|
Equilibrium dissociation constant (KD) for Competitive binding between [3H]WIN-35428 and the compound at human transporter-hDAT
|
None
|
490.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of a potent wide-spectrum serotonin-, norepinephrine-, dopamine-reuptake inhibitor (SNDRI) and a species-selective dopamine-reuptake inhibitor based on the gamma-amino alcohol functional group.
Year : 1998
Volume : 8
Issue : 5
First Page : 487
Last Page : 492
Authors : Carlier PR, Lo MM, Lo PC, Richelson E, Tatsumi M, Reynolds IJ, Sharma TA.
Abstract : A series of gamma-amino alcohols were synthesized and screened for reuptake inhibition and noncompetitive NMDA antagonism. Compound (+/-)-3f simultaneously and potently inhibits reuptake of 5-HT, NE, and DA, representing a potential wide-spectrum reuptake inhibitor antidepressant. In addition, comparative rat and human studies uncovered a species-selective DA reuptake inhibitor (+/-)-2e, KD(hDAT)/KD(rDAT) = 97.
|
Displacement of [3H]WIN-35428(0.5 nM) from Dopamine transporter
|
Rattus norvegicus
|
623.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and ligand binding of tropane ring analogues of paroxetine.
Year : 1998
Volume : 41
Issue : 2
First Page : 247
Last Page : 257
Authors : Keverline-Frantz KI, Boja JW, Kuhar MJ, Abraham P, Burgess JP, Lewin AH, Carroll FI.
Abstract : (3S,4R)-4-(4-Fluorophenyl)-3-[[3,4-(methylenedioxy)phenoxy]methyl] piperidine [(3S,9R)-3, paroxetine] is a selective serotonin reuptake inhibitor (SSRI) used as an antidepressant in humans. In previous studies, we reported that certain (1R)-3 beta-(substituted phenyl)nortropane-2 beta-carboxylic acid methyl esters (2a) exhibited high affinity and reasonable selectivity for the serotonin transporter (5-HTT). The major structural differences between 2a and (3S,4R)-3 are that 2a possesses a different absolute stereochemistry and has an ethylene bridge not present in 3. In addition, 2a possesses a carbomethoxy substituent adjacent to the aryl ring, whereas (3S,4R)-3 contains a [3,4-(methylenedioxy)phenoxy]methyl group. In this study, we present the synthesis and biological evaluations of six of the possible eight isomers of 3-(4-fluorophenyl)-2-[[3,4-(methylenedioxy)phenoxy]methyl]nortropane+ ++ (4). The data for inhibition of [3H]paroxetine binding show that (1R)-2 beta, 3 alpha-4c, which has the same stereochemistry as paroxetine, has the highest affinity at the 5-HTT. Strikingly, the most potent compounds for inhibition of [3H]WIN-35,428 binding were not the (1R)-2 beta, 3 beta-isomers but rather (1R)-2 beta, 3 alpha-4c and (1S)-2 beta, 3 alpha-4f. Conformational analyses show that these isomers exist in a flattened boat conformation with pseudoequatorial substituents. Thus, the binding data show that this conformation is recognized by the DAT-associated binding site and also suggest that this conformation of paroxetine is recognized by the 5-HTT-associated binding site.
|
Inhibitory constant towards reuptake of [125I]-12 from dopamine transporter in rat striatal membranes
|
None
|
400.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and characterization of radioiodinated N-(3-iodopropen-1-yl)-2 beta-carbomethoxy-3 beta-(4-chlorophenyl)tropanes: potential dopamine reuptake site imaging agents.
Year : 1994
Volume : 37
Issue : 10
First Page : 1535
Last Page : 1542
Authors : Goodman MM, Kung MP, Kabalka GW, Kung HF, Switzer R.
Abstract : Methods have been developed for the preparation of radioiodinated N-substituted 2 beta-carbomethoxy-3 beta-(4-chlorophenyl)tropanes. The syntheses, physical properties, radiolabeling, and characterization of the pharmacological properties of N-(3(Z)-iodopropen-1-yl)-2 beta-carbomethoxy-3 beta-(4-chlorophenyl)tropane (12) and N-(3(E)-iodopropen-1-yl)-2 beta-carbomethoxy-3 beta-(4-chlorophenyl)tropane (13) are described. 2 beta-Carbomethoxy-3 beta-(p-substituted-phenyl)tropanes are potent ligands for the dopamine transporter. The radioiodinated derivatives are of interest because of the high uptake and prolonged striatal retention that may result from specific binding to low-capacity, high-affinity, dopamine reuptake sites. Radioiodine was introduced into the 3Z and 3E-position of N-(3-iodopropen-1-yl)-2 beta-carbomethoxy-3 beta-(4-chlorophenyl)tropane by iododemetalation of the corresponding 3-(tri-n-butylstannyl) derivatives. Competition binding data of various dopamine reuptake ligands with rat striatal tissue preparation for either [125I]-12 or [125I]-13 exhibited the following order of potency: E-13 > Z-12 > GBR 12909 >> mazindol >>> (-)-cocaine. Tissue distribution studies in rats showed that the E-13 was the best analogue. E-13 showed high striatal uptake (60 min, 1.23% dose/g; 120 min, 0.61% dose/g) and high striatal to cerebellum ratios (60 min, 15.9/1; 120 min, 16.5/1). These studies indicate that iodine-123-labeled E-13 is a potentially useful agent for imaging the dopamine reuptake sites by single-photon-emission computerized tomography.
|
Tested in vitro for dopamine(DA) neuronal uptake inhibition
|
None
|
460.0
nM
|
|
Journal : J. Med. Chem.
Title : Pyrroloisoquinoline antidepressants. 3. A focus on serotonin.
Year : 1990
Volume : 33
Issue : 10
First Page : 2793
Last Page : 2797
Authors : Maryanoff BE, Vaught JL, Shank RP, McComsey DF, Costanzo MJ, Nortey SO.
Abstract : A collection of hexahydropyrroloisoquinoline derivatives (1-22), which represent a class of compounds that inhibit the neuronal uptake of dopamine (DA), norepinephrine (NE), and serotonin (5-HT), was investigated in vivo for serotonin-potentiating properties in the mouse head-twitch and rat serotonin syndrome assays. The p-methylthio compound 3b (McN-5652-Z) was found to possess exceptional activity in these assays, and the activity was attributable almost exclusively to the (+)-6S,10bR enantiomer. Ten closely related analogues were synthesized, tested, and compared among themselves and with some previously prepared compounds, both in vivo and in vitro. Several trans diastereomers exhibited strong inhibition of 5-HT uptake and substantial potentiation of 5-HT, while the cis diastereomers (3a, 4a, and 10a) tested were virtually devoid of such activity. Although 3b was only moderately selective in inhibiting the uptake of 5-HT vs NE, its 10-substituted analogues 4b, 7b-9b had improved 5-HT selectivity relative to NE, to the extent of 20-25 times (150-200 times relative to DA). Of these more selective compounds (in vitro), only 4b and 7b had substantial activity in vivo. Sulfoxide 11b appeared to function as a prodrug of 3b in vivo.
|
Tested in vitro for norepinephrine (NE) neuronal uptake inhibition
|
None
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Pyrroloisoquinoline antidepressants. 3. A focus on serotonin.
Year : 1990
Volume : 33
Issue : 10
First Page : 2793
Last Page : 2797
Authors : Maryanoff BE, Vaught JL, Shank RP, McComsey DF, Costanzo MJ, Nortey SO.
Abstract : A collection of hexahydropyrroloisoquinoline derivatives (1-22), which represent a class of compounds that inhibit the neuronal uptake of dopamine (DA), norepinephrine (NE), and serotonin (5-HT), was investigated in vivo for serotonin-potentiating properties in the mouse head-twitch and rat serotonin syndrome assays. The p-methylthio compound 3b (McN-5652-Z) was found to possess exceptional activity in these assays, and the activity was attributable almost exclusively to the (+)-6S,10bR enantiomer. Ten closely related analogues were synthesized, tested, and compared among themselves and with some previously prepared compounds, both in vivo and in vitro. Several trans diastereomers exhibited strong inhibition of 5-HT uptake and substantial potentiation of 5-HT, while the cis diastereomers (3a, 4a, and 10a) tested were virtually devoid of such activity. Although 3b was only moderately selective in inhibiting the uptake of 5-HT vs NE, its 10-substituted analogues 4b, 7b-9b had improved 5-HT selectivity relative to NE, to the extent of 20-25 times (150-200 times relative to DA). Of these more selective compounds (in vitro), only 4b and 7b had substantial activity in vivo. Sulfoxide 11b appeared to function as a prodrug of 3b in vivo.
|
Tested in vitro for serotonin(5-HT) neuronal uptake inhibition
|
None
|
0.44
nM
|
|
Journal : J. Med. Chem.
Title : Pyrroloisoquinoline antidepressants. 3. A focus on serotonin.
Year : 1990
Volume : 33
Issue : 10
First Page : 2793
Last Page : 2797
Authors : Maryanoff BE, Vaught JL, Shank RP, McComsey DF, Costanzo MJ, Nortey SO.
Abstract : A collection of hexahydropyrroloisoquinoline derivatives (1-22), which represent a class of compounds that inhibit the neuronal uptake of dopamine (DA), norepinephrine (NE), and serotonin (5-HT), was investigated in vivo for serotonin-potentiating properties in the mouse head-twitch and rat serotonin syndrome assays. The p-methylthio compound 3b (McN-5652-Z) was found to possess exceptional activity in these assays, and the activity was attributable almost exclusively to the (+)-6S,10bR enantiomer. Ten closely related analogues were synthesized, tested, and compared among themselves and with some previously prepared compounds, both in vivo and in vitro. Several trans diastereomers exhibited strong inhibition of 5-HT uptake and substantial potentiation of 5-HT, while the cis diastereomers (3a, 4a, and 10a) tested were virtually devoid of such activity. Although 3b was only moderately selective in inhibiting the uptake of 5-HT vs NE, its 10-substituted analogues 4b, 7b-9b had improved 5-HT selectivity relative to NE, to the extent of 20-25 times (150-200 times relative to DA). Of these more selective compounds (in vitro), only 4b and 7b had substantial activity in vivo. Sulfoxide 11b appeared to function as a prodrug of 3b in vivo.
|
Equilibrium dissociation constant (KD) for Competitive binding between [3H]- nisoxatine and the compound at human Norepinephrine transporter
|
None
|
40.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of a potent wide-spectrum serotonin-, norepinephrine-, dopamine-reuptake inhibitor (SNDRI) and a species-selective dopamine-reuptake inhibitor based on the gamma-amino alcohol functional group.
Year : 1998
Volume : 8
Issue : 5
First Page : 487
Last Page : 492
Authors : Carlier PR, Lo MM, Lo PC, Richelson E, Tatsumi M, Reynolds IJ, Sharma TA.
Abstract : A series of gamma-amino alcohols were synthesized and screened for reuptake inhibition and noncompetitive NMDA antagonism. Compound (+/-)-3f simultaneously and potently inhibits reuptake of 5-HT, NE, and DA, representing a potential wide-spectrum reuptake inhibitor antidepressant. In addition, comparative rat and human studies uncovered a species-selective DA reuptake inhibitor (+/-)-2e, KD(hDAT)/KD(rDAT) = 97.
|
Inhibition of [3H]nisoxetine (0.5 nM) binding to Noradrenaline transporter
|
Rattus norvegicus
|
535.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and ligand binding of tropane ring analogues of paroxetine.
Year : 1998
Volume : 41
Issue : 2
First Page : 247
Last Page : 257
Authors : Keverline-Frantz KI, Boja JW, Kuhar MJ, Abraham P, Burgess JP, Lewin AH, Carroll FI.
Abstract : (3S,4R)-4-(4-Fluorophenyl)-3-[[3,4-(methylenedioxy)phenoxy]methyl] piperidine [(3S,9R)-3, paroxetine] is a selective serotonin reuptake inhibitor (SSRI) used as an antidepressant in humans. In previous studies, we reported that certain (1R)-3 beta-(substituted phenyl)nortropane-2 beta-carboxylic acid methyl esters (2a) exhibited high affinity and reasonable selectivity for the serotonin transporter (5-HTT). The major structural differences between 2a and (3S,4R)-3 are that 2a possesses a different absolute stereochemistry and has an ethylene bridge not present in 3. In addition, 2a possesses a carbomethoxy substituent adjacent to the aryl ring, whereas (3S,4R)-3 contains a [3,4-(methylenedioxy)phenoxy]methyl group. In this study, we present the synthesis and biological evaluations of six of the possible eight isomers of 3-(4-fluorophenyl)-2-[[3,4-(methylenedioxy)phenoxy]methyl]nortropane+ ++ (4). The data for inhibition of [3H]paroxetine binding show that (1R)-2 beta, 3 alpha-4c, which has the same stereochemistry as paroxetine, has the highest affinity at the 5-HTT. Strikingly, the most potent compounds for inhibition of [3H]WIN-35,428 binding were not the (1R)-2 beta, 3 beta-isomers but rather (1R)-2 beta, 3 alpha-4c and (1S)-2 beta, 3 alpha-4f. Conformational analyses show that these isomers exist in a flattened boat conformation with pseudoequatorial substituents. Thus, the binding data show that this conformation is recognized by the DAT-associated binding site and also suggest that this conformation of paroxetine is recognized by the 5-HTT-associated binding site.
|
Binding affinity against norepinephrine transporter (NET) by displacement of [3H]nisoxetine in male wistar rats
|
None
|
659.6
nM
|
|
Journal : J. Med. Chem.
Title : Syntheses and binding studies of new [(aryl)(aryloxy)methyl]piperidine derivatives and related compounds as potential antidepressant drugs with high affinity for serotonin (5-HT) and norepinephrine (NE) transporters.
Year : 2003
Volume : 46
Issue : 25
First Page : 5512
Last Page : 5532
Authors : Orjales A, Mosquera R, Toledo A, Pumar MC, García N, Cortizo L, Labeaga L, Innerárity A.
Abstract : In a wide search program toward new, efficient, and fast-acting antidepressant drugs, we have prepared series of new compounds having an (aryl)(aryloxy)methyl moiety linked directly or through a methylene chain to different substituted and unsubstituted cycles (isoquinoline, piperazine, piperidine, tetrahydropyran, or cyclopentane). These compounds have been evaluated for their affinities for serotonin (5-HT) transporter (SERT) and 5-HT(1A) and 5-HT(2A) receptors. Racemic mixtures of 4-[(aryl)(aryloxy)methyl]piperidine derivatives showed much higher affinity values for SERT than fluoxetine and resulted in lack of affinity for 5-HT(1A) and 5-HT(2A) receptors. Some of these racemic mixtures were resolved to their enantiomers and tested for binding to norepinephrine (NE) transporter (NET), dopamine (DA) transporter (DAT), and alpha(2) receptor. Several of these enantiomers [(-)-15b, (-)-15j, (-)-15t, (+)-15u] displayed a dual binding profile with affinities for SERT and NET with K(i) < 25 nM and a NET/SERT ratio <10. Compound (-)-15j (coded as F-98214-TA for development studies) showed a dual binding profile with very high affinity values for SERT and NET (K(i) = 1.9 and 13.5 nM, respectively), and further pharmacological characterization is in progress for its evaluation as a antidepressant.
|
Evaluated for inhibition of 5-Hydroxytryptamine, biogenic amine reuptake in synaptosomal rat brain preparations
|
Rattus norvegicus
|
6.43
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological characterization of A-80426: A putative novel antidepressant combining -2 antagonism with 5-HT uptake inhibition
Year : 1995
Volume : 5
Issue : 19
First Page : 2287
Last Page : 2292
Authors : Meyer MD, Hancock AA, Tietje K, Sippy kB, Giardina WJ, Kerwin JF
|
Evaluated for inhibition of norepinephrine, biogenic amine reuptake in synaptosomal rat brain preparations
|
Rattus norvegicus
|
160.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological characterization of A-80426: A putative novel antidepressant combining -2 antagonism with 5-HT uptake inhibition
Year : 1995
Volume : 5
Issue : 19
First Page : 2287
Last Page : 2292
Authors : Meyer MD, Hancock AA, Tietje K, Sippy kB, Giardina WJ, Kerwin JF
|
Inhibition of [3H]- NE reuptake into rat hippocampal synaptosomes
|
None
|
33.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of a potent wide-spectrum serotonin-, norepinephrine-, dopamine-reuptake inhibitor (SNDRI) and a species-selective dopamine-reuptake inhibitor based on the gamma-amino alcohol functional group.
Year : 1998
Volume : 8
Issue : 5
First Page : 487
Last Page : 492
Authors : Carlier PR, Lo MM, Lo PC, Richelson E, Tatsumi M, Reynolds IJ, Sharma TA.
Abstract : A series of gamma-amino alcohols were synthesized and screened for reuptake inhibition and noncompetitive NMDA antagonism. Compound (+/-)-3f simultaneously and potently inhibits reuptake of 5-HT, NE, and DA, representing a potential wide-spectrum reuptake inhibitor antidepressant. In addition, comparative rat and human studies uncovered a species-selective DA reuptake inhibitor (+/-)-2e, KD(hDAT)/KD(rDAT) = 97.
|
Inhibition of [3H]5-HT reuptake into rat frontal cortex synaptosomes
|
None
|
0.73
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of a potent wide-spectrum serotonin-, norepinephrine-, dopamine-reuptake inhibitor (SNDRI) and a species-selective dopamine-reuptake inhibitor based on the gamma-amino alcohol functional group.
Year : 1998
Volume : 8
Issue : 5
First Page : 487
Last Page : 492
Authors : Carlier PR, Lo MM, Lo PC, Richelson E, Tatsumi M, Reynolds IJ, Sharma TA.
Abstract : A series of gamma-amino alcohols were synthesized and screened for reuptake inhibition and noncompetitive NMDA antagonism. Compound (+/-)-3f simultaneously and potently inhibits reuptake of 5-HT, NE, and DA, representing a potential wide-spectrum reuptake inhibitor antidepressant. In addition, comparative rat and human studies uncovered a species-selective DA reuptake inhibitor (+/-)-2e, KD(hDAT)/KD(rDAT) = 97.
|
Inhibition of uptake of [3H]5-HT in synaptosomes from rat cortex
|
Rattus norvegicus
|
6.43
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity studies for a novel series of N-(arylethyl)-N-(1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-N-methylamine s possessing dual 5-HT uptake inhibiting and alpha2-antagonistic activities.
Year : 1997
Volume : 40
Issue : 7
First Page : 1049
Last Page : 1062
Authors : Meyer MD, Hancock AA, Tietje K, Sippy KB, Prasad R, Stout DM, Arendsen DL, Donner BG, Carroll WA.
Abstract : In search of an alpha2-antagonist/5-HT uptake inhibitor as a potential new class of antidepressant with a more rapid onset of action, compound 3 was prepared and observed to possess high affinity for the alpha2-receptor (K(i) = 6.71 nM) and the 5-HT uptake site (20.6 nM). A series of tertiary amine analogs of 3 were synthesized and assayed for their affinity at both the alpha2-receptor and the 5-HT uptake site. The structure-activity relationship reveals that a variety of structural modifications to the arylethyl fragment are possible with retention of this dual activity. On the tetralin portion, 5-OMe substitution and the (R) stereochemistry at C-1 are optimal with alternate substitutions producing compounds retaining high affinity for the alpha2-receptor but lacking affinity for the 5-HT uptake site. Data for several rigidified 5-O-alkyl analogs suggests that the favored orientation of the oxygen lone pairs may be away from the 6-position of the tetralin.
|
Equilibrium dissociation constant (KD) for Competitive binding between [3H]- imipramine and the compound at human transporter-hSERT
|
None
|
0.13
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of a potent wide-spectrum serotonin-, norepinephrine-, dopamine-reuptake inhibitor (SNDRI) and a species-selective dopamine-reuptake inhibitor based on the gamma-amino alcohol functional group.
Year : 1998
Volume : 8
Issue : 5
First Page : 487
Last Page : 492
Authors : Carlier PR, Lo MM, Lo PC, Richelson E, Tatsumi M, Reynolds IJ, Sharma TA.
Abstract : A series of gamma-amino alcohols were synthesized and screened for reuptake inhibition and noncompetitive NMDA antagonism. Compound (+/-)-3f simultaneously and potently inhibits reuptake of 5-HT, NE, and DA, representing a potential wide-spectrum reuptake inhibitor antidepressant. In addition, comparative rat and human studies uncovered a species-selective DA reuptake inhibitor (+/-)-2e, KD(hDAT)/KD(rDAT) = 97.
|
The potency of the [3H]paroxetine for 5-HT transporters
|
None
|
0.15
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of 2 beta-acyl-3 beta-aryl-8-azabicyclo[3.2.1]octanes and their binding affinities at dopamine and serotonin transport sites in rat striatum and frontal cortex.
Year : 1994
Volume : 37
Issue : 9
First Page : 1262
Last Page : 1268
Authors : Davies HM, Saikali E, Huby NJ, Gilliatt VJ, Matasi JJ, Sexton T, Childers SR.
Abstract : A novel entry to tropane analogs of cocaine was developed on the basis of the reaction of rhodium-stabilized vinylcarbenoids with pyrroles. These analogs were tested in binding to dopamine and serotonin (5-HT) transporters in membranes from rat striatum and frontal cortex. In all the analogs, the aryl group at the 3-position was directly bound to the tropane ring (as in WIN-35,428), and methyl or ethyl ketone moieties were present at the 2-position instead of the typical ester group. The series of analogs containing a 2-naphthyl group at the 3-position were most potent, with Ki values < 1 nM in binding to both dopamine and 5-HT transporters. Although the unsubstituted 2-naphthyl analog was nonselective at dopamine and 5-HT transport sites, other compounds were selective for either site. In general, compounds with relatively small substituents on the aromatic moiety (such as p-methyl or p-fluoro) were relatively selective for the dopamine transporters, while a p-isopropylphenyl derivative was selective for the 5-HT transport sites. This latter compound represents the first N-methyltropane derivative specific for 5-HT transporters. Resolution of two of the most significant analogs was achieved by HPLC on a chiral stationary phase; the active enantiomer of a 2-naphthyl analog exhibited Ki values of < 0.1 nM at both dopamine and 5-HT transporter sites.
|
Binding affinity to the serotonin transporter (SERT) measured by displacement of [3H]paroxetine in male wistar rats
|
None
|
0.7
nM
|
|
Journal : J. Med. Chem.
Title : Syntheses and binding studies of new [(aryl)(aryloxy)methyl]piperidine derivatives and related compounds as potential antidepressant drugs with high affinity for serotonin (5-HT) and norepinephrine (NE) transporters.
Year : 2003
Volume : 46
Issue : 25
First Page : 5512
Last Page : 5532
Authors : Orjales A, Mosquera R, Toledo A, Pumar MC, García N, Cortizo L, Labeaga L, Innerárity A.
Abstract : In a wide search program toward new, efficient, and fast-acting antidepressant drugs, we have prepared series of new compounds having an (aryl)(aryloxy)methyl moiety linked directly or through a methylene chain to different substituted and unsubstituted cycles (isoquinoline, piperazine, piperidine, tetrahydropyran, or cyclopentane). These compounds have been evaluated for their affinities for serotonin (5-HT) transporter (SERT) and 5-HT(1A) and 5-HT(2A) receptors. Racemic mixtures of 4-[(aryl)(aryloxy)methyl]piperidine derivatives showed much higher affinity values for SERT than fluoxetine and resulted in lack of affinity for 5-HT(1A) and 5-HT(2A) receptors. Some of these racemic mixtures were resolved to their enantiomers and tested for binding to norepinephrine (NE) transporter (NET), dopamine (DA) transporter (DAT), and alpha(2) receptor. Several of these enantiomers [(-)-15b, (-)-15j, (-)-15t, (+)-15u] displayed a dual binding profile with affinities for SERT and NET with K(i) < 25 nM and a NET/SERT ratio <10. Compound (-)-15j (coded as F-98214-TA for development studies) showed a dual binding profile with very high affinity values for SERT and NET (K(i) = 1.9 and 13.5 nM, respectively), and further pharmacological characterization is in progress for its evaluation as a antidepressant.
|
Displacement of [3H]citalopram from rat cortical serotonin transporter (SERT)
|
Rattus norvegicus
|
0.53
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Syntheses and binding affinities of 6-nitroquipazine analogues for serotonin transporter. Part 2: 4-substituted 6-nitroquipazines.
Year : 2002
Volume : 12
Issue : 5
First Page : 811
Last Page : 815
Authors : Se Lee B, Chu S, Lee BS, Yoon Chi D, Song YS, Jin C.
Abstract : Eleven 4-substituted derivatives of 6-nitroquipazine were synthesized and evaluated for their abilities to displace [3H]citalopram binding to the rat cortical synaptic membranes. Among them, 4-chloro-6-nitroquipazine was shown to possess the highest binding affinity (K(i=)0.03 nM) which was approximately 6 times higher than that of 6-nitroquipazine (K(i)=0.17 nM) itself. In this paper, we describe the syntheses of 4-substituted 6-nitroquipazine derivatives, the results of corresponding biological evaluation and the SAR study.
|
Inhibition of [3H]citalopram binding to Serotonin transporter of rat cerebral cortex
|
Rattus norvegicus
|
0.53
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Syntheses and binding affinities of 6-nitroquipazine analogues for serotonin transporter. Part 1.
Year : 2000
Volume : 10
Issue : 14
First Page : 1559
Last Page : 1562
Authors : Lee BS, Chu S, Lee BC, Chi DY, Choe YS, Jeong KJ, Jin C.
Abstract : 6-Nitroquipazine has been known as one of the most potent and selective inhibitors of serotonin transporter in vitro and in vivo. Nine derivatives of 6-nitroquipazine were synthesized and tested for their potential abilities to displace [3H]citalopram binding to the rat cortical membranes.
|
Evaluated for affinity at 5-HT uptake site using [3H]paroxetine as radioligand in radioligand binding assay
|
None
|
0.077
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological characterization of A-80426: A putative novel antidepressant combining -2 antagonism with 5-HT uptake inhibition
Year : 1995
Volume : 5
Issue : 19
First Page : 2287
Last Page : 2292
Authors : Meyer MD, Hancock AA, Tietje K, Sippy kB, Giardina WJ, Kerwin JF
|
Inhibition of [3H]paroxetine (0.2 nM) binding to 5-HT transporter
|
Rattus norvegicus
|
0.28
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and ligand binding of tropane ring analogues of paroxetine.
Year : 1998
Volume : 41
Issue : 2
First Page : 247
Last Page : 257
Authors : Keverline-Frantz KI, Boja JW, Kuhar MJ, Abraham P, Burgess JP, Lewin AH, Carroll FI.
Abstract : (3S,4R)-4-(4-Fluorophenyl)-3-[[3,4-(methylenedioxy)phenoxy]methyl] piperidine [(3S,9R)-3, paroxetine] is a selective serotonin reuptake inhibitor (SSRI) used as an antidepressant in humans. In previous studies, we reported that certain (1R)-3 beta-(substituted phenyl)nortropane-2 beta-carboxylic acid methyl esters (2a) exhibited high affinity and reasonable selectivity for the serotonin transporter (5-HTT). The major structural differences between 2a and (3S,4R)-3 are that 2a possesses a different absolute stereochemistry and has an ethylene bridge not present in 3. In addition, 2a possesses a carbomethoxy substituent adjacent to the aryl ring, whereas (3S,4R)-3 contains a [3,4-(methylenedioxy)phenoxy]methyl group. In this study, we present the synthesis and biological evaluations of six of the possible eight isomers of 3-(4-fluorophenyl)-2-[[3,4-(methylenedioxy)phenoxy]methyl]nortropane+ ++ (4). The data for inhibition of [3H]paroxetine binding show that (1R)-2 beta, 3 alpha-4c, which has the same stereochemistry as paroxetine, has the highest affinity at the 5-HTT. Strikingly, the most potent compounds for inhibition of [3H]WIN-35,428 binding were not the (1R)-2 beta, 3 beta-isomers but rather (1R)-2 beta, 3 alpha-4c and (1S)-2 beta, 3 alpha-4f. Conformational analyses show that these isomers exist in a flattened boat conformation with pseudoequatorial substituents. Thus, the binding data show that this conformation is recognized by the DAT-associated binding site and also suggest that this conformation of paroxetine is recognized by the 5-HTT-associated binding site.
|
Binding inhibition towards human dopamine transporter
|
Homo sapiens
|
400.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally restricted homotryptamines. 2. Indole cyclopropylmethylamines as selective serotonin reuptake inhibitors.
Year : 2005
Volume : 48
Issue : 19
First Page : 6023
Last Page : 6034
Authors : Mattson RJ, Catt JD, Denhart DJ, Deskus JA, Ditta JL, Higgins MA, Marcin LR, Sloan CP, Beno BR, Gao Q, Cunningham MA, Mattson GK, Molski TF, Taber MT, Lodge NJ.
Abstract : A series of indole cyclopropylmethylamines were found to be potent serotonin reuptake inhibitors. Nitrile substituents at the 5 and 7 positions of the indole ring gave high affinity for hSERT, and the preferred cyclopropane stereochemistry was determined to be (1S,2S)-trans. The cis-cyclopropanes had 20- to 30-fold less affinity than the trans, and the preferred cis stereochemistry was (1R,2S)-cis. Substitution of the indole N-1 position with methyl or ethyl groups gave a 10- to 30-fold decrease in affinity for hSERT, suggesting either a hydrogen-bonding interaction or limited steric tolerance in the region of the indole nitrogen. Compound (+)-12a demonstrated potent hSERT binding (Ki = 0.18 nM) in vitro and was more than 1000-fold less potent at hDAT, hNET, 5-HT1A, and 5-HT6. In vivo, (+)-12a produced robust, dose-dependent increases in extracellular serotonin in rat frontal cortex typical of a selective serotonin reuptake inhibitor. The maximal response produced by (+)-12a was similar to that of fluoxetine but at an approximately 10-fold lower dose.
|
Binding inhibition towards human serotonin transporter
|
Homo sapiens
|
0.04
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally restricted homotryptamines. 2. Indole cyclopropylmethylamines as selective serotonin reuptake inhibitors.
Year : 2005
Volume : 48
Issue : 19
First Page : 6023
Last Page : 6034
Authors : Mattson RJ, Catt JD, Denhart DJ, Deskus JA, Ditta JL, Higgins MA, Marcin LR, Sloan CP, Beno BR, Gao Q, Cunningham MA, Mattson GK, Molski TF, Taber MT, Lodge NJ.
Abstract : A series of indole cyclopropylmethylamines were found to be potent serotonin reuptake inhibitors. Nitrile substituents at the 5 and 7 positions of the indole ring gave high affinity for hSERT, and the preferred cyclopropane stereochemistry was determined to be (1S,2S)-trans. The cis-cyclopropanes had 20- to 30-fold less affinity than the trans, and the preferred cis stereochemistry was (1R,2S)-cis. Substitution of the indole N-1 position with methyl or ethyl groups gave a 10- to 30-fold decrease in affinity for hSERT, suggesting either a hydrogen-bonding interaction or limited steric tolerance in the region of the indole nitrogen. Compound (+)-12a demonstrated potent hSERT binding (Ki = 0.18 nM) in vitro and was more than 1000-fold less potent at hDAT, hNET, 5-HT1A, and 5-HT6. In vivo, (+)-12a produced robust, dose-dependent increases in extracellular serotonin in rat frontal cortex typical of a selective serotonin reuptake inhibitor. The maximal response produced by (+)-12a was similar to that of fluoxetine but at an approximately 10-fold lower dose.
|
Binding inhibition towards human norepinephrine transporter
|
Homo sapiens
|
90.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally restricted homotryptamines. 2. Indole cyclopropylmethylamines as selective serotonin reuptake inhibitors.
Year : 2005
Volume : 48
Issue : 19
First Page : 6023
Last Page : 6034
Authors : Mattson RJ, Catt JD, Denhart DJ, Deskus JA, Ditta JL, Higgins MA, Marcin LR, Sloan CP, Beno BR, Gao Q, Cunningham MA, Mattson GK, Molski TF, Taber MT, Lodge NJ.
Abstract : A series of indole cyclopropylmethylamines were found to be potent serotonin reuptake inhibitors. Nitrile substituents at the 5 and 7 positions of the indole ring gave high affinity for hSERT, and the preferred cyclopropane stereochemistry was determined to be (1S,2S)-trans. The cis-cyclopropanes had 20- to 30-fold less affinity than the trans, and the preferred cis stereochemistry was (1R,2S)-cis. Substitution of the indole N-1 position with methyl or ethyl groups gave a 10- to 30-fold decrease in affinity for hSERT, suggesting either a hydrogen-bonding interaction or limited steric tolerance in the region of the indole nitrogen. Compound (+)-12a demonstrated potent hSERT binding (Ki = 0.18 nM) in vitro and was more than 1000-fold less potent at hDAT, hNET, 5-HT1A, and 5-HT6. In vivo, (+)-12a produced robust, dose-dependent increases in extracellular serotonin in rat frontal cortex typical of a selective serotonin reuptake inhibitor. The maximal response produced by (+)-12a was similar to that of fluoxetine but at an approximately 10-fold lower dose.
|
Displacement of [3H]paroxetine from SERT receptor in human platelet membrane
|
Homo sapiens
|
0.09
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 1-Aminocyclopentane-1,2,4-tricarboxylic acids screening on glutamatergic and serotonergic systems.
Year : 2007
Volume : 15
Issue : 24
First Page : 7581
Last Page : 7589
Authors : Gelmi ML, Caputo F, Clerici F, Pellegrino S, Giannaccini G, Betti L, Fabbrini L, Schmid L, Palego L, Lucacchini A.
Abstract : Enantiopure constrained 1-aminocyclopentane-1,2,4-tricarboxylic acids containing the glutamic acid skeleton were prepared as two diastereomers characterized by having the carboxylic groups in position two and four cis-oriented to each other and trans with respect to 1-carboxylic group and all cis-oriented carboxylic groups, respectively. A biochemical screening of activity of the above amino acids was investigated on glutamate and 5-HT receptors to find a possible metabotropic agonist, acting on the serotoninergic system.
|
Displacement of [3H]citalopram from human SERT expressed in HEK293 cells
|
Homo sapiens
|
0.42
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3-(4-(6-Fluoroalkoxy-3,4-dihydroisoquinoline-2(1H)-yl)cyclohexyl)-1H-indole-5-carbonitriles for SERT imaging: chemical synthesis, evaluation in vitro and radiofluorination.
Year : 2008
Volume : 18
Issue : 16
First Page : 4727
Last Page : 4730
Authors : Funke U, Fischer S, Hiller A, Scheunemann M, Deuther-Conrad W, Brust P, Steinbach J.
Abstract : Aminocyclohexyl indoles bind with high affinity and specificity toward the serotonin transporter (SERT). Based on this structural lead, we designed fluoroalkoxydihydroisoquinoline-cyclohexyl indole carbonitriles for future application as (18)F-labeled tracers for SERT imaging by PET. Six compounds, three pairs of cis- and trans-isomer derivatives, respectively, were synthesized and evaluated in vitro. The chemistry of the new compounds, their affinity and specificity data, the general route to the phenolic precursor for labeling, and the successful (18)F-fluoroalkylation of one pair of compounds are described herein.
|
Displacement of [3H]paroxetine from human SERT expressed in HEK293 cells
|
Homo sapiens
|
0.38
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3-(4-(6-Fluoroalkoxy-3,4-dihydroisoquinoline-2(1H)-yl)cyclohexyl)-1H-indole-5-carbonitriles for SERT imaging: chemical synthesis, evaluation in vitro and radiofluorination.
Year : 2008
Volume : 18
Issue : 16
First Page : 4727
Last Page : 4730
Authors : Funke U, Fischer S, Hiller A, Scheunemann M, Deuther-Conrad W, Brust P, Steinbach J.
Abstract : Aminocyclohexyl indoles bind with high affinity and specificity toward the serotonin transporter (SERT). Based on this structural lead, we designed fluoroalkoxydihydroisoquinoline-cyclohexyl indole carbonitriles for future application as (18)F-labeled tracers for SERT imaging by PET. Six compounds, three pairs of cis- and trans-isomer derivatives, respectively, were synthesized and evaluated in vitro. The chemistry of the new compounds, their affinity and specificity data, the general route to the phenolic precursor for labeling, and the successful (18)F-fluoroalkylation of one pair of compounds are described herein.
|
Inhibition of norepinephrine uptake at human NET expressed in MDCK cells
|
Homo sapiens
|
100.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and activity of 1-(3-amino-1-phenylpropyl)indolin-2-ones: a new class of selective norepinephrine reuptake inhibitors.
Year : 2008
Volume : 18
Issue : 18
First Page : 4929
Last Page : 4931
Authors : McComas CC, Vu AT, Mahaney PE, Cohn ST, Fensome A, Marella MA, Nogle L, Trybulski EJ, Ye F, Zhang P, Alfinito P, Bray J, Johnston G, Koury E, Deecher DC.
Abstract : Norepinephrine and serotonin play an important role in a wide variety of biological processes and are implicated in a number of neurological disorders. A novel class of 1-(3-amino-1-phenylpropyl)indolin-2-ones was designed and synthesized that displays potent norepinephrine reuptake inhibition while maintaining high selectivity (>100-fold) against the human serotonin and dopamine transporters.
|
Inhibition of serotonin uptake at human SERT expressed in JAR cells
|
Homo sapiens
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and activity of 1-(3-amino-1-phenylpropyl)indolin-2-ones: a new class of selective norepinephrine reuptake inhibitors.
Year : 2008
Volume : 18
Issue : 18
First Page : 4929
Last Page : 4931
Authors : McComas CC, Vu AT, Mahaney PE, Cohn ST, Fensome A, Marella MA, Nogle L, Trybulski EJ, Ye F, Zhang P, Alfinito P, Bray J, Johnston G, Koury E, Deecher DC.
Abstract : Norepinephrine and serotonin play an important role in a wide variety of biological processes and are implicated in a number of neurological disorders. A novel class of 1-(3-amino-1-phenylpropyl)indolin-2-ones was designed and synthesized that displays potent norepinephrine reuptake inhibition while maintaining high selectivity (>100-fold) against the human serotonin and dopamine transporters.
|
Displacement of [3H]citalopram from human SERT expressed in HEK293 cells
|
Homo sapiens
|
0.42
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Carbon-11 labeled indolylpropylamine analog as a new potential PET agent for imaging of the serotonin transporter.
Year : 2008
Volume : 16
Issue : 12
First Page : 6364
Last Page : 6370
Authors : Ben-Daniel R, Deuther-Conrad W, Scheunemann M, Steinbach J, Brust P, Mishani E.
Abstract : The synthesis and structure-activity relationship of a new class of indole derivatives with low-nanomolar affinity for the SERT and high selectivity versus the 5-HT1A receptor were recently reported. Based on their chemical structure, four new indolylpropylamine derivatives which contain atoms to afford future labeling with PET isotopes, were synthesized and evaluated as SERT ligands. The chemistry of these novel derivatives, their biological evaluation, the general method of preparing the precursor indole for labeling, and the C-11 labeling of the most promising indole derivative, are described herein.
|
Displacement of [3H]paroxetine from human SERT expressed in HEK293 cells
|
Homo sapiens
|
0.38
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Carbon-11 labeled indolylpropylamine analog as a new potential PET agent for imaging of the serotonin transporter.
Year : 2008
Volume : 16
Issue : 12
First Page : 6364
Last Page : 6370
Authors : Ben-Daniel R, Deuther-Conrad W, Scheunemann M, Steinbach J, Brust P, Mishani E.
Abstract : The synthesis and structure-activity relationship of a new class of indole derivatives with low-nanomolar affinity for the SERT and high selectivity versus the 5-HT1A receptor were recently reported. Based on their chemical structure, four new indolylpropylamine derivatives which contain atoms to afford future labeling with PET isotopes, were synthesized and evaluated as SERT ligands. The chemistry of these novel derivatives, their biological evaluation, the general method of preparing the precursor indole for labeling, and the C-11 labeling of the most promising indole derivative, are described herein.
|
Inhibition of NorA in Staphylococcus aureus 1199B assessed as reduction in ethidium bromide efflux at 50 uM by fluorimetry after 5 mins
|
Staphylococcus aureus
|
73.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of novel inhibitors of the NorA multidrug transporter of Staphylococcus aureus.
Year : 2011
Volume : 54
Issue : 1
First Page : 354
Last Page : 365
Authors : Brincat JP, Carosati E, Sabatini S, Manfroni G, Fravolini A, Raygada JL, Patel D, Kaatz GW, Cruciani G.
Abstract : Four novel inhibitors of the NorA efflux pump of Staphylococcus aureus, discovered through a virtual screening process, are reported. The four compounds belong to different chemical classes and were tested for their in vitro ability to block the efflux of a well-known NorA substrate, as well as for their ability to potentiate the effect of ciprofloxacin (CPX) on several strains of S. aureus, including a NorA overexpressing strain. Additionally, the MIC values of each of the compounds individually are reported. A structure-activity relationship study was also performed on these novel chemotypes, revealing three new compounds that are also potent NorA inhibitors. The virtual screening procedure employed FLAP, a new methodology based on GRID force field descriptors.
|
Displacement of [3H]-paroxetine from SERT in rabbit cortical membrane
|
Oryctolagus cuniculus
|
0.31
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, molecular docking and binding studies of selective serotonin transporter inhibitors.
Year : 2011
Volume : 46
Issue : 3
First Page : 825
Last Page : 834
Authors : Nencetti S, Mazzoni MR, Ortore G, Lapucci A, Giuntini J, Orlandini E, Banti I, Nuti E, Lucacchini A, Giannaccini G, Rossello A.
Abstract : With the aim of obtaining compounds possessing high SERT selectivity, in the present work we synthesized and studied the inhibition of serotonin (SERT), dopamine (DAT) and norepinephrine (NET) transporters by docking studies and experimental binding measurements of a series of 4-(aryl)piperidin-3-one O-4-benzyl oxime hydrochlorides (1-10) of both E and Z configuration. E configuration compounds showed high SERT binding affinities (K(i) = 10-98 nM) and high SERT selectivities over both NET and DAT. The molecular docking studies allowed a rationalization of the molecular basis of drug-SERT interactions both of the synthesized compounds and paroxetine and fluoxetine used as reference antidepressant drugs.
|
Displacement of [3H]-Nisoxetine from NET in rabbit cortical membrane
|
Oryctolagus cuniculus
|
80.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, molecular docking and binding studies of selective serotonin transporter inhibitors.
Year : 2011
Volume : 46
Issue : 3
First Page : 825
Last Page : 834
Authors : Nencetti S, Mazzoni MR, Ortore G, Lapucci A, Giuntini J, Orlandini E, Banti I, Nuti E, Lucacchini A, Giannaccini G, Rossello A.
Abstract : With the aim of obtaining compounds possessing high SERT selectivity, in the present work we synthesized and studied the inhibition of serotonin (SERT), dopamine (DAT) and norepinephrine (NET) transporters by docking studies and experimental binding measurements of a series of 4-(aryl)piperidin-3-one O-4-benzyl oxime hydrochlorides (1-10) of both E and Z configuration. E configuration compounds showed high SERT binding affinities (K(i) = 10-98 nM) and high SERT selectivities over both NET and DAT. The molecular docking studies allowed a rationalization of the molecular basis of drug-SERT interactions both of the synthesized compounds and paroxetine and fluoxetine used as reference antidepressant drugs.
|
Displacement of [3H]-WIN 35,428 from DAT in rabbit striatal membrane
|
Oryctolagus cuniculus
|
769.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, molecular docking and binding studies of selective serotonin transporter inhibitors.
Year : 2011
Volume : 46
Issue : 3
First Page : 825
Last Page : 834
Authors : Nencetti S, Mazzoni MR, Ortore G, Lapucci A, Giuntini J, Orlandini E, Banti I, Nuti E, Lucacchini A, Giannaccini G, Rossello A.
Abstract : With the aim of obtaining compounds possessing high SERT selectivity, in the present work we synthesized and studied the inhibition of serotonin (SERT), dopamine (DAT) and norepinephrine (NET) transporters by docking studies and experimental binding measurements of a series of 4-(aryl)piperidin-3-one O-4-benzyl oxime hydrochlorides (1-10) of both E and Z configuration. E configuration compounds showed high SERT binding affinities (K(i) = 10-98 nM) and high SERT selectivities over both NET and DAT. The molecular docking studies allowed a rationalization of the molecular basis of drug-SERT interactions both of the synthesized compounds and paroxetine and fluoxetine used as reference antidepressant drugs.
|
Inhibition of NorA in Staphylococcus aureus 1199B assessed as inhibition of ethidium bromide efflux at 50 uM by fluorimetry
|
Staphylococcus aureus
|
89.7
%
|
|
Journal : J. Med. Chem.
Title : Evolution from a natural flavones nucleus to obtain 2-(4-Propoxyphenyl)quinoline derivatives as potent inhibitors of the S. aureus NorA efflux pump.
Year : 2011
Volume : 54
Issue : 16
First Page : 5722
Last Page : 5736
Authors : Sabatini S, Gosetto F, Manfroni G, Tabarrini O, Kaatz GW, Patel D, Cecchetti V.
Abstract : Overexpression of efflux pumps is an important mechanism by which bacteria evade the effects of substrate antimicrobial agents. Inhibition of such pumps is a promising strategy to circumvent this resistance mechanism. NorA is a Staphylococcus aureus efflux pump that confers reduced susceptibility to many structurally unrelated agents, including fluoroquinolones, resulting in a multidrug resistant phenotype. In this work, a series of 2-phenyl-4(1H)-quinolone and 2-phenyl-4-hydroxyquinoline derivatives, obtained by modifying the flavone nucleus of known efflux pump inhibitors (EPIs), were synthesized in an effort to identify more potent S. aureus NorA EPIs. The 2-phenyl-4-hydroxyquinoline derivatives 28f and 29f display potent EPI activity against SA-1199B, a strain that overexpresses norA, in an ethidium bromide efflux inhibition assay. The same compounds, in combination with ciprofloxacin, were able to completely restore its antibacterial activity against both S. aureus SA-K2378 and SA-1199B, norA-overexpressing strains.
|
DRUGMATRIX: Muscarinic M1 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
145.0
nM
|
|
DRUGMATRIX: Muscarinic M1 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
35.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Muscarinic M2 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
532.0
nM
|
|
DRUGMATRIX: Muscarinic M2 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
189.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Muscarinic M3 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
179.0
nM
|
|
DRUGMATRIX: Muscarinic M3 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
38.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Muscarinic M4 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
244.0
nM
|
|
DRUGMATRIX: Muscarinic M4 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
34.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Muscarinic M5 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
123.0
nM
|
|
DRUGMATRIX: Muscarinic M5 radioligand binding (ligand: [3H] N-Methylscopolamine)
|
None
|
89.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Norepinephrine Transporter radioligand binding (ligand: [125I] RTI-55)
|
None
|
86.0
nM
|
|
DRUGMATRIX: Norepinephrine Transporter radioligand binding (ligand: [125I] RTI-55)
|
None
|
86.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Calcium Channel Type L, Benzothiazepine radioligand binding (ligand: [3H] Diltiazem)
|
Rattus norvegicus
|
373.0
nM
|
|
DRUGMATRIX: Calcium Channel Type L, Benzothiazepine radioligand binding (ligand: [3H] Diltiazem)
|
Rattus norvegicus
|
331.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Calcium Channel Type L, Dihydropyridine radioligand binding (ligand: [3H] Nitrendipine)
|
Rattus norvegicus
|
949.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Transporter, Serotonin (5-Hydroxytryptamine) (SERT) radioligand binding (ligand: [3H] Paroxetine)
|
None
|
0.08
nM
|
|
DRUGMATRIX: Transporter, Serotonin (5-Hydroxytryptamine) (SERT) radioligand binding (ligand: [3H] Paroxetine)
|
None
|
0.043
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Calcium Channel Type L, Phenylalkylamine radioligand binding (ligand: [3H] (-)-Desmethoxyverapamil (D-888))
|
Rattus norvegicus
|
747.0
nM
|
|
DRUGMATRIX: Calcium Channel Type L, Phenylalkylamine radioligand binding (ligand: [3H] (-)-Desmethoxyverapamil (D-888))
|
Rattus norvegicus
|
726.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Dopamine Transporter radioligand binding (ligand: [125I] RTI-55)
|
None
|
672.0
nM
|
|
DRUGMATRIX: Dopamine Transporter radioligand binding (ligand: [125I] RTI-55)
|
None
|
534.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
Inhibition of norA-mediated EtBr efflux in Staphylococcus aureus SA1199B overexpressing norA and expressing A116E GrlA mutation at 50 uM by fluorometry
|
Staphylococcus aureus
|
89.7
%
|
|
Journal : J. Med. Chem.
Title : Pyrazolo[4,3-c][1,2]benzothiazines 5,5-dioxide: a promising new class of Staphylococcus aureus NorA efflux pump inhibitors.
Year : 2012
Volume : 55
Issue : 7
First Page : 3568
Last Page : 3572
Authors : Sabatini S, Gosetto F, Serritella S, Manfroni G, Tabarrini O, Iraci N, Brincat JP, Carosati E, Villarini M, Kaatz GW, Cecchetti V.
Abstract : The increasing resistance to antibacterials commonly employed in the clinic and the growth of multidrug resistant strains suggest that the development of new therapeutic approaches should be of primary concern. In this context, EPIs may restore life to old drugs. In the present work, the EPI activity of the COX-2 inhibitor celecoxib was confirmed and a new class of pyrazolo[4,3-c][1,2]benzothiazine 5,5-dioxide analogues acting as inhibitors of the Staphylococcus aureus NorA multidrug efflux pump was identified.
|
Inhibition of human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting
|
Homo sapiens
|
33.0
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
12.7
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
37.5
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Displacement of [125I]RTI-55 from human recombinant SERT expressed in HEK293 cells after 1 hr by scintillation counting analysis
|
Homo sapiens
|
0.2
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of disubstituted piperidines and homopiperidines as potent dual NK1 receptor antagonists-serotonin reuptake transporter inhibitors for the treatment of depression.
Year : 2013
Volume : 21
Issue : 8
First Page : 2217
Last Page : 2228
Authors : Wu YJ, He H, Bertekap R, Westphal R, Lelas S, Newton A, Wallace T, Taber M, Davis C, Macor JE, Bronson J.
Abstract : This report describes the synthesis, structure-activity relationships and activity of piperidine, homopiperidine, and azocane derivatives combining NK1 receptor (NK1R) antagonism and serotonin reuptake transporter (SERT) inhibition. Our studies culminated in the discovery of piperidine 2 and homopiperidine 8 as potent dual NK1R antagonists-SERT inhibitors. Compound 2 demonstrated significant activity in the gerbil forced swimming test, suggesting that dual NK1R antagonists-SERT inhibitors may be useful in treating depression disorders.
|
Displacement of [125I]substance P from human recombinant NK1 receptor expressed in human U373 cells after 1 hr by scintillation counting analysis
|
Homo sapiens
|
900.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of disubstituted piperidines and homopiperidines as potent dual NK1 receptor antagonists-serotonin reuptake transporter inhibitors for the treatment of depression.
Year : 2013
Volume : 21
Issue : 8
First Page : 2217
Last Page : 2228
Authors : Wu YJ, He H, Bertekap R, Westphal R, Lelas S, Newton A, Wallace T, Taber M, Davis C, Macor JE, Bronson J.
Abstract : This report describes the synthesis, structure-activity relationships and activity of piperidine, homopiperidine, and azocane derivatives combining NK1 receptor (NK1R) antagonism and serotonin reuptake transporter (SERT) inhibition. Our studies culminated in the discovery of piperidine 2 and homopiperidine 8 as potent dual NK1R antagonists-SERT inhibitors. Compound 2 demonstrated significant activity in the gerbil forced swimming test, suggesting that dual NK1R antagonists-SERT inhibitors may be useful in treating depression disorders.
|
Inhibition of NorA in Staphylococcus aureus 1199B harboring grlA A116E mutant assessed as inhibition of ethidium bromide efflux at 50 uM measured for 5 mins by fluorometric analysis relative to control
|
Staphylococcus aureus
|
73.0
%
|
|
Journal : J. Med. Chem.
Title : Re-evolution of the 2-phenylquinolines: ligand-based design, synthesis, and biological evaluation of a potent new class of Staphylococcus aureus NorA efflux pump inhibitors to combat antimicrobial resistance.
Year : 2013
Volume : 56
Issue : 12
First Page : 4975
Last Page : 4989
Authors : Sabatini S, Gosetto F, Iraci N, Barreca ML, Massari S, Sancineto L, Manfroni G, Tabarrini O, Dimovska M, Kaatz GW, Cecchetti V.
Abstract : Overexpression of efflux pumps is an important mechanism by which bacteria evade the effects of antimicrobial agents that are substrates. NorA is a Staphylococcus aureus efflux pump that confers reduced susceptibility to many structurally unrelated agents, including fluoroquinolones, biocides, and dyes, resulting in a multidrug resistant (MDR) phenotype. In this work, a series of 2-phenylquinoline derivatives was designed by means of ligand-based pharmacophore modeling in an attempt to identify improved S. aureus NorA efflux pump inhibitors (EPIs). Most of the 2-phenylquinoline derivatives displayed potent EPI activity against the norA overexpressing strain SA-1199B. The antibacterial activity of ciprofloxacin, when used in combination with some of the synthesized compounds, was completely restored in SA-1199B and SA-K2378, a strain overexpressing norA from a multicopy plasmid. Compounds 3m and 3q also showed potent synergistic activity with the ethidium bromide dye in a strain overexpressing the MepA MDR efflux pump.
|
In vivo inhibition of CYP2D6 in patient at 20 mg, qd relative to control
|
Homo sapiens
|
55.0
%
|
|
Journal : MedChemComm
Title : Metabolism-guided drug design
Year : 2013
Volume : 4
Issue : 4
First Page : 631
Last Page : 652
Authors : Stepan AF, Mascitti V, Beaumont K, Kalgutkar AS
|
Inhibition of NorA efflux pump in Staphylococcus aureus SA-1199B assessed as inhibition of EtBr efflux at 50 uM
|
Staphylococcus aureus
|
90.0
%
|
|
Journal : MedChemComm
Title : Searching for innovative quinolone-like scaffolds: synthesis and biological evaluation of 2,1-benzothiazine 2,2-dioxide derivatives
Year : 2012
Volume : 3
Issue : 9
First Page : 1092
Last Page : 1097
Authors : Pieroni M, Sabatini S, Massari S, Kaatz GW, Cecchetti V, Tabarrini O
|
Inhibition of human CYP2D6 at 10 uM preincubated for 10 mins with cofactor followed by mixture of enzyme-substrate addition by fluorescence assay relative to control
|
Homo sapiens
|
96.5
%
|
|
Journal : MedChemComm
Title : Osthol and curcumin as inhibitors of human Pgp and multidrug efflux pumps of Staphylococcus aureus: reversing the resistance against frontline antibacterial drugs
Year : 2014
Volume : 5
Issue : 10
First Page : 1540
Last Page : 1547
Authors : Joshi P, Singh S, Wani A, Sharma S, Jain SK, Singh B, Gupta BD, Satti NK, Koul S, Khan IA, Kumar A, Bharate SB, Vishwakarma RA
|
Inhibition of ROCK1 (unknown origin) at 10 uM by ADP-Glo kinase assay
|
Homo sapiens
|
10.0
%
|
|
Journal : J. Med. Chem.
Title : Structure-Based Design, Synthesis, and Biological Evaluation of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors.
Year : 2016
Volume : 59
Issue : 8
First Page : 3793
Last Page : 3807
Authors : Waldschmidt HV, Homan KT, Cruz-Rodríguez O, Cato MC, Waninger-Saroni J, Larimore KM, Cannavo A, Song J, Cheung JY, Kirchhoff PD, Koch WJ, Tesmer JJ, Larsen SD.
Abstract : G protein-coupled receptors (GPCRs) are central to many physiological processes. Regulation of this superfamily of receptors is controlled by GPCR kinases (GRKs), some of which have been implicated in heart failure. GSK180736A, developed as a Rho-associated coiled-coil kinase 1 (ROCK1) inhibitor, was identified as an inhibitor of GRK2 and co-crystallized in the active site. Guided by its binding pose overlaid with the binding pose of a known potent GRK2 inhibitor, Takeda103A, a library of hybrid inhibitors was developed. This campaign produced several compounds possessing high potency and selectivity for GRK2 over other GRK subfamilies, PKA, and ROCK1. The most selective compound, 12n (CCG-224406), had an IC50 for GRK2 of 130 nM, >700-fold selectivity over other GRK subfamilies, and no detectable inhibition of ROCK1. Four of the new inhibitors were crystallized with GRK2 to give molecular insights into the binding and kinase selectivity of this class of inhibitors.
|
Inhibition of Schistosoma mansoni SERT
|
Schistosoma mansoni
|
90.0
nM
|
|
Journal : MedChemComm
Title : The antidepressant drug paroxetine as a new lead candidate in schistosome drug discovery
Year : 2016
Volume : 7
Issue : 6
First Page : 1176
Last Page : 1182
Authors : Neves BJ, Dantas RF, Senger MR, Valente WCG, Rezende-Neto JdM, Chaves WT, Kamentsky L, Carpenter A, Silva-Junior FP, Andrade CH
|
Inhibition of human SERT
|
Homo sapiens
|
20.0
nM
|
|
Journal : MedChemComm
Title : The antidepressant drug paroxetine as a new lead candidate in schistosome drug discovery
Year : 2016
Volume : 7
Issue : 6
First Page : 1176
Last Page : 1182
Authors : Neves BJ, Dantas RF, Senger MR, Valente WCG, Rezende-Neto JdM, Chaves WT, Kamentsky L, Carpenter A, Silva-Junior FP, Andrade CH
|
Inhibition of human SERT expressed in CHO cell membranes assessed as reduction in [3H]serotonin uptake preincubated for 10 mins followed by [3H]serotonin addition measured after 20 mins by liquid scintillation counting method
|
Homo sapiens
|
0.56
nM
|
|
Journal : Bioorg Med Chem
Title : Discovery of SMP-304, a novel benzylpiperidine derivative with serotonin transporter inhibitory activity and 5-HT1A weak partial agonistic activity showing the antidepressant-like effect.
Year : 2017
Volume : 25
Issue : 1
First Page : 293
Last Page : 304
Authors : Yoshinaga H, Masumoto S, Koyama K, Kinomura N, Matsumoto Y, Kato T, Baba S, Matsumoto K, Horisawa T, Oki H, Yabuuchi K, Kodo T.
Abstract : We report the discovery of a novel benzylpiperidine derivative with serotonin transporter (SERT) inhibitory activity and 5-HT1A receptor weak partial agonistic activity showing the antidepressant-like effect. The 3-methoxyphenyl group and the phenethyl group of compound 1, which has weak SERT binding activity, but potent 5-HT1A binding activity, were optimized, leading to compound 35 with potent and balanced dual SERT and 5-HT1A binding activity, but also potent CYP2D6 inhibitory activity. Replacement of the methoxy group in the left part of compound 35 with a larger alkoxy group, such as ethoxy, isopropoxy or methoxy-ethoxy group ameliorated CYP2D6 inhibition, giving SMP-304 as a candidate. SMP-304 with serotonin uptake inhibitory activity and 5-HT1A weak partial agonistic activity, which could work as a 5-HT1A antagonist, displayed faster onset of antidepressant-like effect than a representative SSRI paroxetine in an animal model.
|
Displacement of [3H]citalopram from human SERT expressed in HEK293 cell membranes after 1 hr by liquid scintillation counting method
|
Homo sapiens
|
0.11
nM
|
|
Journal : Bioorg Med Chem
Title : Discovery of SMP-304, a novel benzylpiperidine derivative with serotonin transporter inhibitory activity and 5-HT1A weak partial agonistic activity showing the antidepressant-like effect.
Year : 2017
Volume : 25
Issue : 1
First Page : 293
Last Page : 304
Authors : Yoshinaga H, Masumoto S, Koyama K, Kinomura N, Matsumoto Y, Kato T, Baba S, Matsumoto K, Horisawa T, Oki H, Yabuuchi K, Kodo T.
Abstract : We report the discovery of a novel benzylpiperidine derivative with serotonin transporter (SERT) inhibitory activity and 5-HT1A receptor weak partial agonistic activity showing the antidepressant-like effect. The 3-methoxyphenyl group and the phenethyl group of compound 1, which has weak SERT binding activity, but potent 5-HT1A binding activity, were optimized, leading to compound 35 with potent and balanced dual SERT and 5-HT1A binding activity, but also potent CYP2D6 inhibitory activity. Replacement of the methoxy group in the left part of compound 35 with a larger alkoxy group, such as ethoxy, isopropoxy or methoxy-ethoxy group ameliorated CYP2D6 inhibition, giving SMP-304 as a candidate. SMP-304 with serotonin uptake inhibitory activity and 5-HT1A weak partial agonistic activity, which could work as a 5-HT1A antagonist, displayed faster onset of antidepressant-like effect than a representative SSRI paroxetine in an animal model.
|
Inhibition of recombinant MPO (unknown origin) assessed as reduction in taurine chloramine production preincubated with enzyme and taurine followed by H2O2 addition measured after 5 mins
|
Homo sapiens
|
20.0
nM
|
|
Journal : J Med Chem
Title : Discovery of Novel Potent Reversible and Irreversible Myeloperoxidase Inhibitors Using Virtual Screening Procedure.
Year : 2017
Volume : 60
Issue : 15
First Page : 6563
Last Page : 6586
Authors : Soubhye J, Chikh Alard I, Aldib I, Prévost M, Gelbcke M, De Carvalho A, Furtmüller PG, Obinger C, Flemmig J, Tadrent S, Meyer F, Rousseau A, Nève J, Mathieu V, Zouaoui Boudjeltia K, Dufrasne F, Van Antwerpen P.
Abstract : The heme enzyme myeloperoxidase (MPO) participates in innate immune defense mechanism through formation of microbicidal reactive oxidants. However, evidence has emerged that MPO-derived oxidants contribute to propagation of inflammatory diseases. Because of the deleterious effects of circulating MPO, there is a great interest in the development of new efficient and specific inhibitors. Here, we have performed a novel virtual screening procedure, depending on ligand-based pharmacophore modeling followed by structure-based virtual screening. Starting from a set of 727842 compounds, 28 molecules were selected by this virtual method and tested on MPO in vitro. Twelve out of 28 compounds were found to have an IC50 less than 5 μM. The best inhibitors were 2-(7-methoxy-4-methylquinazolin-2-yl)guanidine (28) and (R)-2-(1-((2,3-dihydro-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-5-fluoro-1H-benzo[d]imidazole (42) with IC50 values of 44 and 50 nM, respectively. Studies on the mechanism of inhibition suggest that 28 is the first potent mechanism-based inhibitor and inhibits irreversibly MPO at nanomolar concentration.
|
Inhibition of ROCK1 (unknown origin) at 10 uM by ADP-Glo kinase assay
|
Homo sapiens
|
10.0
%
|
|
Journal : J Med Chem
Title : Structure-Based Design of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors Based on Paroxetine.
Year : 2017
Volume : 60
Issue : 7
First Page : 3052
Last Page : 3069
Authors : Waldschmidt HV, Homan KT, Cato MC, Cruz-Rodríguez O, Cannavo A, Wilson MW, Song J, Cheung JY, Koch WJ, Tesmer JJ, Larsen SD.
Abstract : In heart failure, the β-adrenergic receptors (βARs) become desensitized and uncoupled from heterotrimeric G proteins. This process is initiated by G protein-coupled receptor kinases (GRKs), some of which are upregulated in the failing heart, making them desirable therapeutic targets. The selective serotonin reuptake inhibitor, paroxetine, was previously identified as a GRK2 inhibitor. Utilizing a structure-based drug design approach, we modified paroxetine to generate a small compound library. Included in this series is a highly potent and selective GRK2 inhibitor, 14as, with an IC50 of 30 nM against GRK2 and greater than 230-fold selectivity over other GRKs and kinases. Furthermore, 14as showed a 100-fold improvement in cardiomyocyte contractility assays over paroxetine and a plasma concentration higher than its IC50 for over 7 h. Three of these inhibitors, including 14as, were additionally crystallized in complex with GRK2 to give insights into the structural determinants of potency and selectivity of these inhibitors.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
9.08
%
|
|
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
|
2.92
%
|
|
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
|
2.92
%
|
|
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.
|
Inhibition of bovine GRK2 using porcine brain tubulin as substrate incubated for 3 to 5 mins by [gamma32P]ATP based radiometric assay
|
Bos taurus
|
780.0
nM
|
|
Journal : J Med Chem
Title : Generation of Highly Selective, Potent, and Covalent G Protein-Coupled Receptor Kinase 5 Inhibitors.
Year : 2021
Volume : 64
Issue : 1.0
First Page : 566
Last Page : 585
Authors : Rowlands RA,Chen Q,Bouley RA,Avramova LV,Tesmer JJG,White AD
Abstract : The ability of G protein-coupled receptor (GPCR) kinases (GRKs) to regulate the desensitization of GPCRs has made GRK2 and GRK5 attractive targets for treating diseases such as heart failure and cancer. Previously, our work showed that Cys474, a GRK5 subfamily-specific residue located on a flexible loop adjacent to the active site, can be used as a covalent handle to achieve selective inhibition of GRK5 over GRK2 subfamily members. However, the potency of the most selective inhibitors remained modest. Herein, we describe a successful campaign to adapt an indolinone scaffold with covalent warheads, resulting in a series of 2-haloacetyl-containing compounds that react quickly and exhibit three orders of magnitude selectivity for GRK5 over GRK2 and low nanomolar potency. They however retain a similar selectivity profile across the kinome as the core scaffold, which was based on Sunitinib.
|
Displacement of [125I]RTI55 binding from human wild type SERT
|
Homo sapiens
|
0.08
nM
|
|
