, Lehmann T, Utz W, Hübner H, Gmeiner P.
Abstract : As an extension of a series of dopamine D(3) receptor agonists involving FAUC 54, ex-chiral pool synthesis, and biological evaluation of 3-substituted 7-aminotetrahydroindolizines was performed. Considering the structural features of both series of enantiomers, we developed a novel alignment hypothesis for D(3) agonists, allowing for the placement of the aromatic moieties on two alternative, adjacent positions. CoMFA and CoMSIA analyses yielded significant cross-validated q(2) values of 0.726 and 0.590, respectively, when a newly invented program application (IRAS) controlling the alignment selection proved to be useful. Employing the CoMFA/CoMSIA contribution maps, we were able to transform a previously constructed homology model of the D(3) receptor from an inactive into an activate state. Besides the established ionic interactions, we propose pi-stacking with Phe6.51 and a hydrogen bond between His6.55 and the acyl moiety to be primarily involved in the D(3) receptor binding of FAUC 54 and its analogues.
|
High inhibition constant against [3H]spiperone binding to human Dopamine receptor D3 expressed in CHO cells
|
Homo sapiens
|
0.88
nM
|
|
Journal : J. Med. Chem.
Title : CoMFA and CoMSIA investigations revealing novel insights into the binding modes of dopamine D3 receptor agonists.
Year : 2005
Volume : 48
Issue : 7
First Page : 2493
Last Page : 2508
Authors : Boeckler F, Ohnmacht U, Lehmann T, Utz W, Hübner H, Gmeiner P.
Abstract : As an extension of a series of dopamine D(3) receptor agonists involving FAUC 54, ex-chiral pool synthesis, and biological evaluation of 3-substituted 7-aminotetrahydroindolizines was performed. Considering the structural features of both series of enantiomers, we developed a novel alignment hypothesis for D(3) agonists, allowing for the placement of the aromatic moieties on two alternative, adjacent positions. CoMFA and CoMSIA analyses yielded significant cross-validated q(2) values of 0.726 and 0.590, respectively, when a newly invented program application (IRAS) controlling the alignment selection proved to be useful. Employing the CoMFA/CoMSIA contribution maps, we were able to transform a previously constructed homology model of the D(3) receptor from an inactive into an activate state. Besides the established ionic interactions, we propose pi-stacking with Phe6.51 and a hydrogen bond between His6.55 and the acyl moiety to be primarily involved in the D(3) receptor binding of FAUC 54 and its analogues.
|
High inhibition constant against [3H]spiperone binding to human Dopamine receptor D2L expressed in CHO cells
|
Homo sapiens
|
21.0
nM
|
|
Journal : J. Med. Chem.
Title : CoMFA and CoMSIA investigations revealing novel insights into the binding modes of dopamine D3 receptor agonists.
Year : 2005
Volume : 48
Issue : 7
First Page : 2493
Last Page : 2508
Authors : Boeckler F, Ohnmacht U, Lehmann T, Utz W, Hübner H, Gmeiner P.
Abstract : As an extension of a series of dopamine D(3) receptor agonists involving FAUC 54, ex-chiral pool synthesis, and biological evaluation of 3-substituted 7-aminotetrahydroindolizines was performed. Considering the structural features of both series of enantiomers, we developed a novel alignment hypothesis for D(3) agonists, allowing for the placement of the aromatic moieties on two alternative, adjacent positions. CoMFA and CoMSIA analyses yielded significant cross-validated q(2) values of 0.726 and 0.590, respectively, when a newly invented program application (IRAS) controlling the alignment selection proved to be useful. Employing the CoMFA/CoMSIA contribution maps, we were able to transform a previously constructed homology model of the D(3) receptor from an inactive into an activate state. Besides the established ionic interactions, we propose pi-stacking with Phe6.51 and a hydrogen bond between His6.55 and the acyl moiety to be primarily involved in the D(3) receptor binding of FAUC 54 and its analogues.
|
High inhibition constant against [3H]spiperone binding to human Dopamine receptor D2S expressed in CHO cells
|
Homo sapiens
|
21.0
nM
|
|
Journal : J. Med. Chem.
Title : CoMFA and CoMSIA investigations revealing novel insights into the binding modes of dopamine D3 receptor agonists.
Year : 2005
Volume : 48
Issue : 7
First Page : 2493
Last Page : 2508
Authors : Boeckler F, Ohnmacht U, Lehmann T, Utz W, Hübner H, Gmeiner P.
Abstract : As an extension of a series of dopamine D(3) receptor agonists involving FAUC 54, ex-chiral pool synthesis, and biological evaluation of 3-substituted 7-aminotetrahydroindolizines was performed. Considering the structural features of both series of enantiomers, we developed a novel alignment hypothesis for D(3) agonists, allowing for the placement of the aromatic moieties on two alternative, adjacent positions. CoMFA and CoMSIA analyses yielded significant cross-validated q(2) values of 0.726 and 0.590, respectively, when a newly invented program application (IRAS) controlling the alignment selection proved to be useful. Employing the CoMFA/CoMSIA contribution maps, we were able to transform a previously constructed homology model of the D(3) receptor from an inactive into an activate state. Besides the established ionic interactions, we propose pi-stacking with Phe6.51 and a hydrogen bond between His6.55 and the acyl moiety to be primarily involved in the D(3) receptor binding of FAUC 54 and its analogues.
|
Low inhibition constant against [3H]spiperone binding to human Dopamine receptor D4.4 expressed in CHO cells
|
Homo sapiens
|
130.0
nM
|
|
Journal : J. Med. Chem.
Title : CoMFA and CoMSIA investigations revealing novel insights into the binding modes of dopamine D3 receptor agonists.
Year : 2005
Volume : 48
Issue : 7
First Page : 2493
Last Page : 2508
Authors : Boeckler F, Ohnmacht U, Lehmann T, Utz W, Hübner H, Gmeiner P.
Abstract : As an extension of a series of dopamine D(3) receptor agonists involving FAUC 54, ex-chiral pool synthesis, and biological evaluation of 3-substituted 7-aminotetrahydroindolizines was performed. Considering the structural features of both series of enantiomers, we developed a novel alignment hypothesis for D(3) agonists, allowing for the placement of the aromatic moieties on two alternative, adjacent positions. CoMFA and CoMSIA analyses yielded significant cross-validated q(2) values of 0.726 and 0.590, respectively, when a newly invented program application (IRAS) controlling the alignment selection proved to be useful. Employing the CoMFA/CoMSIA contribution maps, we were able to transform a previously constructed homology model of the D(3) receptor from an inactive into an activate state. Besides the established ionic interactions, we propose pi-stacking with Phe6.51 and a hydrogen bond between His6.55 and the acyl moiety to be primarily involved in the D(3) receptor binding of FAUC 54 and its analogues.
|
High inhibition constant against [3H]spiperone binding to human Dopamine receptor D4.4 expressed in CHO cells
|
Homo sapiens
|
8.1
nM
|
|
Journal : J. Med. Chem.
Title : CoMFA and CoMSIA investigations revealing novel insights into the binding modes of dopamine D3 receptor agonists.
Year : 2005
Volume : 48
Issue : 7
First Page : 2493
Last Page : 2508
Authors : Boeckler F, Ohnmacht U, Lehmann T, Utz W, Hübner H, Gmeiner P.
Abstract : As an extension of a series of dopamine D(3) receptor agonists involving FAUC 54, ex-chiral pool synthesis, and biological evaluation of 3-substituted 7-aminotetrahydroindolizines was performed. Considering the structural features of both series of enantiomers, we developed a novel alignment hypothesis for D(3) agonists, allowing for the placement of the aromatic moieties on two alternative, adjacent positions. CoMFA and CoMSIA analyses yielded significant cross-validated q(2) values of 0.726 and 0.590, respectively, when a newly invented program application (IRAS) controlling the alignment selection proved to be useful. Employing the CoMFA/CoMSIA contribution maps, we were able to transform a previously constructed homology model of the D(3) receptor from an inactive into an activate state. Besides the established ionic interactions, we propose pi-stacking with Phe6.51 and a hydrogen bond between His6.55 and the acyl moiety to be primarily involved in the D(3) receptor binding of FAUC 54 and its analogues.
|
Inhibition constant against [3H]-spiperone binding to human Dopamine receptor D3 expressed in CHO cells
|
Homo sapiens
|
0.7244
nM
|
|
Journal : J. Med. Chem.
Title : CoMFA and CoMSIA investigations revealing novel insights into the binding modes of dopamine D3 receptor agonists.
Year : 2005
Volume : 48
Issue : 7
First Page : 2493
Last Page : 2508
Authors : Boeckler F, Ohnmacht U, Lehmann T, Utz W, Hübner H, Gmeiner P.
Abstract : As an extension of a series of dopamine D(3) receptor agonists involving FAUC 54, ex-chiral pool synthesis, and biological evaluation of 3-substituted 7-aminotetrahydroindolizines was performed. Considering the structural features of both series of enantiomers, we developed a novel alignment hypothesis for D(3) agonists, allowing for the placement of the aromatic moieties on two alternative, adjacent positions. CoMFA and CoMSIA analyses yielded significant cross-validated q(2) values of 0.726 and 0.590, respectively, when a newly invented program application (IRAS) controlling the alignment selection proved to be useful. Employing the CoMFA/CoMSIA contribution maps, we were able to transform a previously constructed homology model of the D(3) receptor from an inactive into an activate state. Besides the established ionic interactions, we propose pi-stacking with Phe6.51 and a hydrogen bond between His6.55 and the acyl moiety to be primarily involved in the D(3) receptor binding of FAUC 54 and its analogues.
|
Effective concentration to stimulate rat Dopamine receptor D2L mediated [3H]thymidine incorporation into growing cells using mitogenesis assay
|
Rattus norvegicus
|
9.2
nM
|
|
Journal : J. Med. Chem.
Title : CoMFA and CoMSIA investigations revealing novel insights into the binding modes of dopamine D3 receptor agonists.
Year : 2005
Volume : 48
Issue : 7
First Page : 2493
Last Page : 2508
Authors : Boeckler F, Ohnmacht U, Lehmann T, Utz W, Hübner H, Gmeiner P.
Abstract : As an extension of a series of dopamine D(3) receptor agonists involving FAUC 54, ex-chiral pool synthesis, and biological evaluation of 3-substituted 7-aminotetrahydroindolizines was performed. Considering the structural features of both series of enantiomers, we developed a novel alignment hypothesis for D(3) agonists, allowing for the placement of the aromatic moieties on two alternative, adjacent positions. CoMFA and CoMSIA analyses yielded significant cross-validated q(2) values of 0.726 and 0.590, respectively, when a newly invented program application (IRAS) controlling the alignment selection proved to be useful. Employing the CoMFA/CoMSIA contribution maps, we were able to transform a previously constructed homology model of the D(3) receptor from an inactive into an activate state. Besides the established ionic interactions, we propose pi-stacking with Phe6.51 and a hydrogen bond between His6.55 and the acyl moiety to be primarily involved in the D(3) receptor binding of FAUC 54 and its analogues.
|
Effective concentration to stimulate rat Dopamine receptor D2S mediated [3H]thymidine incorporation into growing cells using mitogenesis assay
|
Rattus norvegicus
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : CoMFA and CoMSIA investigations revealing novel insights into the binding modes of dopamine D3 receptor agonists.
Year : 2005
Volume : 48
Issue : 7
First Page : 2493
Last Page : 2508
Authors : Boeckler F, Ohnmacht U, Lehmann T, Utz W, Hübner H, Gmeiner P.
Abstract : As an extension of a series of dopamine D(3) receptor agonists involving FAUC 54, ex-chiral pool synthesis, and biological evaluation of 3-substituted 7-aminotetrahydroindolizines was performed. Considering the structural features of both series of enantiomers, we developed a novel alignment hypothesis for D(3) agonists, allowing for the placement of the aromatic moieties on two alternative, adjacent positions. CoMFA and CoMSIA analyses yielded significant cross-validated q(2) values of 0.726 and 0.590, respectively, when a newly invented program application (IRAS) controlling the alignment selection proved to be useful. Employing the CoMFA/CoMSIA contribution maps, we were able to transform a previously constructed homology model of the D(3) receptor from an inactive into an activate state. Besides the established ionic interactions, we propose pi-stacking with Phe6.51 and a hydrogen bond between His6.55 and the acyl moiety to be primarily involved in the D(3) receptor binding of FAUC 54 and its analogues.
|
Effective concentration to stimulate human Dopamine receptor D3 mediated [3H]-thymidine incorporation into growing cells using mitogenesis assay
|
Homo sapiens
|
1.5
nM
|
|
Journal : J. Med. Chem.
Title : CoMFA and CoMSIA investigations revealing novel insights into the binding modes of dopamine D3 receptor agonists.
Year : 2005
Volume : 48
Issue : 7
First Page : 2493
Last Page : 2508
Authors : Boeckler F, Ohnmacht U, Lehmann T, Utz W, Hübner H, Gmeiner P.
Abstract : As an extension of a series of dopamine D(3) receptor agonists involving FAUC 54, ex-chiral pool synthesis, and biological evaluation of 3-substituted 7-aminotetrahydroindolizines was performed. Considering the structural features of both series of enantiomers, we developed a novel alignment hypothesis for D(3) agonists, allowing for the placement of the aromatic moieties on two alternative, adjacent positions. CoMFA and CoMSIA analyses yielded significant cross-validated q(2) values of 0.726 and 0.590, respectively, when a newly invented program application (IRAS) controlling the alignment selection proved to be useful. Employing the CoMFA/CoMSIA contribution maps, we were able to transform a previously constructed homology model of the D(3) receptor from an inactive into an activate state. Besides the established ionic interactions, we propose pi-stacking with Phe6.51 and a hydrogen bond between His6.55 and the acyl moiety to be primarily involved in the D(3) receptor binding of FAUC 54 and its analogues.
|
Effective concentration to stimulate human Dopamine receptor D4.2 mediated [3H]thymidine incorporation into growing cells using mitogenesis assay
|
Homo sapiens
|
15.0
nM
|
|
Journal : J. Med. Chem.
Title : CoMFA and CoMSIA investigations revealing novel insights into the binding modes of dopamine D3 receptor agonists.
Year : 2005
Volume : 48
Issue : 7
First Page : 2493
Last Page : 2508
Authors : Boeckler F, Ohnmacht U, Lehmann T, Utz W, Hübner H, Gmeiner P.
Abstract : As an extension of a series of dopamine D(3) receptor agonists involving FAUC 54, ex-chiral pool synthesis, and biological evaluation of 3-substituted 7-aminotetrahydroindolizines was performed. Considering the structural features of both series of enantiomers, we developed a novel alignment hypothesis for D(3) agonists, allowing for the placement of the aromatic moieties on two alternative, adjacent positions. CoMFA and CoMSIA analyses yielded significant cross-validated q(2) values of 0.726 and 0.590, respectively, when a newly invented program application (IRAS) controlling the alignment selection proved to be useful. Employing the CoMFA/CoMSIA contribution maps, we were able to transform a previously constructed homology model of the D(3) receptor from an inactive into an activate state. Besides the established ionic interactions, we propose pi-stacking with Phe6.51 and a hydrogen bond between His6.55 and the acyl moiety to be primarily involved in the D(3) receptor binding of FAUC 54 and its analogues.
|
Low binding affinity towards human dopamine receptor 3 expressed in Chinese hamster ovary cells using [3H]spiperone (0.5 nM) as radioligand
|
Homo sapiens
|
38.0
nM
|
|
Journal : J. Med. Chem.
Title : Pharmacophore-guided drug discovery investigations leading to bioactive 5-aminotetrahydropyrazolopyridines. Implications for the binding mode of heterocyclic dopamine D3 receptor agonists.
Year : 2005
Volume : 48
Issue : 18
First Page : 5771
Last Page : 5779
Authors : Elsner J, Boeckler F, Heinemann FW, Hübner H, Gmeiner P.
Abstract : Taking advantage of a 3D-QSAR based pharmacophore hypothesis, synthesis and biological evaluation of dopaminergic 5-aminotetrahydropyrazolo[1,5-a]pyridines are described. The data displayed substantial and selective D3 receptor affinity for the heterocyclic test compound (+/-)-1 when the enantiomer (S)-1 turned out to be responsible for the D3 binding (K(i) (high) = 4.0 nM). (S)-1 exhibited binding affinity and ligand efficacy comparable to those of our previously described D3 agonist FAUC 54, when subtype selectivity could be significantly improved. The results indicate that the sp(2) nitrogens of the pyrazole and thiazole rings of the dopaminergics (S)-1 and pramipexole, respectively, are pharmacophoric elements of major importance. To provide putative explanations for the high affinity of (S)-1, computational studies were performed employing an active state D3 model.
|
High binding affinity towards human dopamine receptor 3 expressed in Chinese hamster ovary cells using [3H]spiperone (0.5 nM) as radioligand
|
Homo sapiens
|
0.88
nM
|
|
Journal : J. Med. Chem.
Title : Pharmacophore-guided drug discovery investigations leading to bioactive 5-aminotetrahydropyrazolopyridines. Implications for the binding mode of heterocyclic dopamine D3 receptor agonists.
Year : 2005
Volume : 48
Issue : 18
First Page : 5771
Last Page : 5779
Authors : Elsner J, Boeckler F, Heinemann FW, Hübner H, Gmeiner P.
Abstract : Taking advantage of a 3D-QSAR based pharmacophore hypothesis, synthesis and biological evaluation of dopaminergic 5-aminotetrahydropyrazolo[1,5-a]pyridines are described. The data displayed substantial and selective D3 receptor affinity for the heterocyclic test compound (+/-)-1 when the enantiomer (S)-1 turned out to be responsible for the D3 binding (K(i) (high) = 4.0 nM). (S)-1 exhibited binding affinity and ligand efficacy comparable to those of our previously described D3 agonist FAUC 54, when subtype selectivity could be significantly improved. The results indicate that the sp(2) nitrogens of the pyrazole and thiazole rings of the dopaminergics (S)-1 and pramipexole, respectively, are pharmacophoric elements of major importance. To provide putative explanations for the high affinity of (S)-1, computational studies were performed employing an active state D3 model.
|
Low binding affinity towards human dopamine receptor 4.4 expressed in Chinese hamster ovary cells using [3H]spiperone (0.5 nM) as radioligand
|
Homo sapiens
|
130.0
nM
|
|
Journal : J. Med. Chem.
Title : Pharmacophore-guided drug discovery investigations leading to bioactive 5-aminotetrahydropyrazolopyridines. Implications for the binding mode of heterocyclic dopamine D3 receptor agonists.
Year : 2005
Volume : 48
Issue : 18
First Page : 5771
Last Page : 5779
Authors : Elsner J, Boeckler F, Heinemann FW, Hübner H, Gmeiner P.
Abstract : Taking advantage of a 3D-QSAR based pharmacophore hypothesis, synthesis and biological evaluation of dopaminergic 5-aminotetrahydropyrazolo[1,5-a]pyridines are described. The data displayed substantial and selective D3 receptor affinity for the heterocyclic test compound (+/-)-1 when the enantiomer (S)-1 turned out to be responsible for the D3 binding (K(i) (high) = 4.0 nM). (S)-1 exhibited binding affinity and ligand efficacy comparable to those of our previously described D3 agonist FAUC 54, when subtype selectivity could be significantly improved. The results indicate that the sp(2) nitrogens of the pyrazole and thiazole rings of the dopaminergics (S)-1 and pramipexole, respectively, are pharmacophoric elements of major importance. To provide putative explanations for the high affinity of (S)-1, computational studies were performed employing an active state D3 model.
|
High binding affinity towards human dopamine receptor 4.4 expressed in Chinese hamster ovary cells using [3H]spiperone (0.5 nM) as radioligand
|
Homo sapiens
|
8.1
nM
|
|
Journal : J. Med. Chem.
Title : Pharmacophore-guided drug discovery investigations leading to bioactive 5-aminotetrahydropyrazolopyridines. Implications for the binding mode of heterocyclic dopamine D3 receptor agonists.
Year : 2005
Volume : 48
Issue : 18
First Page : 5771
Last Page : 5779
Authors : Elsner J, Boeckler F, Heinemann FW, Hübner H, Gmeiner P.
Abstract : Taking advantage of a 3D-QSAR based pharmacophore hypothesis, synthesis and biological evaluation of dopaminergic 5-aminotetrahydropyrazolo[1,5-a]pyridines are described. The data displayed substantial and selective D3 receptor affinity for the heterocyclic test compound (+/-)-1 when the enantiomer (S)-1 turned out to be responsible for the D3 binding (K(i) (high) = 4.0 nM). (S)-1 exhibited binding affinity and ligand efficacy comparable to those of our previously described D3 agonist FAUC 54, when subtype selectivity could be significantly improved. The results indicate that the sp(2) nitrogens of the pyrazole and thiazole rings of the dopaminergics (S)-1 and pramipexole, respectively, are pharmacophoric elements of major importance. To provide putative explanations for the high affinity of (S)-1, computational studies were performed employing an active state D3 model.
|
High binding affinity towards human dopamine receptor 2 (long) expressed in Chinese hamster ovary cells using [3H]spiperone (0.5 nM) as radioligand
|
Homo sapiens
|
21.0
nM
|
|
Journal : J. Med. Chem.
Title : Pharmacophore-guided drug discovery investigations leading to bioactive 5-aminotetrahydropyrazolopyridines. Implications for the binding mode of heterocyclic dopamine D3 receptor agonists.
Year : 2005
Volume : 48
Issue : 18
First Page : 5771
Last Page : 5779
Authors : Elsner J, Boeckler F, Heinemann FW, Hübner H, Gmeiner P.
Abstract : Taking advantage of a 3D-QSAR based pharmacophore hypothesis, synthesis and biological evaluation of dopaminergic 5-aminotetrahydropyrazolo[1,5-a]pyridines are described. The data displayed substantial and selective D3 receptor affinity for the heterocyclic test compound (+/-)-1 when the enantiomer (S)-1 turned out to be responsible for the D3 binding (K(i) (high) = 4.0 nM). (S)-1 exhibited binding affinity and ligand efficacy comparable to those of our previously described D3 agonist FAUC 54, when subtype selectivity could be significantly improved. The results indicate that the sp(2) nitrogens of the pyrazole and thiazole rings of the dopaminergics (S)-1 and pramipexole, respectively, are pharmacophoric elements of major importance. To provide putative explanations for the high affinity of (S)-1, computational studies were performed employing an active state D3 model.
|
High binding affinity towards human dopamine receptor 2 (short) expressed in Chinese hamster ovary cells using [3H]spiperone (0.5 nM) as radioligand
|
Homo sapiens
|
21.0
nM
|
|
Journal : J. Med. Chem.
Title : Pharmacophore-guided drug discovery investigations leading to bioactive 5-aminotetrahydropyrazolopyridines. Implications for the binding mode of heterocyclic dopamine D3 receptor agonists.
Year : 2005
Volume : 48
Issue : 18
First Page : 5771
Last Page : 5779
Authors : Elsner J, Boeckler F, Heinemann FW, Hübner H, Gmeiner P.
Abstract : Taking advantage of a 3D-QSAR based pharmacophore hypothesis, synthesis and biological evaluation of dopaminergic 5-aminotetrahydropyrazolo[1,5-a]pyridines are described. The data displayed substantial and selective D3 receptor affinity for the heterocyclic test compound (+/-)-1 when the enantiomer (S)-1 turned out to be responsible for the D3 binding (K(i) (high) = 4.0 nM). (S)-1 exhibited binding affinity and ligand efficacy comparable to those of our previously described D3 agonist FAUC 54, when subtype selectivity could be significantly improved. The results indicate that the sp(2) nitrogens of the pyrazole and thiazole rings of the dopaminergics (S)-1 and pramipexole, respectively, are pharmacophoric elements of major importance. To provide putative explanations for the high affinity of (S)-1, computational studies were performed employing an active state D3 model.
|
Effective concentration against dopamine D3 receptor
|
Homo sapiens
|
1.5
nM
|
|
Journal : J. Med. Chem.
Title : Pharmacophore-guided drug discovery investigations leading to bioactive 5-aminotetrahydropyrazolopyridines. Implications for the binding mode of heterocyclic dopamine D3 receptor agonists.
Year : 2005
Volume : 48
Issue : 18
First Page : 5771
Last Page : 5779
Authors : Elsner J, Boeckler F, Heinemann FW, Hübner H, Gmeiner P.
Abstract : Taking advantage of a 3D-QSAR based pharmacophore hypothesis, synthesis and biological evaluation of dopaminergic 5-aminotetrahydropyrazolo[1,5-a]pyridines are described. The data displayed substantial and selective D3 receptor affinity for the heterocyclic test compound (+/-)-1 when the enantiomer (S)-1 turned out to be responsible for the D3 binding (K(i) (high) = 4.0 nM). (S)-1 exhibited binding affinity and ligand efficacy comparable to those of our previously described D3 agonist FAUC 54, when subtype selectivity could be significantly improved. The results indicate that the sp(2) nitrogens of the pyrazole and thiazole rings of the dopaminergics (S)-1 and pramipexole, respectively, are pharmacophoric elements of major importance. To provide putative explanations for the high affinity of (S)-1, computational studies were performed employing an active state D3 model.
|
Agonist activity at human recombinant dopamine D2 receptor expressed in rat pituitary cells assessed as inhibition of forskolin-stimulated cAMP accumulation
|
Homo sapiens
|
27.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of a functionally selective D3 agonist and its in vivo delivery via the intranasal route.
Year : 2007
Volume : 17
Issue : 24
First Page : 6691
Last Page : 6696
Authors : Blagg J, Allerton CM, Batchelor DV, Baxter AD, Burring DJ, Carr CL, Cook AS, Nichols CL, Phipps J, Sanderson VG, Verrier H, Wong S.
Abstract : This paper reports the synthesis and biological activity of a novel series of aryl-morpholine dopamine receptor agonists. Several compounds show high levels of functional selectivity for the D3 over the D2 dopamine receptor. Compound 26 has >1000-fold functional selectivity and has been successfully progressed in vivo using an intranasal delivery route.
|
Agonist activity at human recombinant dopamine D3 receptor expressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP accumulation
|
Homo sapiens
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of a functionally selective D3 agonist and its in vivo delivery via the intranasal route.
Year : 2007
Volume : 17
Issue : 24
First Page : 6691
Last Page : 6696
Authors : Blagg J, Allerton CM, Batchelor DV, Baxter AD, Burring DJ, Carr CL, Cook AS, Nichols CL, Phipps J, Sanderson VG, Verrier H, Wong S.
Abstract : This paper reports the synthesis and biological activity of a novel series of aryl-morpholine dopamine receptor agonists. Several compounds show high levels of functional selectivity for the D3 over the D2 dopamine receptor. Compound 26 has >1000-fold functional selectivity and has been successfully progressed in vivo using an intranasal delivery route.
|
Agonist activity at human dopamine D2 receptor expressed in CHO cells assessed as inhibition of forskolin-stimulated cAMP production
|
Homo sapiens
|
5.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : A novel synthesis and pharmacological evaluation of a potential dopamine D1/D2 agonist: 1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol.
Year : 2008
Volume : 16
Issue : 6
First Page : 3438
Last Page : 3444
Authors : Liu D, Dijkstra D, de Vries JB, Wikström HV.
Abstract : Previously, we have demonstrated that enone prodrugs of dopaminergic catecholamines represent a new type of dopamine (DA) agonist. Trans-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol (TL-334), the active form of trans-1-propyl-2,3,4,4a,5,7,8,9,10,10a-decahydro-1H-benzo[g]quinolin-6-one (GMC-6650), in vivo showed an extremely potent dopaminergic activity. Here, we report a novel synthesis and a pharmacological evaluation of TL-334 by means of microdialysis.
|
Displacement of [3H]PD128907 from dopamine D3 receptor in Sprague-Dawley rat ventral striatum
|
Rattus norvegicus
|
0.78
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and evaluation of potent and selective ligands for the dopamine 3 (D3) receptor with a novel in vivo behavioral profile.
Year : 2008
Volume : 51
Issue : 19
First Page : 5905
Last Page : 5908
Authors : Chen J, Collins GT, Zhang J, Yang CY, Levant B, Woods J, Wang S.
Abstract : A series of compounds structurally related to pramipexole were designed, synthesized, and evaluated as ligands for the dopamine 3 (D3) receptor. Compound 12 has a K(i) value of 0.41 nM to D3 and a selectivity of >30000- and 800-fold over the D1-like and D2 receptors, respectively. Our in vivo functional assays showed that this compound is a partial agonist at the D3 receptor with no detectable activity at the D2 receptor.
|
Displacement of [3H]Spiperone from D2 receptor in Sprague-Dawley rat caudate-putamen
|
Rattus norvegicus
|
3.1
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and evaluation of potent and selective ligands for the dopamine 3 (D3) receptor with a novel in vivo behavioral profile.
Year : 2008
Volume : 51
Issue : 19
First Page : 5905
Last Page : 5908
Authors : Chen J, Collins GT, Zhang J, Yang CY, Levant B, Woods J, Wang S.
Abstract : A series of compounds structurally related to pramipexole were designed, synthesized, and evaluated as ligands for the dopamine 3 (D3) receptor. Compound 12 has a K(i) value of 0.41 nM to D3 and a selectivity of >30000- and 800-fold over the D1-like and D2 receptors, respectively. Our in vivo functional assays showed that this compound is a partial agonist at the D3 receptor with no detectable activity at the D2 receptor.
|
Displacement of [3H]-R(+)-7-OHDPAT from dopamine D3 receptor in rat brain homogenates
|
Rattus norvegicus
|
0.78
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : High-affinity and selective dopamine D₃ receptor full agonists.
Year : 2012
Volume : 22
Issue : 17
First Page : 5612
Last Page : 5617
Authors : Chen J, Levant B, Wang S.
Abstract : We have designed, synthesized and evaluated a series of new compounds with the goal to identify potent and selective D(3) ligands. The two most potent and selective new D(3) ligands are compounds 38 and 52, which bind to the D(3) receptors with a K(i) value of <nM and display a selectivity of 450-494 times over the D(2) receptors and >10,000 times over the D(1) receptors. Both 38 and 52 are full agonists with high potency at the D(3) receptor in a D(3) functional assay.
|
Displacement of [3H]Spiperone from dopamine D2 like receptor in rat brain homogenates
|
Rattus norvegicus
|
3.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : High-affinity and selective dopamine D₃ receptor full agonists.
Year : 2012
Volume : 22
Issue : 17
First Page : 5612
Last Page : 5617
Authors : Chen J, Levant B, Wang S.
Abstract : We have designed, synthesized and evaluated a series of new compounds with the goal to identify potent and selective D(3) ligands. The two most potent and selective new D(3) ligands are compounds 38 and 52, which bind to the D(3) receptors with a K(i) value of <nM and display a selectivity of 450-494 times over the D(2) receptors and >10,000 times over the D(1) receptors. Both 38 and 52 are full agonists with high potency at the D(3) receptor in a D(3) functional assay.
|
Displacement of [3H]R(+)-7-OH-DPAT from Sprague-Dawley rat dopamine D3 receptor after 90 mins
|
Rattus norvegicus
|
0.45
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : CJ-1639: A Potent and Highly Selective Dopamine D3 Receptor Full Agonist.
Year : 2011
Volume : 2
Issue : 8
First Page : 620
Last Page : 625
Authors : Chen J, Collins GT, Levant B, Woods J, Deschamps JR, Wang S.
Abstract : We have identified several ligands with high binding affinities to the dopamine D3 receptor and excellent selectivity over the D2 and D1 receptors. CJ-1639 (17) binds to the D3 receptor with a K(i) value of 0.50 nM and displays a selectivity of >5,000 times over D2 and D1 receptors in binding assays using dopamine receptors expressed in the native rat brain tissues. CJ-1639 binds to human D3 receptor with a K(i) value of 3.61 nM and displays over >1000-fold selectivity over human D1 and D2 receptors. CJ-1639 is active at 0.01 mg/kg at the dopamine D3 receptor in the rat and only starts to show a modest D2 activity at doses as high as 10 mg/kg. CJ-1639 is the most potent and selective D3 full agonist reported to date.
|
Displacement of [3H]Spiperone from Sprague-Dawley rat dopamine D2-like receptor after 90 mins
|
Rattus norvegicus
|
39.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : CJ-1639: A Potent and Highly Selective Dopamine D3 Receptor Full Agonist.
Year : 2011
Volume : 2
Issue : 8
First Page : 620
Last Page : 625
Authors : Chen J, Collins GT, Levant B, Woods J, Deschamps JR, Wang S.
Abstract : We have identified several ligands with high binding affinities to the dopamine D3 receptor and excellent selectivity over the D2 and D1 receptors. CJ-1639 (17) binds to the D3 receptor with a K(i) value of 0.50 nM and displays a selectivity of >5,000 times over D2 and D1 receptors in binding assays using dopamine receptors expressed in the native rat brain tissues. CJ-1639 binds to human D3 receptor with a K(i) value of 3.61 nM and displays over >1000-fold selectivity over human D1 and D2 receptors. CJ-1639 is active at 0.01 mg/kg at the dopamine D3 receptor in the rat and only starts to show a modest D2 activity at doses as high as 10 mg/kg. CJ-1639 is the most potent and selective D3 full agonist reported to date.
|
Agonist activity at Rattus norvegicus (rat) dopamine D2/D3 receptor transfected in african green monkey COS7 cells assessed as inhibition of forskolin-stimulated adenylyl cyclase activity after 10 min
|
Rattus norvegicus
|
1.98
nM
|
|
Journal : Med Chem Res
Title : Heterodimerization of G-Protein-Coupled Receptors Reveals an Unexpected Level of Pharmacological Diversity
Year : 2004
Volume : 13
Issue : 1
First Page : 25
Last Page : 33
Authors : Maggio R, Scarselli M, Novi F, Corsini GU
|
Agonist activity at Rattus norvegicus (rat) dopamine D2 receptor transfected in african green monkey COS7 cells assessed as inhibition of forskolin-stimulated adenylyl cyclase activity after 10 min
|
Rattus norvegicus
|
21.5
nM
|
|
Journal : Med Chem Res
Title : Heterodimerization of G-Protein-Coupled Receptors Reveals an Unexpected Level of Pharmacological Diversity
Year : 2004
Volume : 13
Issue : 1
First Page : 25
Last Page : 33
Authors : Maggio R, Scarselli M, Novi F, Corsini GU
|
Displacement of [3H]nemonapride from Rattus norvegicus (rat) wild type dopamine D3 receptor transfected in african green monkey COS7 cells after 1 hr by beta scintillation counting
|
Rattus norvegicus
|
7.8
nM
|
|
Journal : Med Chem Res
Title : Heterodimerization of G-Protein-Coupled Receptors Reveals an Unexpected Level of Pharmacological Diversity
Year : 2004
Volume : 13
Issue : 1
First Page : 25
Last Page : 33
Authors : Maggio R, Scarselli M, Novi F, Corsini GU
|
Displacement of [3H]nemonapride from Rattus norvegicus (rat) chimeric dopamine D3 trunk/D2 tail receptor transfected in african green monkey COS7 cells after 1 hr by beta scintillation counting
|
Rattus norvegicus
|
133.0
nM
|
|
Journal : Med Chem Res
Title : Heterodimerization of G-Protein-Coupled Receptors Reveals an Unexpected Level of Pharmacological Diversity
Year : 2004
Volume : 13
Issue : 1
First Page : 25
Last Page : 33
Authors : Maggio R, Scarselli M, Novi F, Corsini GU
|
Displacement of [3H]nemonapride from Rattus norvegicus (rat) chimeric dopamine D2 trunk/D3 tail receptor transfected in african green monkey COS7 cells after 1 hr by beta scintillation counting
|
Rattus norvegicus
|
17.1
nM
|
|
Journal : Med Chem Res
Title : Heterodimerization of G-Protein-Coupled Receptors Reveals an Unexpected Level of Pharmacological Diversity
Year : 2004
Volume : 13
Issue : 1
First Page : 25
Last Page : 33
Authors : Maggio R, Scarselli M, Novi F, Corsini GU
|
Displacement of [3H]nemonapride from Rattus norvegicus (rat) wild type dopamine D2 receptor transfected in african green monkey COS7 cells after 1 hr by beta scintillation counting
|
Rattus norvegicus
|
450.0
nM
|
|
Journal : Med Chem Res
Title : Heterodimerization of G-Protein-Coupled Receptors Reveals an Unexpected Level of Pharmacological Diversity
Year : 2004
Volume : 13
Issue : 1
First Page : 25
Last Page : 33
Authors : Maggio R, Scarselli M, Novi F, Corsini GU
|
Agonist activity at dopamine D3 receptor (unknown origin)
|
Homo sapiens
|
8.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and binding affinity of new 1,4-disubstituted triazoles as potential dopamine D(3) receptor ligands.
Year : 2013
Volume : 23
Issue : 20
First Page : 5586
Last Page : 5591
Authors : Insua I, Alvarado M, Masaguer CF, Iglesias A, Brea J, Loza MI, Carro L.
Abstract : A series of new 1,4-disubstituted triazoles was prepared from appropriate arylacetylenes and aminoalkylazides using click chemistry methodology. These compounds were evaluated as potential ligands on several subtypes of dopamine receptors in in vitro competition assays, showing high affinity for dopamine D3 receptors, lower affinity for D2 and D4, and no affinity for the D1 receptors. Compound 18 displayed the highest affinity at the D3 receptor with a Ki value of 2.7 nM, selectivity over D2 (70-fold) and D4 (200-fold), and behaviour as a competitive antagonist in the low nanomolar range.
|
Displacement of [3H]spiperone from human D2S receptor expressed in CHO cells
|
Homo sapiens
|
60.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-guided development of dual β2 adrenergic/dopamine D2 receptor agonists.
Year : 2016
Volume : 24
Issue : 12
First Page : 2641
Last Page : 2653
Authors : Weichert D, Stanek M, Hübner H, Gmeiner P.
Abstract : Aiming to discover dual-acting β2 adrenergic/dopamine D2 receptor ligands, a structure-guided approach for the evolution of GPCR agonists that address multiple targets was elaborated. Starting from GPCR crystal structures, we describe the design, synthesis and biological investigation of a defined set of compounds leading to the identification of the benzoxazinone (R)-3, which shows agonist properties at the adrenergic β2 receptor and substantial G protein-promoted activation at the D2 receptor. This directed approach yielded molecular probes with tuned dual activity. The congener desOH-3 devoid of the benzylic hydroxyl function was shown to be a β2 adrenergic antagonist/D2 receptor agonist with Ki values in the low nanomolar range. The compounds may serve as a promising starting point for the investigation and treatment of neurological disorders.
|
Agonist activity at dopamine D2 receptor short isoform (unknown origin) expressed in mouse NIH/3T3 cells by R-SAT assay
|
Homo sapiens
|
7.079
nM
|
|
Title : Selective serotonin 2A/2C receptor inverse agonists as therapeutics for neurodegenerative diseases
Year : 2004
|
Partial agonist activity at human D2SR expressed in HEK293T cells co-expressing (EA)beta-arrestin2 assessed as induction of beta-arrestin2 recruitment after 5 hrs by chemiluminescence assay
|
Homo sapiens
|
27.0
nM
|
|
Journal : J Med Chem
Title : Hydroxy-Substituted Heteroarylpiperazines: Novel Scaffolds for β-Arrestin-Biased D2R Agonists.
Year : 2017
Volume : 60
Issue : 11
First Page : 4693
Last Page : 4713
Authors : Männel B, Dengler D, Shonberg J, Hübner H, Möller D, Gmeiner P.
Abstract : By means of a formal structural hybridization of the antipsychotic drug aripiprazole and the heterocyclic catecholamine surrogates present in the β2-adrenoceptor agonists procaterol and BI-167107 (4), we designed and synthesized a collection of novel hydroxy-substituted heteroarylpiperazines and heteroarylhomopiperazines with high dopamine D2 receptor (D2R) affinity. In contrast to the weak agonistic behavior of aripiprazole, these ligands are capable of effectively mimicking those interactions of dopamine and the D2R that are crucial for an active state, leading to the recruitment of β-arrestin-2. Interestingly, some ligands show considerably lower intrinsic activity in guanine nucleotide exchange experiments at D2R and consequently represent biased agonists favoring β-arrestin-2 recruitment over canonical G protein activation. The ligands' agonistic properties are substantially driven by the presence of an endocyclic H-bond donor.
|
Agonist activity at human D2S receptor expressed in HEK293T cell membranes coexpressing Galphao1 assessed as induction of nucleotide exchange preincubated for 30 mins followed by addition of [35S]GTPgammaS measured after 30 mins by [35S]GTPgammaS binding assay
|
Homo sapiens
|
100.0
nM
|
|
Journal : J Med Chem
Title : Hydroxy-Substituted Heteroarylpiperazines: Novel Scaffolds for β-Arrestin-Biased D2R Agonists.
Year : 2017
Volume : 60
Issue : 11
First Page : 4693
Last Page : 4713
Authors : Männel B, Dengler D, Shonberg J, Hübner H, Möller D, Gmeiner P.
Abstract : By means of a formal structural hybridization of the antipsychotic drug aripiprazole and the heterocyclic catecholamine surrogates present in the β2-adrenoceptor agonists procaterol and BI-167107 (4), we designed and synthesized a collection of novel hydroxy-substituted heteroarylpiperazines and heteroarylhomopiperazines with high dopamine D2 receptor (D2R) affinity. In contrast to the weak agonistic behavior of aripiprazole, these ligands are capable of effectively mimicking those interactions of dopamine and the D2R that are crucial for an active state, leading to the recruitment of β-arrestin-2. Interestingly, some ligands show considerably lower intrinsic activity in guanine nucleotide exchange experiments at D2R and consequently represent biased agonists favoring β-arrestin-2 recruitment over canonical G protein activation. The ligands' agonistic properties are substantially driven by the presence of an endocyclic H-bond donor.
|
Partial agonist activity at human D2SR expressed in HEK293T cells co-expressing (EA)beta-arrestin2 and GRK2 assessed as induction of beta-arrestin2 recruitment after 5 hrs by chemiluminescence assay
|
Homo sapiens
|
9.6
nM
|
|
Journal : J Med Chem
Title : Hydroxy-Substituted Heteroarylpiperazines: Novel Scaffolds for β-Arrestin-Biased D2R Agonists.
Year : 2017
Volume : 60
Issue : 11
First Page : 4693
Last Page : 4713
Authors : Männel B, Dengler D, Shonberg J, Hübner H, Möller D, Gmeiner P.
Abstract : By means of a formal structural hybridization of the antipsychotic drug aripiprazole and the heterocyclic catecholamine surrogates present in the β2-adrenoceptor agonists procaterol and BI-167107 (4), we designed and synthesized a collection of novel hydroxy-substituted heteroarylpiperazines and heteroarylhomopiperazines with high dopamine D2 receptor (D2R) affinity. In contrast to the weak agonistic behavior of aripiprazole, these ligands are capable of effectively mimicking those interactions of dopamine and the D2R that are crucial for an active state, leading to the recruitment of β-arrestin-2. Interestingly, some ligands show considerably lower intrinsic activity in guanine nucleotide exchange experiments at D2R and consequently represent biased agonists favoring β-arrestin-2 recruitment over canonical G protein activation. The ligands' agonistic properties are substantially driven by the presence of an endocyclic H-bond donor.
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media, using NBS plates, by OD(600)
|
Staphylococcus aureus subsp. aureus
|
-18.52
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
2.75
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
5.86
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
15.84
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
8.28
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
5.21
%
|
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
-0.71
%
|
|
|
Displacement of [3H]-(R)-(+)-7-OH-DPAT from recombinant human D2L receptor expressed in HEK293 cell membranes measured after 90 mins by microbeta scintillation counting analysis
|
Homo sapiens
|
11.1
nM
|
|
Journal : J Med Chem
Title : The Significance of Chirality in Drug Design and Synthesis of Bitopic Ligands as D3 Receptor (D3R) Selective Agonists.
Year : 2019
Volume : 62
Issue : 13
First Page : 6287
Last Page : 6314
Authors : Battiti FO, Cemaj SL, Guerrero AM, Shaik AB, Lam J, Rais R, Slusher BS, Deschamps JR, Imler GH, Newman AH, Bonifazi A.
Abstract : Because of the large degree of homology among dopamine D2-like receptors, discovering ligands capable of discriminating between the D2, D3, and D4 receptor subtypes remains a significant challenge. Previous work has exemplified the use of bitopic ligands as a powerful strategy in achieving subtype selectivity for agonists and antagonists alike. Inspired by the potential for chemical modification of the D3 preferential agonists (+)-PD128,907 (1) and PF592,379 (2), we synthesized bitopic structures to further improve their D3R selectivity. We found that the (2S,5S) conformation of scaffold 2 resulted in a privileged architecture with increased affinity and selectivity for the D3R. In addition, a cyclopropyl moiety incorporated into the linker and full resolution of the chiral centers resulted in lead compound 53 and eutomer 53a that demonstrate significantly higher D3R binding selectivities than the reference compounds. Moreover, the favorable metabolic stability in rat liver microsomes supports future studies in in vivo models of dopamine system dysregulation.
|
Displacement of [3H]-(R)-(+)-7-OH-DPAT from recombinant human D3 receptor expressed in HEK293 cell membranes measured after 90 mins by microbeta scintillation counting analysis
|
Homo sapiens
|
1.32
nM
|
|
Journal : J Med Chem
Title : The Significance of Chirality in Drug Design and Synthesis of Bitopic Ligands as D3 Receptor (D3R) Selective Agonists.
Year : 2019
Volume : 62
Issue : 13
First Page : 6287
Last Page : 6314
Authors : Battiti FO, Cemaj SL, Guerrero AM, Shaik AB, Lam J, Rais R, Slusher BS, Deschamps JR, Imler GH, Newman AH, Bonifazi A.
Abstract : Because of the large degree of homology among dopamine D2-like receptors, discovering ligands capable of discriminating between the D2, D3, and D4 receptor subtypes remains a significant challenge. Previous work has exemplified the use of bitopic ligands as a powerful strategy in achieving subtype selectivity for agonists and antagonists alike. Inspired by the potential for chemical modification of the D3 preferential agonists (+)-PD128,907 (1) and PF592,379 (2), we synthesized bitopic structures to further improve their D3R selectivity. We found that the (2S,5S) conformation of scaffold 2 resulted in a privileged architecture with increased affinity and selectivity for the D3R. In addition, a cyclopropyl moiety incorporated into the linker and full resolution of the chiral centers resulted in lead compound 53 and eutomer 53a that demonstrate significantly higher D3R binding selectivities than the reference compounds. Moreover, the favorable metabolic stability in rat liver microsomes supports future studies in in vivo models of dopamine system dysregulation.
|
Agonist activity at human D3R expressed in CHOK1 cells assessed as induction of beta-arrestin recruitment measured after 90 mins by beta-galactosidase based PathHunter assay
|
Homo sapiens
|
5.4
nM
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-methylspiperon from human D3R expressed in HEK293 cell membranes measured after 90 mins in EBSS buffer by topcount assay
|
Homo sapiens
|
8.2
nM
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-methylspiperon from human D2RL expressed in HEK293 cell membranes measured after 90 mins by topcount assay
|
Homo sapiens
|
4.7
nM
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-methylspiperon from human D3R expressed in HEK293 cell membranes measured after 90 mins in Tris buffer by topcount assay
|
Homo sapiens
|
13.0
nM
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-methylspiperon from human D3R expressed in HEK293 cell membranes measured after 90 mins in Tris buffer containing NaCl by topcount assay
|
Homo sapiens
|
17.0
nM
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-7-OH-DPAT from human D3R expressed in HEK293 cell membranes measured after 90 mins in EBSS buffer by topcount assay
|
Homo sapiens
|
1.1
nM
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-7-OH-DPAT from human D3R expressed in HEK293 cell membranes measured after 90 mins in Tris buffer by topcount assay
|
Homo sapiens
|
0.94
nM
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-7-OH-DPAT from human D3R expressed in HEK293 cell membranes measured after 90 mins in Tris buffer containing NaCl by topcount assay
|
Homo sapiens
|
5.6
nM
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-rauwolscine from recombinant human alpha2A adrenergic receptor stably expressed in MDCK cell membranes measured after 90 mins by microbeta scintillation counting method
|
Homo sapiens
|
75.7
nM
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-rauwolscine from recombinant human alpha2B adrenergic receptor transiently expressed in HEKT cell membranes measured after 90 mins by microbeta scintillation counting method
|
Homo sapiens
|
67.7
nM
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-rauwolscine from recombinant human alpha2C adrenergic receptor stably expressed in MDCK cell membranes measured after 90 mins by microbeta scintillation counting method
|
Homo sapiens
|
52.2
nM
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-N-methylspiperone from recombinant human D2 receptor stably expressed in fibroblast cell membranes measured after 90 mins by microbeta scintillation counting method
|
Homo sapiens
|
743.7
nM
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-N-methylspiperone from D3 receptor (unknown origin) measured after 90 mins by microbeta scintillation counting method
|
Homo sapiens
|
0.9
nM
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-N-methylspiperone from recombinant human D4 receptor stably expressed in HEK cell membranes measured after 90 mins by microbeta scintillation counting method
|
Homo sapiens
|
29.0
nM
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-Way100635 from recombinant human 5HT1A receptor stably expressed in CHO cell membranes at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]5-CT from recombinant human 5HT1B receptor stably expressed in HEK cell membranes at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]5-CT from recombinant human 5HT1D receptor transiently expressed in HEKT cell membranes at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]5-HT from recombinant human 5HT1E receptor stably expressed in HEK cell membranes at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-Ketanserin from 5HT2A receptor (unknown origin) at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-LSD from recombinant human 5HT2B receptor stably expressed in HEK cell membranes at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-Mesulergine from recombinant human 5HT2C receptor expressed in HEK cell membranes at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]GR65630 from recombinant human 5HT3 receptor transiently expressed in HEKT cell membranes at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-LSD from recombinant human 5HT5A receptor stably expressed in Flp-In CHO cell membranes at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-LSD from recombinant human 5HT6 receptor stably expressed in HEK cell membranes at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-LSD from recombinant human 5HT7A receptor stably expressed in HEK cell membranes at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-prazosin from recombinant human alpha1A adrenergic receptor at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-prazosin from recombinant human alpha1B adrenergic receptor transiently expressed in HEKT cell membranes at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-prazosin from recombinant human alpha1D adrenergic receptor at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-rauwolscine from recombinant human alpha2A adrenergic receptor stably expressed in MDCK cell membranes at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-rauwolscine from recombinant human alpha2B adrenergic receptor transiently expressed in HEKT cell membranes at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-rauwolscine from recombinant human alpha2C adrenergic receptor stably expressed in MDCK cell membranes at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [125I]-pindolol from recombinant human beta1 adrenergic receptor expressed in CHO Flp-In cell membranes at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-CGP12177 from recombinant human beta2 adrenergic receptor expressed in HEK Flp-In cell membranes at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-CGP12177 from recombinant human beta3 adrenergic receptor expressed in HEK Flp-In cell membranes at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-SCH23390 from recombinant human D1 receptor transiently expressed in HEKT cell membranes at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-N-methylspiperone from recombinant human D2 receptor stably expressed in fibroblast cell membranes at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-N-methylspiperone from D3 receptor (unknown origin) at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-N-methylspiperone from recombinant human D4 receptor stably expressed in HEK cell membranes at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-SCH23390 from recombinant human D5 receptor transiently expressed in HEKT cell membranes at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-Win35428 from human DAT expressed in stable HEK cell membranes at 10 uM after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-DADLE from recombinant human DOR stably expressed in HEK cell membranes at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-pyrilamine from human histamine H1 receptor expressed in stable HEK cell membranes at 10 uM after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [125I]-Iodo-aminopotentidine from human histamine H2 receptor expressed in stable HEK cell membranes at 10 uM after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-alpha-methylhistamine from recombinant human histamine H3 receptor expressed in HEK Flp-In cell membranes at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-Histamine from recombinant human histamine H4 receptor expressed in HEKT cell membranes at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-U69593 from KOR (unknown origin) at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-QNB/[3H]-NMS from human muscarinic M1 receptor expressed in stable CHO cell membranes at 10 uM after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-QNB/[3H]-NMS from human muscarinic M2 receptor expressed in stable CHO cell membranes at 10 uM after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-QNB/[3H]-NMS from human muscarinic M3 receptor expressed in stable CHO cell membranes at 10 uM after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-QNB/[3H]-NMS from human muscarinic M4 receptor expressed in stable CHO cell membranes at 10 uM after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-QNB/[3H]-NMS from human muscarinic M5 receptor expressed in stable CHO cell membranes at 10 uM after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-DAMGO from recombinant human MOR stably expressed in HEK cell membranes at 10 uM measured after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-Nisoxetine from human NET receptor expressed in stable HEK cell membranes at 10 uM after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-citalopram from human SERT receptor expressed in stable HEK cell membranes at 10 uM after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-pentazocine from sigma1 receptor (unknown origin) at 10 uM after 90 mins by microbeta scintillation counting method relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
Displacement of [3H]-DTG from sigma 2 receptor (unknown origin) at 10 uM measured after 90 mins by microbeta counting analysis relative to control
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist.
Year : 2020
Volume : 63
Issue : 10
First Page : 5526
Last Page : 5567
Authors : Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR.
Abstract : To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-2.27
%
|
|
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
|
0.35
%
|
|
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
|
0.35
%
|
|
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.
