|
Binding affinity towards human Alpha-1C adrenergic receptor by the displacement of [3H]prazosin
|
None
|
977.24
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A convenient synthesis of 2-amino-2-oxazolines and their pharmacological evaluation at cloned human adrenergic receptors
Year : 1994
Volume : 4
Issue : 19
First Page : 2317
Last Page : 2322
Authors : Wong WC, Wang D, Forray C, Vaysse PJ, Branchek TA, Gluchowski C
|
Displacement of [3H]clonidine from Alpha-2 adrenergic receptor of rat brain membranes
|
Rattus norvegicus
|
5.7
nM
|
|
Journal : J. Med. Chem.
Title : alpha 2 adrenoceptors: classification, localization, mechanisms, and targets for drugs.
Year : 1982
Volume : 25
Issue : 12
First Page : 1389
Last Page : 1401
Authors : Timmermans PB, van Zwieten PA.
|
Binding affinity towards alpha-2 adrenergic receptor in rat using [3H]rauwolscine as radioligand
|
None
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally defined adrenergic agents. 1. Design and synthesis of novel alpha 2 selective adrenergic agents: electrostatic repulsion based conformational prototypes.
Year : 1985
Volume : 28
Issue : 10
First Page : 1398
Last Page : 1404
Authors : DeBernardis JF, Kerkman DJ, Winn M, Bush EN, Arendsen DL, McClellan WJ, Kyncl JJ, Basha FZ.
Abstract : A previous report of the adrenergic selectivity of 2- and 6-fluoronorepinephrine prompted us to formulate a hypothesis that accounted for this selectivity on the basis of a conformational preference induced by electrostatic repulsion between the aromatic fluorine atom and the side-chain hydroxyl group. A series of nitrogen-substituted catechol (aminomethyl)benzocyclobutenes, indanes, tetralins, and benzocycloheptenes were prepared, and when their radioligand binding affinities were determined, it was found that the overall pattern of binding affinity results supported the electrostatic repulsion hypothesis. The radioligand binding assay also revealed several highly alpha 2 selective adrenergic agents among these compounds, with the binding selectivity maximizing for compounds having nitrogen substituted with a group no larger than methyl and having a five-membered carbocyclic ring (i.e., 16, 17, and 19).
|
Compound was tested for the inhibition of [3H]prazosin binding Alpha-1 adrenergic receptor of crude rat brain membrane.
|
None
|
527.6
nM
|
|
Journal : J. Med. Chem.
Title : 1-(alkylamino)isochromans: hypotensives with peripheral and central activities.
Year : 1982
Volume : 25
Issue : 1
First Page : 75
Last Page : 81
Authors : McCall JM, McCall RB, TenBrink RE, Kamdar BV, Humphrey SJ, Sethy VH, Harris DW, Daenzer C.
Abstract : A series of 1-[1-(3,4-dimethoxy-1H-2-benzopyran-1-yl)alkyl]-4-arylpiperazines that shows hypotensive activity in the conscious rat has been investigated. Structure-activity relationships are described. A typical example that was investigated in greater detail is 1-[2-(3,4-dihydro-6,7-dimethoxy-1H-2-benzopyran-1-yl)ethyl]-4-(4-fluorophenyl)piperazine. This compound decreases sympathetic nerve activity recorded from the external carotid and splanchnic nerves of baroreceptor-denervated cats and, therefore, has a central component to its mechanism of action. It also blocks pressor effects of norepinephrine and phenylephrine and is thus an alpha-adrenergic antagonist. Binding data characterize this as alpha 1-adrenergic receptor blockade.
|
In vitro binding affinity was measured as the inhibition of [3H]WB-4101 binding to alpha-1 adrenergic receptor of rat cortical membranes
|
None
|
310.0
nM
|
|
Journal : J. Med. Chem.
Title : 4-Amino-6-chloro-2-piperazinopyrimidines with selective affinity for alpha 2-adrenoceptors.
Year : 1986
Volume : 29
Issue : 8
First Page : 1394
Last Page : 1398
Authors : Guérémy C, Audiau F, Renault C, Benavides J, Uzan A, Le Fur G.
Abstract : A series of 4-amino-6-chloro-2-piperazinopyrimidines were synthesized and evaluated for their ability to interact with alpha 1- and alpha 2-adrenoceptors in vitro in binding assays using [3H]WB-4101, [3H]clonidine, and [3H]idazoxan as radioligands. Some compounds were also tested as inhibitors of [3H]spiroperidol binding. Several members of this series showed high and selective affinity for alpha 2-adrenoceptors. The nature of the 4-amino substituent seems to be the most critical factor in determining the potency at these receptors.
|
Tested for Binding affinity towards alpha-1 adrenergic receptor
|
Rattus norvegicus
|
116.0
nM
|
|
Journal : J. Med. Chem.
Title : alpha(2) Adrenoceptor agonists as potential analgesic agents. 2. Discovery of 4-(4-Imidazo)-1,3-dimethyl-6,7-dihydrothianaphthene [corrected] as a high-affinity ligand for the alpha(2D) adrenergic receptor.
Year : 2000
Volume : 43
Issue : 5
First Page : 765
Last Page : 768
Authors : Ross TM, Jetter MC, McDonnell ME, Boyd RE, Connelly CD, Martinez RP, Lewis MA, Codd EE, Raffa RB, Reitz AB.
|
Binding affinity against alpha-1 adrenergic receptor in rat using [3H]prazosin as radioligand
|
None
|
520.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally defined adrenergic agents. 1. Design and synthesis of novel alpha 2 selective adrenergic agents: electrostatic repulsion based conformational prototypes.
Year : 1985
Volume : 28
Issue : 10
First Page : 1398
Last Page : 1404
Authors : DeBernardis JF, Kerkman DJ, Winn M, Bush EN, Arendsen DL, McClellan WJ, Kyncl JJ, Basha FZ.
Abstract : A previous report of the adrenergic selectivity of 2- and 6-fluoronorepinephrine prompted us to formulate a hypothesis that accounted for this selectivity on the basis of a conformational preference induced by electrostatic repulsion between the aromatic fluorine atom and the side-chain hydroxyl group. A series of nitrogen-substituted catechol (aminomethyl)benzocyclobutenes, indanes, tetralins, and benzocycloheptenes were prepared, and when their radioligand binding affinities were determined, it was found that the overall pattern of binding affinity results supported the electrostatic repulsion hypothesis. The radioligand binding assay also revealed several highly alpha 2 selective adrenergic agents among these compounds, with the binding selectivity maximizing for compounds having nitrogen substituted with a group no larger than methyl and having a five-membered carbocyclic ring (i.e., 16, 17, and 19).
|
in vitro alpha-1 adrenergic receptor binding assay from rats, using RX 821002 as the displaceable ligand
|
None
|
116.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha(2) adrenoceptor agonists as potential analgesic agents. 2. Discovery of 4-(4-imidazo)-1,3-dimethyl-6,7-dihydro-thianaphthene as a high-affinity ligand for the alpha(2D) adrenergic receptor.
Year : 2000
Volume : 43
Issue : 7
First Page : 1423
Last Page : 1426
Authors : Ross TM, Jetter MC, McDonnell ME, Boyd RE, Connelly CD, Martinez RP, Lewis MA, Codd EE, Raffa RB, Reitz AB.
|
Concentration necessary to achieve half maximal inhibition of [3H]clonidine binding to Alpha-2 adrenergic receptor at 1 uM
|
None
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : 2H-[1]benzopyrano[3,4-b]pyridines: synthesis and activity at central monoamine receptors.
Year : 1989
Volume : 32
Issue : 3
First Page : 720
Last Page : 727
Authors : Hutchison A, Williams M, de Jesus R, Stone GA, Sylvester L, Clarke FH, Sills MA.
Abstract : Two general synthetic approaches to a novel series of 2H-[1]benzopyrano[3,4-b]pyridines are described together with their receptor binding profile at a variety of monoamine receptors in mammalian brain tissue. The biologically active members of this series fall into into one of two broad classes: 3,4,4a,5-tetrahydro-2H-[1]benzopyrano[3,4-b]pyridines or trans-1,3,4,4a,5,10b-hexahydro-2H-[1]benzopyrano[3,4-b]pyridines. By appropriate pharmacophoric modification potent selective ligands for D2, alpha-2, 5HT1A, and 5HT2 receptors may be obtained. The previously published in vivo data on certain key representatives of these series are also summarized.
|
Binding affinity for human Alpha-2A adrenergic receptor
|
Homo sapiens
|
3.8
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacologic evaluation of 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane: a potent imidazoline1 receptor specific agent.
Year : 1996
Volume : 39
Issue : 6
First Page : 1193
Last Page : 1195
Authors : Munk SA, Lai RK, Burke JE, Arasasingham PN, Kharlamb AB, Manlapaz CA, Padillo EU, Wijono MK, Hasson DW, Wheeler LA, Garst ME.
|
Compound was tested in vitro for binding affinity against Alpha-2A adrenergic receptor from cloned human C-10 receptor transfected into Chinese hamster ovary (CHO) cells
|
None
|
3.8
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of 2-[(5-methylbenz-1-ox-4-azin-6-yl)imino]imidazoline, a potent, peripherally acting alpha 2 adrenoceptor agonist.
Year : 1996
Volume : 39
Issue : 18
First Page : 3533
Last Page : 3538
Authors : Munk SA, Harcourt D, Ambrus G, Denys L, Gluchowski C, Burke JA, Kharlamb AB, Manlapaz CA, Padillo EU, Runde E, Williams L, Wheeler LA, Garst ME.
Abstract : We have synthesized 2-[(5-methylbenz-1-ox-4-azin-6-yl)imidazoline, 3, a potent, peripherally acting alpha 2 adrenoceptor agonist. The agent is conveniently prepared in five steps from 2-amino-m-cresol. The agent has demonstrated good selectivity for alpha 2 adrenoceptors in binding and functional studies. When applied topically to eyes, the agent is efficacious for the reduction of intraocular pressure. The agent does not penetrate the blood-brain barrier and, as a consequence, does not lower blood pressure or induce sedation when administered topically or intravenously. We have determined the pKa and log P in water versus both octanol and dodecane of 3 and a set of related agents. The best physical parameter to explain its lack of central nervous system penetration appears to be log P measured in octanol versus water.
|
Binding affinity towards Alpha-2A adrenergic receptor
|
Homo sapiens
|
853.0
nM
|
|
Journal : J. Med. Chem.
Title : alpha(2) Adrenoceptor agonists as potential analgesic agents. 2. Discovery of 4-(4-Imidazo)-1,3-dimethyl-6,7-dihydrothianaphthene [corrected] as a high-affinity ligand for the alpha(2D) adrenergic receptor.
Year : 2000
Volume : 43
Issue : 5
First Page : 765
Last Page : 768
Authors : Ross TM, Jetter MC, McDonnell ME, Boyd RE, Connelly CD, Martinez RP, Lewis MA, Codd EE, Raffa RB, Reitz AB.
|
Agonistic activity towards human Alpha-2A adrenergic receptor was measured as ability to inhibit forskolin-stimulated synthesis of cyclic adenosine monophosphate
|
None
|
8.128
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A convenient synthesis of 2-amino-2-oxazolines and their pharmacological evaluation at cloned human adrenergic receptors
Year : 1994
Volume : 4
Issue : 19
First Page : 2317
Last Page : 2322
Authors : Wong WC, Wang D, Forray C, Vaysse PJ, Branchek TA, Gluchowski C
|
Binding affinity towards human Alpha-2A adrenergic receptor by the displacement of [3H]rauwolscine
|
None
|
7.943
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A convenient synthesis of 2-amino-2-oxazolines and their pharmacological evaluation at cloned human adrenergic receptors
Year : 1994
Volume : 4
Issue : 19
First Page : 2317
Last Page : 2322
Authors : Wong WC, Wang D, Forray C, Vaysse PJ, Branchek TA, Gluchowski C
|
in vitro alpha-2A adrenergic receptor binding assay from rats, using RX 821002 as the displaceable ligand
|
None
|
853.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha(2) adrenoceptor agonists as potential analgesic agents. 2. Discovery of 4-(4-imidazo)-1,3-dimethyl-6,7-dihydro-thianaphthene as a high-affinity ligand for the alpha(2D) adrenergic receptor.
Year : 2000
Volume : 43
Issue : 7
First Page : 1423
Last Page : 1426
Authors : Ross TM, Jetter MC, McDonnell ME, Boyd RE, Connelly CD, Martinez RP, Lewis MA, Codd EE, Raffa RB, Reitz AB.
|
Compound was tested for binding affinity based on dissociation constant of Alpha-1 adrenergic receptor
|
None
|
510.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of 2-[(5-methylbenz-1-ox-4-azin-6-yl)imino]imidazoline, a potent, peripherally acting alpha 2 adrenoceptor agonist.
Year : 1996
Volume : 39
Issue : 18
First Page : 3533
Last Page : 3538
Authors : Munk SA, Harcourt D, Ambrus G, Denys L, Gluchowski C, Burke JA, Kharlamb AB, Manlapaz CA, Padillo EU, Runde E, Williams L, Wheeler LA, Garst ME.
Abstract : We have synthesized 2-[(5-methylbenz-1-ox-4-azin-6-yl)imidazoline, 3, a potent, peripherally acting alpha 2 adrenoceptor agonist. The agent is conveniently prepared in five steps from 2-amino-m-cresol. The agent has demonstrated good selectivity for alpha 2 adrenoceptors in binding and functional studies. When applied topically to eyes, the agent is efficacious for the reduction of intraocular pressure. The agent does not penetrate the blood-brain barrier and, as a consequence, does not lower blood pressure or induce sedation when administered topically or intravenously. We have determined the pKa and log P in water versus both octanol and dodecane of 3 and a set of related agents. The best physical parameter to explain its lack of central nervous system penetration appears to be log P measured in octanol versus water.
|
Binding affinity for human brain Alpha-1 adrenergic receptor
|
Homo sapiens
|
510.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacologic evaluation of 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane: a potent imidazoline1 receptor specific agent.
Year : 1996
Volume : 39
Issue : 6
First Page : 1193
Last Page : 1195
Authors : Munk SA, Lai RK, Burke JE, Arasasingham PN, Kharlamb AB, Manlapaz CA, Padillo EU, Wijono MK, Hasson DW, Wheeler LA, Garst ME.
|
The compound was tested for alpha-adrenergic activity against Alpha-1 adrenergic receptor from rat aorta.
|
None
|
257.04
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and ocular antihypertensive activity of new imidazolidine derivatives containing a beta-blocking side chain.
Year : 1991
Volume : 34
Issue : 11
First Page : 3197
Last Page : 3204
Authors : Huber D, Ehrhardt JD, Decker N, Himber J, Andermann G, Leclerc G.
Abstract : The syntheses of new phenylimidazolidine derivatives (3-6)1 containing a propanolamine oxime or an oxypropanolamine moiety attached either to the aromatic or to the imidazolidine ring are described. These compounds were evaluated for potential ocular antihypertensive activity in alpha-chymotrypsin-induced ocular hypertension in rabbits. These compounds represent a unique series of effective ocular antihypertensive agents that despite possessing structural characteristics of beta-blockers and of imidazolidine derivatives, exhibit weak alpha- and beta-adrenergic agonist and antagonist activities. These findings may be of significant therapeutic importance in the medical management of glaucoma.
|
Inhibition of [3H]p-aminoclonidine (PAC) binding to alpha-2 adrenergic receptor of purified human platelet plasma membranes
|
None
|
21.0
nM
|
|
Journal : J. Med. Chem.
Title : Radioiodinated p-iodoclonidine: a high-affinity probe for the alpha 2-adrenergic receptor.
Year : 1987
Volume : 30
Issue : 7
First Page : 1241
Last Page : 1244
Authors : Van Dort M, Neubig R, Counsell RE.
Abstract : The chemical synthesis of 2-[(2,6-dichloro-4-iodophenyl)imino]imidazolidine (PIC) and its radioiodinated analogue [125I]PIC is described. PIC was synthesized from 2,6-dichloroaniline in five synthetic steps. This agent displayed a high affinity for the alpha 2-adrenergic receptor (IC50 = 1.5 nM) in competitive binding assays conducted with purified human platelet plasma membrane fractions. For the synthesis of radioiodinated PIC the triazene intermediate 11 was synthesized from 2,6-dichloro-4-nitroaniline in five synthetic steps. Acid-catalyzed decomposition of 11 with no-carrier-added Na125I afforded high specific activity [125I]PIC. In view of its high affinity for the alpha 2-adrenergic receptor, [125I]PIC is a potentially useful probe for studies in adrenergic pharmacology.
|
Agonistic activity towards human Alpha-2B adrenergic receptor was measured as ability to inhibit forskolin-stimulated synthesis of cyclic adenosine monophosphate
|
None
|
165.96
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A convenient synthesis of 2-amino-2-oxazolines and their pharmacological evaluation at cloned human adrenergic receptors
Year : 1994
Volume : 4
Issue : 19
First Page : 2317
Last Page : 2322
Authors : Wong WC, Wang D, Forray C, Vaysse PJ, Branchek TA, Gluchowski C
|
Binding affinity towards human Alpha-2B adrenergic receptor by the displacement of [3H]rauwolscine
|
None
|
6.166
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A convenient synthesis of 2-amino-2-oxazolines and their pharmacological evaluation at cloned human adrenergic receptors
Year : 1994
Volume : 4
Issue : 19
First Page : 2317
Last Page : 2322
Authors : Wong WC, Wang D, Forray C, Vaysse PJ, Branchek TA, Gluchowski C
|
Binding affinity for rat Alpha-2B adrenergic receptor
|
Rattus norvegicus
|
8.3
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacologic evaluation of 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane: a potent imidazoline1 receptor specific agent.
Year : 1996
Volume : 39
Issue : 6
First Page : 1193
Last Page : 1195
Authors : Munk SA, Lai RK, Burke JE, Arasasingham PN, Kharlamb AB, Manlapaz CA, Padillo EU, Wijono MK, Hasson DW, Wheeler LA, Garst ME.
|
Compound was tested for concentration that produced 50% contractile relative response to maximum response to norepinephrine for Alpha-1 adrenergic receptor
|
Oryctolagus cuniculus
|
290.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of 2-[(5-methylbenz-1-ox-4-azin-6-yl)imino]imidazoline, a potent, peripherally acting alpha 2 adrenoceptor agonist.
Year : 1996
Volume : 39
Issue : 18
First Page : 3533
Last Page : 3538
Authors : Munk SA, Harcourt D, Ambrus G, Denys L, Gluchowski C, Burke JA, Kharlamb AB, Manlapaz CA, Padillo EU, Runde E, Williams L, Wheeler LA, Garst ME.
Abstract : We have synthesized 2-[(5-methylbenz-1-ox-4-azin-6-yl)imidazoline, 3, a potent, peripherally acting alpha 2 adrenoceptor agonist. The agent is conveniently prepared in five steps from 2-amino-m-cresol. The agent has demonstrated good selectivity for alpha 2 adrenoceptors in binding and functional studies. When applied topically to eyes, the agent is efficacious for the reduction of intraocular pressure. The agent does not penetrate the blood-brain barrier and, as a consequence, does not lower blood pressure or induce sedation when administered topically or intravenously. We have determined the pKa and log P in water versus both octanol and dodecane of 3 and a set of related agents. The best physical parameter to explain its lack of central nervous system penetration appears to be log P measured in octanol versus water.
|
Compound was tested in vitro for binding affinity against Alpha-2B adrenergic receptor from cloned rat RNG receptor transfected into Chinese hamster ovary (CHO) cells
|
None
|
8.3
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of 2-[(5-methylbenz-1-ox-4-azin-6-yl)imino]imidazoline, a potent, peripherally acting alpha 2 adrenoceptor agonist.
Year : 1996
Volume : 39
Issue : 18
First Page : 3533
Last Page : 3538
Authors : Munk SA, Harcourt D, Ambrus G, Denys L, Gluchowski C, Burke JA, Kharlamb AB, Manlapaz CA, Padillo EU, Runde E, Williams L, Wheeler LA, Garst ME.
Abstract : We have synthesized 2-[(5-methylbenz-1-ox-4-azin-6-yl)imidazoline, 3, a potent, peripherally acting alpha 2 adrenoceptor agonist. The agent is conveniently prepared in five steps from 2-amino-m-cresol. The agent has demonstrated good selectivity for alpha 2 adrenoceptors in binding and functional studies. When applied topically to eyes, the agent is efficacious for the reduction of intraocular pressure. The agent does not penetrate the blood-brain barrier and, as a consequence, does not lower blood pressure or induce sedation when administered topically or intravenously. We have determined the pKa and log P in water versus both octanol and dodecane of 3 and a set of related agents. The best physical parameter to explain its lack of central nervous system penetration appears to be log P measured in octanol versus water.
|
in vitro alpha-2B adrenergic receptor binding assay from rats, using RX 821002 as the displaceable ligand
|
None
|
160.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha(2) adrenoceptor agonists as potential analgesic agents. 2. Discovery of 4-(4-imidazo)-1,3-dimethyl-6,7-dihydro-thianaphthene as a high-affinity ligand for the alpha(2D) adrenergic receptor.
Year : 2000
Volume : 43
Issue : 7
First Page : 1423
Last Page : 1426
Authors : Ross TM, Jetter MC, McDonnell ME, Boyd RE, Connelly CD, Martinez RP, Lewis MA, Codd EE, Raffa RB, Reitz AB.
|
Binding affinity for human Alpha-2C adrenergic receptor
|
Homo sapiens
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacologic evaluation of 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane: a potent imidazoline1 receptor specific agent.
Year : 1996
Volume : 39
Issue : 6
First Page : 1193
Last Page : 1195
Authors : Munk SA, Lai RK, Burke JE, Arasasingham PN, Kharlamb AB, Manlapaz CA, Padillo EU, Wijono MK, Hasson DW, Wheeler LA, Garst ME.
|
Compound was tested in vitro for binding affinity against Alpha-2C adrenergic receptor from cloned human C-2 receptor transfected into Chinese hamster ovary (CHO) cells
|
None
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of 2-[(5-methylbenz-1-ox-4-azin-6-yl)imino]imidazoline, a potent, peripherally acting alpha 2 adrenoceptor agonist.
Year : 1996
Volume : 39
Issue : 18
First Page : 3533
Last Page : 3538
Authors : Munk SA, Harcourt D, Ambrus G, Denys L, Gluchowski C, Burke JA, Kharlamb AB, Manlapaz CA, Padillo EU, Runde E, Williams L, Wheeler LA, Garst ME.
Abstract : We have synthesized 2-[(5-methylbenz-1-ox-4-azin-6-yl)imidazoline, 3, a potent, peripherally acting alpha 2 adrenoceptor agonist. The agent is conveniently prepared in five steps from 2-amino-m-cresol. The agent has demonstrated good selectivity for alpha 2 adrenoceptors in binding and functional studies. When applied topically to eyes, the agent is efficacious for the reduction of intraocular pressure. The agent does not penetrate the blood-brain barrier and, as a consequence, does not lower blood pressure or induce sedation when administered topically or intravenously. We have determined the pKa and log P in water versus both octanol and dodecane of 3 and a set of related agents. The best physical parameter to explain its lack of central nervous system penetration appears to be log P measured in octanol versus water.
|
Binding affinity towards alpha-2C adrenergic receptor
|
Homo sapiens
|
160.0
nM
|
|
Journal : J. Med. Chem.
Title : alpha(2) Adrenoceptor agonists as potential analgesic agents. 2. Discovery of 4-(4-Imidazo)-1,3-dimethyl-6,7-dihydrothianaphthene [corrected] as a high-affinity ligand for the alpha(2D) adrenergic receptor.
Year : 2000
Volume : 43
Issue : 5
First Page : 765
Last Page : 768
Authors : Ross TM, Jetter MC, McDonnell ME, Boyd RE, Connelly CD, Martinez RP, Lewis MA, Codd EE, Raffa RB, Reitz AB.
|
Compound was tested for concentration that produced 50% contractile relative response to maximum response to norepinephrine for Alpha-2 adrenergic receptor
|
Oryctolagus cuniculus
|
4.4
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of 2-[(5-methylbenz-1-ox-4-azin-6-yl)imino]imidazoline, a potent, peripherally acting alpha 2 adrenoceptor agonist.
Year : 1996
Volume : 39
Issue : 18
First Page : 3533
Last Page : 3538
Authors : Munk SA, Harcourt D, Ambrus G, Denys L, Gluchowski C, Burke JA, Kharlamb AB, Manlapaz CA, Padillo EU, Runde E, Williams L, Wheeler LA, Garst ME.
Abstract : We have synthesized 2-[(5-methylbenz-1-ox-4-azin-6-yl)imidazoline, 3, a potent, peripherally acting alpha 2 adrenoceptor agonist. The agent is conveniently prepared in five steps from 2-amino-m-cresol. The agent has demonstrated good selectivity for alpha 2 adrenoceptors in binding and functional studies. When applied topically to eyes, the agent is efficacious for the reduction of intraocular pressure. The agent does not penetrate the blood-brain barrier and, as a consequence, does not lower blood pressure or induce sedation when administered topically or intravenously. We have determined the pKa and log P in water versus both octanol and dodecane of 3 and a set of related agents. The best physical parameter to explain its lack of central nervous system penetration appears to be log P measured in octanol versus water.
|
Agonistic activity towards human Alpha-2C adrenergic receptor was measured as ability to inhibit forskolin-stimulated synthesis of cyclic adenosine monophosphate
|
None
|
54.95
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A convenient synthesis of 2-amino-2-oxazolines and their pharmacological evaluation at cloned human adrenergic receptors
Year : 1994
Volume : 4
Issue : 19
First Page : 2317
Last Page : 2322
Authors : Wong WC, Wang D, Forray C, Vaysse PJ, Branchek TA, Gluchowski C
|
Binding affinity towards human Alpha-2C adrenergic receptor by the displacement of [3H]rauwolscine
|
None
|
56.23
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A convenient synthesis of 2-amino-2-oxazolines and their pharmacological evaluation at cloned human adrenergic receptors
Year : 1994
Volume : 4
Issue : 19
First Page : 2317
Last Page : 2322
Authors : Wong WC, Wang D, Forray C, Vaysse PJ, Branchek TA, Gluchowski C
|
Binding affinity towards alpha-2D adrenergic receptor
|
Rattus norvegicus
|
0.39
nM
|
|
Journal : J. Med. Chem.
Title : alpha(2) Adrenoceptor agonists as potential analgesic agents. 2. Discovery of 4-(4-Imidazo)-1,3-dimethyl-6,7-dihydrothianaphthene [corrected] as a high-affinity ligand for the alpha(2D) adrenergic receptor.
Year : 2000
Volume : 43
Issue : 5
First Page : 765
Last Page : 768
Authors : Ross TM, Jetter MC, McDonnell ME, Boyd RE, Connelly CD, Martinez RP, Lewis MA, Codd EE, Raffa RB, Reitz AB.
|
In vitro rat alpha-2D adrenergic receptor binding using p-aminoclonidine
|
Rattus norvegicus
|
0.39
nM
|
|
Journal : J. Med. Chem.
Title : Alpha(2) adrenoceptor agonists as potential analgesic agents. 2. Discovery of 4-(4-imidazo)-1,3-dimethyl-6,7-dihydro-thianaphthene as a high-affinity ligand for the alpha(2D) adrenergic receptor.
Year : 2000
Volume : 43
Issue : 7
First Page : 1423
Last Page : 1426
Authors : Ross TM, Jetter MC, McDonnell ME, Boyd RE, Connelly CD, Martinez RP, Lewis MA, Codd EE, Raffa RB, Reitz AB.
|
Binding affinity towards human Alpha-1A adrenergic receptor by the displacement of [3H]prazosin
|
None
|
512.86
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A convenient synthesis of 2-amino-2-oxazolines and their pharmacological evaluation at cloned human adrenergic receptors
Year : 1994
Volume : 4
Issue : 19
First Page : 2317
Last Page : 2322
Authors : Wong WC, Wang D, Forray C, Vaysse PJ, Branchek TA, Gluchowski C
|
50% inhibition of specific [3H]clonidine binding (0.4 nM) to Alpha-2 adrenergic receptors in rat isolated brain membranes
|
None
|
3.1
nM
|
|
Journal : J. Med. Chem.
Title : Quantitative relationships between alpha-adrenergic activity and binding affinity of alpha-adrenoceptor agonists and antagonists.
Year : 1984
Volume : 27
Issue : 4
First Page : 495
Last Page : 503
Authors : Timmermans PB, de Jonge A, Thoolen MJ, Wilffert B, Batink H, van Zwieten PA.
Abstract : Quantitative relationships between in vitro affinity for alpha 1- and alpha 2-adrenoceptors (specific binding sites in rat brain membranes of [3H]prazosin and [3H]clonidine, respectively) and in vitro and in vivo alpha 1/alpha 2-adrenoceptor agonist/antagonist activities were derived for a series of 11 alpha-adrenergic antagonists and 35 agonists of dissimilar chemical structure. For the antagonists, the alpha 1/alpha 2-binding selectivity ratio most significantly correlated with the functional alpha 1/alpha 2-blocking selectivity ratios assessed in vitro (rabbit isolated pulmonary artery: antagonism of alpha 1-adrenoceptor-induced vasoconstriction and alpha 2-adrenoceptor-evoked facilitation of transmitter release) and in vivo (antagonism of alpha 1- and alpha 2-adrenoceptor-mediated vasoconstriction in pithed normotensive rats). These results show that the in vitro alpha 1- and alpha 2-adrenoceptor binding affinities of the antagonists provide adequate information concerning their functional alpha 1- and alpha 2-adrenoceptor blocking potencies against agonists. For the agonists, the central, alpha 2-adrenoceptor-elicited, hypotensive activity was not correlated with alpha 1-adrenoceptor binding affinity but was most significantly described in terms of affinity for alpha 2-adrenoceptors and a parabolic dependence on log P' (octanol/buffer; pH 7.4; 37 degrees C). The relevance of log P' in the regression is explained by the difference in accessibility to the membrane-bound alpha 2-adrenoceptors in the radioligand displacement experiments and the central medullary (hypotensive) alpha 2-adrenoceptors in the intact animal. In contrast, the affinity parameters for alpha 1- and alpha 2-adrenoceptors were found to be poor descriptors of the hypertensive potency of the agonists in which alpha 1- and alpha 2-adrenoceptors are known to play a role. The correlations in which the individual binding parameters and the combination of both variables were included reached only a moderate significance level.(ABSTRACT TRUNCATED AT 250 WORDS)
|
The compound was evaluated for the alpha-2 adrenergic receptor antagonistic activity in rat vas deferens vs clonidine
|
None
|
3.9
nM
|
|
Journal : J. Med. Chem.
Title : Alpha 2-adrenergic agonists/antagonists: the synthesis and structure-activity relationships of a series of indolin-2-yl and tetrahydroquinolin-2-yl imidazolines.
Year : 1987
Volume : 30
Issue : 9
First Page : 1555
Last Page : 1562
Authors : Hlasta DJ, Luttinger D, Perrone MH, Silbernagel MJ, Ward SJ, Haubrich DR.
Abstract : The synthesis and alpha 2-adrenergic activity of a series of indolin-2-yl and tetrahydroquinolin-2-yl imidazolines are described. The indolin-2-yl imidazoline 4b was found to possess potent alpha 2-adrenergic agonist and antagonist activity. The modification of the substituents on the indoline ring of 4b has led to the separation of these activities. Substitution on the aromatic ring of 4b with halogen or increasing the size of the N-alkyl substituent of 4b gave alpha 2-adrenergic antagonists without agonist activity. The N-allylindoline 4d is more potent than idazoxan in vitro and is equipotent in vivo, but is less receptor selective (alpha 2 vs. alpha 1) than idazoxan. The cis-1,3-dimethylindolin-2-yl imidazoline 6a is an alpha 2-adrenergic agonist equal in potency to clonidine in vitro, while the trans-1,3-dimethylindolin-2-yl imidazoline 6b is a moderately potent alpha 2-adrenergic antagonist.
|
Binding affinity against alpha-2 adrenergic receptor was determined by the displacement of [3H]clonidine from rat brain cortical membranes
|
None
|
1.8
nM
|
|
Journal : J. Med. Chem.
Title : Alpha 2-adrenergic agonists/antagonists: the synthesis and structure-activity relationships of a series of indolin-2-yl and tetrahydroquinolin-2-yl imidazolines.
Year : 1987
Volume : 30
Issue : 9
First Page : 1555
Last Page : 1562
Authors : Hlasta DJ, Luttinger D, Perrone MH, Silbernagel MJ, Ward SJ, Haubrich DR.
Abstract : The synthesis and alpha 2-adrenergic activity of a series of indolin-2-yl and tetrahydroquinolin-2-yl imidazolines are described. The indolin-2-yl imidazoline 4b was found to possess potent alpha 2-adrenergic agonist and antagonist activity. The modification of the substituents on the indoline ring of 4b has led to the separation of these activities. Substitution on the aromatic ring of 4b with halogen or increasing the size of the N-alkyl substituent of 4b gave alpha 2-adrenergic antagonists without agonist activity. The N-allylindoline 4d is more potent than idazoxan in vitro and is equipotent in vivo, but is less receptor selective (alpha 2 vs. alpha 1) than idazoxan. The cis-1,3-dimethylindolin-2-yl imidazoline 6a is an alpha 2-adrenergic agonist equal in potency to clonidine in vitro, while the trans-1,3-dimethylindolin-2-yl imidazoline 6b is a moderately potent alpha 2-adrenergic antagonist.
|
Binding affinity for alpha-2 adrenergic receptor in rat cortex using [3H]rauwolscine.
|
None
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally defined adrenergic agents. 5. Resolution, absolute configuration, and pharmacological characterization of the enantiomers of 2-(5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphthyl)imidazoline: a potent agonist at alpha-adrenoceptors.
Year : 1987
Volume : 30
Issue : 6
First Page : 1011
Last Page : 1017
Authors : DeBernardis JF, Kerkman DJ, Arendsen DL, Buckner SA, Kyncl JJ, Hancock AA.
Abstract : (+/-)-2-(5,6-Dimethoxy-1,2,3,4-tetrahydro-1-naphthyl)imidazoline has been resolved into its (+) and (-) enantiomers, and the absolute configuration was established by single-crystal X-ray diffraction studies. The more active isomer has been assigned the R absolute configuration. Cleavage of the respective (+)- and (-)-dimethyl ethers with boron tribromide provided the corresponding (+)- and (-)-2-(5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphthl)imidazoline hydrobromides and these were pharmacologically characterized. In various preparations, the R enantiomer has been shown to be an extremely potent alpha agonist with preferential activity at the alpha 2-adrenergic receptor.
|
Binding affinity for alpha-1 adrenergic receptor in rat liver using [3H]prazosin.
|
None
|
520.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally defined adrenergic agents. 5. Resolution, absolute configuration, and pharmacological characterization of the enantiomers of 2-(5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphthyl)imidazoline: a potent agonist at alpha-adrenoceptors.
Year : 1987
Volume : 30
Issue : 6
First Page : 1011
Last Page : 1017
Authors : DeBernardis JF, Kerkman DJ, Arendsen DL, Buckner SA, Kyncl JJ, Hancock AA.
Abstract : (+/-)-2-(5,6-Dimethoxy-1,2,3,4-tetrahydro-1-naphthyl)imidazoline has been resolved into its (+) and (-) enantiomers, and the absolute configuration was established by single-crystal X-ray diffraction studies. The more active isomer has been assigned the R absolute configuration. Cleavage of the respective (+)- and (-)-dimethyl ethers with boron tribromide provided the corresponding (+)- and (-)-2-(5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphthl)imidazoline hydrobromides and these were pharmacologically characterized. In various preparations, the R enantiomer has been shown to be an extremely potent alpha agonist with preferential activity at the alpha 2-adrenergic receptor.
|
Compound was tested for the inhibition of [3H]clonidine binding Alpha-2 adrenergic receptor of crude rat brain membrane
|
None
|
1.7
nM
|
|
Journal : J. Med. Chem.
Title : 1-(alkylamino)isochromans: hypotensives with peripheral and central activities.
Year : 1982
Volume : 25
Issue : 1
First Page : 75
Last Page : 81
Authors : McCall JM, McCall RB, TenBrink RE, Kamdar BV, Humphrey SJ, Sethy VH, Harris DW, Daenzer C.
Abstract : A series of 1-[1-(3,4-dimethoxy-1H-2-benzopyran-1-yl)alkyl]-4-arylpiperazines that shows hypotensive activity in the conscious rat has been investigated. Structure-activity relationships are described. A typical example that was investigated in greater detail is 1-[2-(3,4-dihydro-6,7-dimethoxy-1H-2-benzopyran-1-yl)ethyl]-4-(4-fluorophenyl)piperazine. This compound decreases sympathetic nerve activity recorded from the external carotid and splanchnic nerves of baroreceptor-denervated cats and, therefore, has a central component to its mechanism of action. It also blocks pressor effects of norepinephrine and phenylephrine and is thus an alpha-adrenergic antagonist. Binding data characterize this as alpha 1-adrenergic receptor blockade.
|
In vitro binding affinity was measured as the inhibition of [3H]clonidine binding to alpha-2 adrenergic receptor of rat cortical membranes
|
None
|
1.5
nM
|
|
Journal : J. Med. Chem.
Title : 4-Amino-6-chloro-2-piperazinopyrimidines with selective affinity for alpha 2-adrenoceptors.
Year : 1986
Volume : 29
Issue : 8
First Page : 1394
Last Page : 1398
Authors : Guérémy C, Audiau F, Renault C, Benavides J, Uzan A, Le Fur G.
Abstract : A series of 4-amino-6-chloro-2-piperazinopyrimidines were synthesized and evaluated for their ability to interact with alpha 1- and alpha 2-adrenoceptors in vitro in binding assays using [3H]WB-4101, [3H]clonidine, and [3H]idazoxan as radioligands. Some compounds were also tested as inhibitors of [3H]spiroperidol binding. Several members of this series showed high and selective affinity for alpha 2-adrenoceptors. The nature of the 4-amino substituent seems to be the most critical factor in determining the potency at these receptors.
|
Tested for antinociceptive activity at a screening dose of 30 mg/kg, po in the mouse abdominal irritant test (MAIT) using acetylcholine as irritant.[95% confidence limit]
|
Mus musculus
|
0.05
%
|
|
Journal : J. Med. Chem.
Title : alpha(2) Adrenoceptor agonists as potential analgesic agents. 2. Discovery of 4-(4-Imidazo)-1,3-dimethyl-6,7-dihydrothianaphthene [corrected] as a high-affinity ligand for the alpha(2D) adrenergic receptor.
Year : 2000
Volume : 43
Issue : 5
First Page : 765
Last Page : 768
Authors : Ross TM, Jetter MC, McDonnell ME, Boyd RE, Connelly CD, Martinez RP, Lewis MA, Codd EE, Raffa RB, Reitz AB.
|
Compound was tested for its ability to inhibit specific binding of [3H]-clonidine to alpha-2-adrenoceptor.
|
None
|
17.3
nM
|
|
Journal : J. Med. Chem.
Title : Two stereoisomeric imidazoline derivatives: synthesis and optical and alpha 2-adrenoceptor activities.
Year : 1986
Volume : 29
Issue : 7
First Page : 1183
Last Page : 1188
Authors : Biedermann J, León-Lomelí A, Borbe HO, Prop G.
Abstract : Two eight-step pathways for synthesizing the stereoisomeric compounds (-)-2-[1-(2,6-dichlorophenoxy)ethyl]-2-imidazoline hydrochloride ("levlofexidine" hydrochloride; (-)-lofexidine hydrochloride) and (+)-2-[1-(2,6-dichlorophenoxy)ethyl]-2-imidazoline hydrochloride ("dexlofexidine" hydrochloride; (+)-lofexidine hydrochloride) and the optical resolution of (+/-)-lofexidine are described. (-)-Lofexidine, a stereoselective alpha 2-adrenoceptor agonist, due to its center of asymmetry, is demonstrated to be a potent drug for the treatment of hypertension (doses 0.561 microgram/kg) and to have the highest affinity and a concentration dependency for alpha 2-adrenoceptors in direct binding studies (0.36 nmol/L). (+)-Lofexidine is 10 times less potent.
|
Displacement of [3H]-clonidine from bovine imidazoline receptor I-1
|
Bos taurus
|
8.9
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacologic evaluation of 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane: a potent imidazoline1 receptor specific agent.
Year : 1996
Volume : 39
Issue : 6
First Page : 1193
Last Page : 1195
Authors : Munk SA, Lai RK, Burke JE, Arasasingham PN, Kharlamb AB, Manlapaz CA, Padillo EU, Wijono MK, Hasson DW, Wheeler LA, Garst ME.
|
Binding affinity for imidazoline receptor I-1
|
Homo sapiens
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 2. Structure-activity relationships and therapeutic applications.
Year : 1995
Volume : 38
Issue : 19
First Page : 3681
Last Page : 3716
Authors : Ruffolo RR, Bondinell W, Hieble JP.
|
Binding affinity for imidazoline receptor I-2
|
Homo sapiens
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 2. Structure-activity relationships and therapeutic applications.
Year : 1995
Volume : 38
Issue : 19
First Page : 3681
Last Page : 3716
Authors : Ruffolo RR, Bondinell W, Hieble JP.
|
potential antinociceptive activity initially at a screening dose of 30 mg/kg po in the mouse abdominal irritant test(MAIT) using acetylcholine bromide as irritant
|
Mus musculus
|
0.05
%
|
|
Journal : J. Med. Chem.
Title : Alpha(2) adrenoceptor agonists as potential analgesic agents. 2. Discovery of 4-(4-imidazo)-1,3-dimethyl-6,7-dihydro-thianaphthene as a high-affinity ligand for the alpha(2D) adrenergic receptor.
Year : 2000
Volume : 43
Issue : 7
First Page : 1423
Last Page : 1426
Authors : Ross TM, Jetter MC, McDonnell ME, Boyd RE, Connelly CD, Martinez RP, Lewis MA, Codd EE, Raffa RB, Reitz AB.
|
Percent displacement of radioligand from human 5-hydroxytryptamine 1B receptor at 1000 nM
|
Homo sapiens
|
5.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-(Anilino)imidazolines and 2-(benzyl)imidazoline derivatives as h5-HT1D serotonin receptor ligands.
Year : 2004
Volume : 14
Issue : 18
First Page : 4697
Last Page : 4699
Authors : Prisinzano T, Dukat M, Law H, Slassi A, MacLean N, DeLannoy I, Glennon RA.
Abstract : 2-(Anilino)imidazolines were identified as novel human 5-HT(1D) receptor ligands, but offered no particular advantage over previously reported 2-(benzyl)imidazolines. Pharmacokinetic and functional data were obtained for selected 2-(benzyl)imidazoline derivatives.
|
Percent displacement of radioligand from human 5-hydroxytryptamine 1D receptor at 1000 nM
|
Homo sapiens
|
5.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-(Anilino)imidazolines and 2-(benzyl)imidazoline derivatives as h5-HT1D serotonin receptor ligands.
Year : 2004
Volume : 14
Issue : 18
First Page : 4697
Last Page : 4699
Authors : Prisinzano T, Dukat M, Law H, Slassi A, MacLean N, DeLannoy I, Glennon RA.
Abstract : 2-(Anilino)imidazolines were identified as novel human 5-HT(1D) receptor ligands, but offered no particular advantage over previously reported 2-(benzyl)imidazolines. Pharmacokinetic and functional data were obtained for selected 2-(benzyl)imidazoline derivatives.
|
Displacement of [3H]RX821002 from adrenergic alpha2 receptor in human brain frontal cortex
|
Homo sapiens
|
20.89
nM
|
|
Journal : J. Med. Chem.
Title : Guanidine and 2-aminoimidazoline aromatic derivatives as alpha(2)-adrenoceptor antagonists, 1: toward new antidepressants with heteroatomic linkers.
Year : 2007
Volume : 50
Issue : 18
First Page : 4516
Last Page : 4527
Authors : Rodriguez F, Rozas I, Ortega JE, Meana JJ, Callado LF, Callado LF.
Abstract : The efficient preparation and pharmacological characterization of different families of (bis)guanidine and (bis)2-aminoimidazoline derivatives ("twin" and "half" molecules) as potential alpha(2)-adrenoceptor antagonists for the treatment of depression is presented. The affinity toward the alpha(2)-adrenoceptor of all the compounds prepared was measured in vitro in human brain tissue. Additionally, the activity as agonist or antagonist of those compounds with a pK(i) larger than 7 was determined in functional [(35)S]GTPgammaS binding assays in human brain tissue. Finally, the activity of the most promising compounds was confirmed by means of in vivo microdialysis experiments in rats. Compounds 1, 2b, 3b, 12b, 13b, 17b, 18b, 22b, 25b, 26b, 28b, and 30 showed a good affinity toward the alpha(2)-ARs. In general, the 2-aminoimidazoline derivatives displayed higher affinities than their guanidine analogues. Finally and most importantly, compounds 18b and 26b showed antagonistic properties over alpha(2)-ARs not only in vitro [(35)S]GTPgammaS binding but also in vivo microdialysis experiments. Moreover, both compounds have shown to be able to cross the blood-brain barrier and, therefore, they can be considered as potential antidepressants.
|
Displacement of [125I]PIC from human alpha2 adrenoceptors expressed in CHO cells
|
Homo sapiens
|
16.5
nM
|
|
Journal : Bioorg. Med. Chem.
Title : QSAR study of imidazoline antihypertensive drugs.
Year : 2008
Volume : 16
Issue : 15
First Page : 7134
Last Page : 7140
Authors : Nikolic K, Filipic S, Agbaba D.
Abstract : The hypotensive effect of imidazoline ligands was attributed to both alpha(2)-adrenergic receptors and nonadrenergic imidazoline-1 receptors (I(1)-R). Selective I(1)-R ligands, devoid of the typical side effects of other centrally acting antihypertensive drugs, could be widely used in antihypertensive therapy. Thus, there is significant interest in developing new imidazoline analogs with higher selectivity and affinity for I(1) receptors. The quantitative structure-activity relationship (QSAR) study of 12 ligands was carried out using multilinear regression method on I(1)-R and alpha(2)-adrenergic receptors binding affinities on human platelets. The compounds have been studied using Becke3LYP/3-21G (d,p) and Becke3LYP/6-31G(d,p) DFT methods. Among 42 descriptors that were considered in generating the QSAR model, three descriptors such as partial atomic charges of nitrogen in the heterocyclic moiety, distribution coefficient, and molar refractivity of the ligands resulted in a statistically significant model with R(2)=0.935 and cross-validation parameter q(2)(pre) =0.803. The validation of the QSAR models was done by cross-validation and external test set prediction. The developed multiple linear regression models for the I(1)-R ligands were aimed to link the structures to their reported I(1)-R binding affinity log(1/K(i)). The theoretical approach indicates that an increase in distribution coefficient and molar refractivity value, together with a decrease in average N-charge in the heterocyclic moiety of the ligands, causes better binding affinity for active site of the I(1) receptors. The developed QSAR model is intended to predict I(1)-R binding affinity of related compounds and to define possible physicochemical, electrical, and structural requirements for selective I(1)-receptor ligands.
|
Displacement of [125I]PIC from human imidazoline receptor 1 in human platelets analyzed under norepinephrine mask of alpha 2AR
|
Homo sapiens
|
54.95
nM
|
|
Displacement of [125I]PIC from human imidazoline receptor 1 in human platelets analyzed under norepinephrine mask of alpha 2AR
|
Homo sapiens
|
55.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : QSAR study of imidazoline antihypertensive drugs.
Year : 2008
Volume : 16
Issue : 15
First Page : 7134
Last Page : 7140
Authors : Nikolic K, Filipic S, Agbaba D.
Abstract : The hypotensive effect of imidazoline ligands was attributed to both alpha(2)-adrenergic receptors and nonadrenergic imidazoline-1 receptors (I(1)-R). Selective I(1)-R ligands, devoid of the typical side effects of other centrally acting antihypertensive drugs, could be widely used in antihypertensive therapy. Thus, there is significant interest in developing new imidazoline analogs with higher selectivity and affinity for I(1) receptors. The quantitative structure-activity relationship (QSAR) study of 12 ligands was carried out using multilinear regression method on I(1)-R and alpha(2)-adrenergic receptors binding affinities on human platelets. The compounds have been studied using Becke3LYP/3-21G (d,p) and Becke3LYP/6-31G(d,p) DFT methods. Among 42 descriptors that were considered in generating the QSAR model, three descriptors such as partial atomic charges of nitrogen in the heterocyclic moiety, distribution coefficient, and molar refractivity of the ligands resulted in a statistically significant model with R(2)=0.935 and cross-validation parameter q(2)(pre) =0.803. The validation of the QSAR models was done by cross-validation and external test set prediction. The developed multiple linear regression models for the I(1)-R ligands were aimed to link the structures to their reported I(1)-R binding affinity log(1/K(i)). The theoretical approach indicates that an increase in distribution coefficient and molar refractivity value, together with a decrease in average N-charge in the heterocyclic moiety of the ligands, causes better binding affinity for active site of the I(1) receptors. The developed QSAR model is intended to predict I(1)-R binding affinity of related compounds and to define possible physicochemical, electrical, and structural requirements for selective I(1)-receptor ligands.
|
Displacement of [3H]RX821002 from alpha2 adrenoceptor in human prefrontal cortex neural membrane
|
Homo sapiens
|
20.89
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Novel synthesis and pharmacological evaluation as alpha2-adrenoceptor ligands of O-phenylisouronium salts.
Year : 2008
Volume : 16
Issue : 17
First Page : 8210
Last Page : 8217
Authors : Goonan A, Kahvedzić A, Rodriguez F, Nagle PS, McCabe T, Rozas I, Erdozain AM, Meana JJ, Callado LF, Callado LF.
Abstract : The synthesis of nine new mono- and bis-O-phenylisouronium compounds (2, 6b-10b and 12b-14b) and their Boc-protected isourea precursors (2a, 6a-10a and 12a-14a) is described. The carbodiimide 4, which was formed, had been suggested as the reactive intermediate species and driving force of the reaction. All final substrates were tested as potential alpha(2)-ARs ligands in human brain tissue by means of radioligand binding experiments and were compared to the potential antidepressant 1, as well as other related guanidine containing derivatives.
|
Displacement of [3H]RX821002 from alpha2 adrenoceptor in human prefrontal cortex neural membrane after 30 mins by liquid scintillation spectrometry
|
Homo sapiens
|
20.89
nM
|
|
Journal : J. Med. Chem.
Title : Guanidine and 2-aminoimidazoline aromatic derivatives as alpha2-adrenoceptor ligands: searching for structure-activity relationships.
Year : 2009
Volume : 52
Issue : 3
First Page : 601
Last Page : 609
Authors : Rodriguez F, Rozas I, Ortega JE, Erdozain AM, Meana JJ, Callado LF, Callado LF.
Abstract : In this paper, we report the synthesis of three new 2-aminoimidazoline (compounds 4b, 5b, and 6b) and three new guanidine derivatives (compounds 7b, 8b, and 9b) as potential alpha(2)-adrenoceptor antagonists for the treatment of depression. Their pharmacological profile was evaluated in vitro in human brain tissue and compared to the potential antidepressant 1 and the agonists 2 and 3. All new substrates were evaluated by in vitro functional [(35)S]GTPgammaS binding assays in human prefrontal cortex to determine their agonistic or antagonistic activity. Compound 8b was found to be an antagonist in vitro and was subjected to in vivo microdialysis experiments in rats. Moreover, a new synthesis of the precursor amines for compounds 4b-9b is presented.
|
Displacement of [3H]clonidine from imidazoline I1 receptor in Sprague-Dawley rat kidney by liquid scintillation counting
|
Rattus norvegicus
|
366.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New analogues of agmatine with higher affinity to imidazoline receptors.
Year : 2009
Volume : 19
Issue : 3
First Page : 1009
Last Page : 1011
Authors : Treder AP, Andruszkiewicz R, Zgoda W, Ford C, Hudson AL.
Abstract : Compilation of agmatine structure and imidazoline ring leads to a new family of imidazoline/alpha(2)-adrenoceptor ligands, 4(5)-(2-aminoethyl)imidazoline derivatives. Constraining of the guanidine moiety into heterocyclic ring improved the affinities of the resultant fusion compounds in comparison to agmatine itself. In this work, the synthetic approach and results for I(1), I(2), and alpha(2)-adrenoceptors affinities are reported.
|
Displacement of [3H]2BFI from imidazoline I2 receptor in Sprague-Dawley rat brain by liquid scintillation counting
|
Rattus norvegicus
|
364.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New analogues of agmatine with higher affinity to imidazoline receptors.
Year : 2009
Volume : 19
Issue : 3
First Page : 1009
Last Page : 1011
Authors : Treder AP, Andruszkiewicz R, Zgoda W, Ford C, Hudson AL.
Abstract : Compilation of agmatine structure and imidazoline ring leads to a new family of imidazoline/alpha(2)-adrenoceptor ligands, 4(5)-(2-aminoethyl)imidazoline derivatives. Constraining of the guanidine moiety into heterocyclic ring improved the affinities of the resultant fusion compounds in comparison to agmatine itself. In this work, the synthetic approach and results for I(1), I(2), and alpha(2)-adrenoceptors affinities are reported.
|
Displacement of [3H]RX821002 from alpha2 adrenoceptor in Sprague-Dawley rat kidney by liquid scintillation counting
|
Rattus norvegicus
|
8.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New analogues of agmatine with higher affinity to imidazoline receptors.
Year : 2009
Volume : 19
Issue : 3
First Page : 1009
Last Page : 1011
Authors : Treder AP, Andruszkiewicz R, Zgoda W, Ford C, Hudson AL.
Abstract : Compilation of agmatine structure and imidazoline ring leads to a new family of imidazoline/alpha(2)-adrenoceptor ligands, 4(5)-(2-aminoethyl)imidazoline derivatives. Constraining of the guanidine moiety into heterocyclic ring improved the affinities of the resultant fusion compounds in comparison to agmatine itself. In this work, the synthetic approach and results for I(1), I(2), and alpha(2)-adrenoceptors affinities are reported.
|
Inhibition of 4-(4-(dimethylamino)styryl)-N-methylpyridinium uptake at human OCT1 expressed in HEK293 cells at 100 uM by confocal microscopy
|
Homo sapiens
|
65.4
%
|
|
Journal : J. Med. Chem.
Title : Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1.
Year : 2008
Volume : 51
Issue : 19
First Page : 5932
Last Page : 5942
Authors : Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergström CA, Artursson P.
Abstract : The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.
|
Displacement of [3H]RX821002 from alpha2 adrenergic receptor in human brain prefrontal cortex tissue by liquid scintillation spectrometry
|
Homo sapiens
|
20.89
nM
|
|
Journal : J. Med. Chem.
Title : Guanidine and 2-aminoimidazoline aromatic derivatives as alpha2-adrenoceptor antagonists. 2. Exploring alkyl linkers for new antidepressants.
Year : 2008
Volume : 51
Issue : 11
First Page : 3304
Last Page : 3312
Authors : Rodriguez F, Rozas I, Ortega JE, Erdozain AM, Meana JJ, Callado LF, Callado LF.
Abstract : The preparation of a number of (bis)guanidine and (bis)2-aminoimidazoline derivatives as potential alpha 2-adrenoceptor antagonists for the treatment of depression is presented. Human brain tissue was used to measure their affinity toward the alpha 2-adrenoceptors in vitro. Compounds 6b, 8b, 9b, 10b, 15b, 17b, 18b, 20b, and 21b displayed a good affinity (pKi > 7) and were evaluated in in vitro functional [(35)S]GTPgammaS binding assays in human prefrontal cortex to determine their agonistic or antagonistic activity. Among these compounds, 17b and 20b showed the expected behavior for an antagonist and were subject to in vivo microdialysis experiments in rats. Significantly, these experiments confirmed the antagonistic properties of 17b and 20b, and therefore both compounds can be considered as potential antidepressants.
|
Inhibition of human FAAH at 1 uM
|
Homo sapiens
|
20.5
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Mining biologically-active molecules for inhibitors of fatty acid amide hydrolase (FAAH): identification of phenmedipham and amperozide as FAAH inhibitors.
Year : 2009
Volume : 19
Issue : 23
First Page : 6793
Last Page : 6796
Authors : Vincent F, Nguyen MT, Emerling DE, Kelly MG, Duncton MA.
Abstract : The screening of known medicinal agents against new biological targets has been shown to be a valuable approach for revealing new pharmacology of marketed compounds. Recently, carbamate, urea and ketone inhibitors of fatty acid amide hydrolase (FAAH) have been described as promising treatments for pain, anxiety, depression and other CNS-related conditions. In order to find novel FAAH inhibitors, a focused screen of molecules containing potentially reactive moieties or having in vivo effects that are possibly relevant to the biology of FAAH was conducted. These studies revealed phenmedipham 13 and amperozide 14 to be inhibitors of human FAAH, with an IC(50) of 377 nM and 1.34 microM, respectively.
|
Agonist activity at human alpha2A adrenoceptor expressed in CHO cells assessed as induction of extracellular acidification by microphysiometry
|
Homo sapiens
|
8.318
nM
|
|
Journal : J. Med. Chem.
Title : Fruitful adrenergic α(2C)-agonism/α(2A)-antagonism combination to prevent and contrast morphine tolerance and dependence.
Year : 2010
Volume : 53
Issue : 21
First Page : 7825
Last Page : 7835
Authors : Del Bello F, Mattioli L, Ghelfi F, Giannella M, Piergentili A, Quaglia W, Cardinaletti C, Perfumi M, Thomas RJ, Zanelli U, Marchioro C, Dal Cin M, Pigini M.
Abstract : The functional in vitro study of the enantiomers of imidazolines 4-7 highlighted the role played by the nature of the ortho phenyl substituent in determining the preferred α(2C)-AR configuration. Indeed, the (S) enantiomers of 4-6 or (R) enantiomer of 7 behave as eutomers and activate this subtype as full agonists; the corresponding distomers are partial agonists. Because in clinical pain management with opioids α(2C)-AR agonists, devoid of the α(2A)-AR-mediated side effects, may represent an improvement over current therapies with clonidine like drugs, 4 and its enantiomers, showing α(2C)-agonism/α(2A)-antagonism, have been studied in vivo. The data suggest that partial α(2C)-activation is compatible with effective enhancement of morphine analgesia and reduction both of morphine tolerance acquisition and morphine dependence acquisition and expression. On the contrary, full α(2C)-activation appears advantageous in reducing morphine tolerance expression. Interestingly, the biological profile displayed by 4 (allyphenyline) and its eutomer (S)-(+)-4 has been found to be very unusual.
|
Agonist activity at human Alpha-2C adrenoceptor expressed in CHO cells assessed as induction of extracellular acidification by microphysiometry
|
Homo sapiens
|
57.54
nM
|
|
Journal : J. Med. Chem.
Title : Fruitful adrenergic α(2C)-agonism/α(2A)-antagonism combination to prevent and contrast morphine tolerance and dependence.
Year : 2010
Volume : 53
Issue : 21
First Page : 7825
Last Page : 7835
Authors : Del Bello F, Mattioli L, Ghelfi F, Giannella M, Piergentili A, Quaglia W, Cardinaletti C, Perfumi M, Thomas RJ, Zanelli U, Marchioro C, Dal Cin M, Pigini M.
Abstract : The functional in vitro study of the enantiomers of imidazolines 4-7 highlighted the role played by the nature of the ortho phenyl substituent in determining the preferred α(2C)-AR configuration. Indeed, the (S) enantiomers of 4-6 or (R) enantiomer of 7 behave as eutomers and activate this subtype as full agonists; the corresponding distomers are partial agonists. Because in clinical pain management with opioids α(2C)-AR agonists, devoid of the α(2A)-AR-mediated side effects, may represent an improvement over current therapies with clonidine like drugs, 4 and its enantiomers, showing α(2C)-agonism/α(2A)-antagonism, have been studied in vivo. The data suggest that partial α(2C)-activation is compatible with effective enhancement of morphine analgesia and reduction both of morphine tolerance acquisition and morphine dependence acquisition and expression. On the contrary, full α(2C)-activation appears advantageous in reducing morphine tolerance expression. Interestingly, the biological profile displayed by 4 (allyphenyline) and its eutomer (S)-(+)-4 has been found to be very unusual.
|
Agonist activity at human recombinant alpha2A adrenergic receptor expressed in CHO cells assessed as induction of [35S]GTPgammaS binding after 60 mins by scintillation counting
|
Homo sapiens
|
28.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 3-[(Imidazolidin-2-yl)imino]indazole ligands with selectivity for the α(2)-adrenoceptor compared to the imidazoline I(1) receptor.
Year : 2011
Volume : 19
Issue : 1
First Page : 321
Last Page : 329
Authors : Sączewski F, Kornicka A, Hudson AL, Laird S, Scheinin M, Laurila JM, Rybczyńska A, Boblewski K, Lehmann A, Gdaniec M.
Abstract : A series of 3-[(4,5-dihydroimidazolidin-2-yl)imino]indazoles has been synthesized as positional analogues of marsanidine, a highly selective α(2)-adrenoceptor ligand. Parent compound 4a and its 4-chloro (4c) and 4-methyl (4d) derivatives display α(2)-adrenoceptor affinity at nanomolar concentrations (K(i)=39.4, 15.9 and 22.6nM, respectively) and relatively high α(2)/I(1) selectivity ratios of 82, 115 and 690, respectively. Evidence was obtained that these compounds act as partial agonists at α(2A)-adrenoceptors. Compound 4d with intrinsic activity comparable with that of marsanidine, but lower than that of clonidine, elicited pronounced cardiovascular effects in anesthetized rats at doses as low as 0.01mg/kg iv.
|
Inhibition of Sprague-Dawley rat imidazoline I1 receptor
|
Rattus norvegicus
|
366.2
nM
|
|
Journal : Bioorg. Med. Chem.
Title : New imidazoline/α(2)-adrenoceptors affecting compounds-4(5)-(2-aminoethyl)imidazoline (dihydrohistamine) derivatives. Synthesis and receptor affinity studies.
Year : 2011
Volume : 19
Issue : 1
First Page : 156
Last Page : 167
Authors : Treder AP, Andruszkiewicz R, Zgoda W, Walkowiak A, Ford C, Hudson AL.
Abstract : Compilation of agmatine structure and imidazoline moiety leads to a new group of imidazoline/α(2)-adrenoceptor ligands, 4(5)-(2-aminoethyl)imidazoline derivatives. In this study the exploration of previously unknown 4(5)-(2-aminoethyl)imidazolines including the analogues of reported imidazoline and α(2)-aderenoceptors ligands: clonidine, rilmenidine, idazoxan, efaroxan, antazoline, tracizoline is described. The synthesis of a variety of novel 4(5)-(2-aminoethyl)imidazolines and their I(1), I(2), α(2)-adrenoceptors affinities are reported.
|
Inhibition of Sprague-Dawley rat imidazoline I2 receptor
|
Rattus norvegicus
|
364.5
nM
|
|
Journal : Bioorg. Med. Chem.
Title : New imidazoline/α(2)-adrenoceptors affecting compounds-4(5)-(2-aminoethyl)imidazoline (dihydrohistamine) derivatives. Synthesis and receptor affinity studies.
Year : 2011
Volume : 19
Issue : 1
First Page : 156
Last Page : 167
Authors : Treder AP, Andruszkiewicz R, Zgoda W, Walkowiak A, Ford C, Hudson AL.
Abstract : Compilation of agmatine structure and imidazoline moiety leads to a new group of imidazoline/α(2)-adrenoceptor ligands, 4(5)-(2-aminoethyl)imidazoline derivatives. In this study the exploration of previously unknown 4(5)-(2-aminoethyl)imidazolines including the analogues of reported imidazoline and α(2)-aderenoceptors ligands: clonidine, rilmenidine, idazoxan, efaroxan, antazoline, tracizoline is described. The synthesis of a variety of novel 4(5)-(2-aminoethyl)imidazolines and their I(1), I(2), α(2)-adrenoceptors affinities are reported.
|
Inhibition of Sprague-Dawley rat alpha-2 adrenergic receptor
|
Rattus norvegicus
|
8.7
nM
|
|
Journal : Bioorg. Med. Chem.
Title : New imidazoline/α(2)-adrenoceptors affecting compounds-4(5)-(2-aminoethyl)imidazoline (dihydrohistamine) derivatives. Synthesis and receptor affinity studies.
Year : 2011
Volume : 19
Issue : 1
First Page : 156
Last Page : 167
Authors : Treder AP, Andruszkiewicz R, Zgoda W, Walkowiak A, Ford C, Hudson AL.
Abstract : Compilation of agmatine structure and imidazoline moiety leads to a new group of imidazoline/α(2)-adrenoceptor ligands, 4(5)-(2-aminoethyl)imidazoline derivatives. In this study the exploration of previously unknown 4(5)-(2-aminoethyl)imidazolines including the analogues of reported imidazoline and α(2)-aderenoceptors ligands: clonidine, rilmenidine, idazoxan, efaroxan, antazoline, tracizoline is described. The synthesis of a variety of novel 4(5)-(2-aminoethyl)imidazolines and their I(1), I(2), α(2)-adrenoceptors affinities are reported.
|
DRUGMATRIX: Alpha-1A adrenergic receptor radioligand binding (ligand: prazosin)
|
Rattus norvegicus
|
372.0
nM
|
|
DRUGMATRIX: Alpha-1A adrenergic receptor radioligand binding (ligand: prazosin)
|
Rattus norvegicus
|
151.0
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: Alpha-1D adrenergic receptor radioligand binding (ligand: prazosin)
|
None
|
595.0
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: Alpha-2A adrenergic receptor radioligand binding (ligand: MK-912)
|
None
|
280.0
nM
|
|
DRUGMATRIX: Alpha-2A adrenergic receptor radioligand binding (ligand: MK-912)
|
None
|
105.0
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: Alpha-2B adrenergic receptor radioligand binding (ligand: Rauwolscine)
|
None
|
83.0
nM
|
|
DRUGMATRIX: Alpha-2B adrenergic receptor radioligand binding (ligand: Rauwolscine)
|
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: Imidazoline I2, Central radioligand binding (ligand: [3H] Idazoxan)
|
Rattus norvegicus
|
64.0
nM
|
|
DRUGMATRIX: Imidazoline I2, Central radioligand binding (ligand: [3H] Idazoxan)
|
Rattus norvegicus
|
43.0
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
|
Agonist activity at human adrenoceptor alpha2A expressed in CHOK1 cells assessed as stimulation of agonist-induced [35S]GTPgammaS binding by scintillation counting
|
Homo sapiens
|
30.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological activities of 2-[(heteroaryl)methyl]imidazolines.
Year : 2012
Volume : 20
Issue : 1
First Page : 108
Last Page : 116
Authors : Saczewski J, Hudson A, Scheinin M, Rybczynska A, Ma D, Saczewski F, Laird S, Laurila JM, Boblewski K, Lehmann A, Gu J, Watts H.
Abstract : A series of 2-[(heteroaryl)methyl]imidazolines was synthesized and tested for their activities at α(1)- and α(2)-adrenoceptors and imidazoline I(1) and I(2) receptors. The most active 2-[(indazol-1-yl)methyl]imidazolines showed high or moderate affinities for α(1)- and α(2)-adrenoceptors. However, their intrinsic activities at α(2A)-adrenoceptors proved to be negligible. A selected 7-chloro derivative behaved as a potent α(1)-adrenoceptor antagonist and exhibited peripherally mediated hypotensive effects in rats.
|
Displacement of [3H]paraiodoclonidine from imidazoline I1 receptor in rat PC12 cells after 30 mins by gamma counter
|
Rattus norvegicus
|
281.84
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Methylation of imidazoline related compounds leads to loss of α₂-adrenoceptor affinity. Synthesis and biological evaluation of selective I₁ imidazoline receptor ligands.
Year : 2012
Volume : 20
Issue : 15
First Page : 4710
Last Page : 4715
Authors : Schann S, Greney H, Gasparik V, Dontenwill M, Rascente C, Lacroix G, Monassier L, Bruban V, Feldman J, Ehrhardt JD, Bousquet P.
Abstract : Methylated analogues of imidazoline related compounds (IRC) were prepared; their abilities to bind I(1) imidazoline receptors (I(1)Rs), I(2) imidazoline binding sites (I(2)BS) and α(2)-adrenoceptor subtypes (α(2)ARs) were assessed. Methylation of the heterocyclic moiety of IRC resulted in a significant loss of α(2)AR affinity. Amongst the selective ligands obtained, LNP 630 (4) constitutes the first highly selective I(1)R agent showing hypotensive activity after intravenous administration.
|
Displacement of [3H]RX821001 from human alpha2A adrenoceptor expressed in CHO cells after 60 mins by gamma counter
|
Homo sapiens
|
8.71
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Methylation of imidazoline related compounds leads to loss of α₂-adrenoceptor affinity. Synthesis and biological evaluation of selective I₁ imidazoline receptor ligands.
Year : 2012
Volume : 20
Issue : 15
First Page : 4710
Last Page : 4715
Authors : Schann S, Greney H, Gasparik V, Dontenwill M, Rascente C, Lacroix G, Monassier L, Bruban V, Feldman J, Ehrhardt JD, Bousquet P.
Abstract : Methylated analogues of imidazoline related compounds (IRC) were prepared; their abilities to bind I(1) imidazoline receptors (I(1)Rs), I(2) imidazoline binding sites (I(2)BS) and α(2)-adrenoceptor subtypes (α(2)ARs) were assessed. Methylation of the heterocyclic moiety of IRC resulted in a significant loss of α(2)AR affinity. Amongst the selective ligands obtained, LNP 630 (4) constitutes the first highly selective I(1)R agent showing hypotensive activity after intravenous administration.
|
Displacement of [3H]RX821001 from human alpha2B adrenoceptor expressed in CHO cells after 60 mins by gamma counter
|
Homo sapiens
|
31.62
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Methylation of imidazoline related compounds leads to loss of α₂-adrenoceptor affinity. Synthesis and biological evaluation of selective I₁ imidazoline receptor ligands.
Year : 2012
Volume : 20
Issue : 15
First Page : 4710
Last Page : 4715
Authors : Schann S, Greney H, Gasparik V, Dontenwill M, Rascente C, Lacroix G, Monassier L, Bruban V, Feldman J, Ehrhardt JD, Bousquet P.
Abstract : Methylated analogues of imidazoline related compounds (IRC) were prepared; their abilities to bind I(1) imidazoline receptors (I(1)Rs), I(2) imidazoline binding sites (I(2)BS) and α(2)-adrenoceptor subtypes (α(2)ARs) were assessed. Methylation of the heterocyclic moiety of IRC resulted in a significant loss of α(2)AR affinity. Amongst the selective ligands obtained, LNP 630 (4) constitutes the first highly selective I(1)R agent showing hypotensive activity after intravenous administration.
|
Displacement of [3H]RX821001 from human alpha2C adrenoceptor expressed in CHO cells after 60 mins by gamma counter
|
Homo sapiens
|
9.333
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Methylation of imidazoline related compounds leads to loss of α₂-adrenoceptor affinity. Synthesis and biological evaluation of selective I₁ imidazoline receptor ligands.
Year : 2012
Volume : 20
Issue : 15
First Page : 4710
Last Page : 4715
Authors : Schann S, Greney H, Gasparik V, Dontenwill M, Rascente C, Lacroix G, Monassier L, Bruban V, Feldman J, Ehrhardt JD, Bousquet P.
Abstract : Methylated analogues of imidazoline related compounds (IRC) were prepared; their abilities to bind I(1) imidazoline receptors (I(1)Rs), I(2) imidazoline binding sites (I(2)BS) and α(2)-adrenoceptor subtypes (α(2)ARs) were assessed. Methylation of the heterocyclic moiety of IRC resulted in a significant loss of α(2)AR affinity. Amongst the selective ligands obtained, LNP 630 (4) constitutes the first highly selective I(1)R agent showing hypotensive activity after intravenous administration.
|
TP_TRANSPORTER: inhibition of TEA uptake (TEA: 20 uM, Clonidine: 5000 uM) in OCT3-expressing HRPE cells
|
None
|
90.0
%
|
|
Journal : Am. J. Physiol. Renal Physiol.
Title : Structure, function, and regional distribution of the organic cation transporter OCT3 in the kidney.
Year : 2000
Volume : 279
Issue : 1
First Page : F449
Last Page : F458
Authors : Wu X, Huang W, Ganapathy ME, Wang H, Kekuda R, Conway SJ, Leibach FH, Ganapathy V.
Abstract : We examined in this study the expression of the potential-sensitive organic cation transporter OCT3 in the kidney. A functionally active OCT3 was cloned from a mouse kidney cDNA library. The cloned transporter was found to be capable of mediating potential-dependent transport of a variety of organic cations including tetraethylammonium. This function was confirmed in two different heterologous expression systems involving mammalian cells and Xenopus laevis oocytes. We have also isolated the mouse OCT3 gene and deduced its structure and organization. The OCT3 gene consists of 11 exons and 10 introns. In situ hybridization studies in the mouse kidney have shown that OCT3 mRNA is expressed primarily in the cortex. The expression is evident in the proximal and distal convoluted tubules. The expression of OCT3 in human kidney was confirmed by RT-PCR. We have also cloned OCT3 from human placenta and human kidney. Human OCT3 exhibits 86% identity with mouse OCT3 in amino acid sequence. Human OCT3 was found to transport tetraethylammonium and a variety of other organic cations. The transport process was electrogenic. We conclude that OCT3 is expressed in mammalian kidney and that it plays an important role in the renal clearance of cationic drugs.
|
TP_TRANSPORTER: inhibition of TEA uptake in OCT1-expressing HeLa cells
|
None
|
550.0
nM
|
|
Journal : J. Pharmacol. Exp. Ther.
Title : Functional characterization of an organic cation transporter (hOCT1) in a transiently transfected human cell line (HeLa).
Year : 1998
Volume : 286
Issue : 1
First Page : 354
Last Page : 361
Authors : Zhang L, Schaner ME, Giacomini KM.
Abstract : Recently, a polyspecific organic cation transporter, hOCT1, was cloned from human liver. To date, limited studies examining the functional characteristics of the transporter have been performed. The purpose of the present study was to develop a mammalian expression system for hOCT1 and to characterize the interactions of various compounds with the cloned transporter. Lipofection was used to transiently transfect the hOCT1 plasmid DNA in a human cell line, HeLa. We tested the interaction of an array of organic cations and other compounds with hOCT1 by determining Ki values in inhibiting 14C-tetraethylammonium (TEA) transport in the transfected cells. Transient expression of hOCT1 activity was observed between 24 and 72 hr post-transfection, with maximal expression at approximately 40 hr. TEA transport was temperature dependent and saturable with Vmax and K(m) values of 2.89 +/- 0.448 nmol/mg protein/30 min and 229 +/- 78.4 microM, respectively. 14C-TEA uptake in hOCT1 plasmid DNA-transfected HeLa cells was trans-stimulated by unlabeled TEA and 1-methyl-4-phenyl-pyridinium. Organic cations, including clonidine, quinine, quinidine and verapamil (0.1 mM), significantly inhibited 14C-TEA uptake, whereas the organic anion, p-aminohippuric acid (5 mM), did not. The neutral compounds, corticosterone (Ki, 7.0 microM) and midazolam (Ki, 3.7 microM) potently inhibited 14C-TEA uptake. The Ki values of several compounds in interacting with hOCT1 differed substantially from the corresponding values for the rat organic cation transporter, rOCT1, and the human kidney-specific organic cation transporter, hOCT2, determined in previous studies. Transiently transfected HeLa cells represent a useful tool in studying the interactions and kinetics of organic cations and other xenobiotics with hOCT1 and in understanding the molecular events involved in organic cation transport.
|
Binding affinity to I2 imidazoline binding site (unknown origin)
|
Homo sapiens
|
954.99
nM
|
|
Journal : Med Chem Res
Title : Alpha2-Adrenergic Receptors in Intestinal Epithelial Cells: Mechanisms of Signaling, Role, and Regulation
Year : 2004
Volume : 13
Issue : 3
First Page : 170
Last Page : 189
Authors : Nicolotti O, Carotti A, Carrieri A, Pigini M, Gentili F, Brasili L, Giannella M, Quaglia W, Piergentili A, Bousquet P, Dontenwill M
|
Binding affinity to I1 imidazoline binding site in Rattus norvegicus (rat) PC12 cells
|
Rattus norvegicus
|
112.2
nM
|
|
Journal : Med Chem Res
Title : Alpha2-Adrenergic Receptors in Intestinal Epithelial Cells: Mechanisms of Signaling, Role, and Regulation
Year : 2004
Volume : 13
Issue : 3
First Page : 170
Last Page : 189
Authors : Nicolotti O, Carotti A, Carrieri A, Pigini M, Gentili F, Brasili L, Giannella M, Quaglia W, Piergentili A, Bousquet P, Dontenwill M
|
Inhibition of human MATE1-mediated ASP+ uptake expressed in HEK293 cells at 20 uM after 1.5 mins by fluorescence assay
|
Homo sapiens
|
1.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling.
Year : 2013
Volume : 56
Issue : 3
First Page : 781
Last Page : 795
Authors : Wittwer MB, Zur AA, Khuri N, Kido Y, Kosaka A, Zhang X, Morrissey KM, Sali A, Huang Y, Giacomini KM.
Abstract : The human multidrug and toxin extrusion (MATE) transporter 1 contributes to the tissue distribution and excretion of many drugs. Inhibition of MATE1 may result in potential drug-drug interactions (DDIs) and alterations in drug exposure and accumulation in various tissues. The primary goals of this project were to identify MATE1 inhibitors with clinical importance or in vitro utility and to elucidate the physicochemical properties that differ between MATE1 and OCT2 inhibitors. Using a fluorescence assay of ASP(+) uptake in cells stably expressing MATE1, over 900 prescription drugs were screened and 84 potential MATE1 inhibitors were found. We identified several MATE1 selective inhibitors including four FDA-approved medications that may be clinically relevant MATE1 inhibitors and could cause a clinical DDI. In parallel, a QSAR model identified distinct molecular properties of MATE1 versus OCT2 inhibitors and was used to screen the DrugBank in silico library for new hits in a larger chemical space.
|
Displacement of [3H]clonidine from rat cerebral cortex alpha-2 adrenergic receptor by liquid scintillation counting analysis
|
Rattus norvegicus
|
2.512
nM
|
|
Journal : Bioorg. Med. Chem.
Title : α-Adrenoceptor antagonistic and hypotensive properties of novel arylpiperazine derivatives of pyrrolidin-2-one.
Year : 2015
Volume : 23
Issue : 9
First Page : 2104
Last Page : 2111
Authors : Zaręba P, Dudek M, Lustyk K, Siwek A, Starowicz G, Bednarski M, Nowiński L, Raźny K, Sapa J, Malawska B, Kulig K.
Abstract : This study focused on a series of pyrrolidin-2-one derivatives connected via two or four methylene units to arylpiperazine fragment. The compounds obtained for α₁- and α₂-adrenoceptors were assessed. The compound with highest affinity for the α₁-adrenoceptors was 1-{4-[4-(2-chloro-phenyl)-piperazin-1-yl]-butyl}-pyrrolidin-2-one (10 h) with pKi=7.30. Compound with pKi (α₁) ⩾6.44 were evaluated in functional bioassays for intrinsic activity at α₁A- and α₁B-adrenoceptors. All compounds tested were antagonists of the α₁B-adrenoceptors. Additionally, compounds 10e and 10h were α₁A-adrenoceptors antagonist. The dual α₁A-/α₁B-adrenoceptors antagonists, compounds 10e and 10h were also tested in vivo for their hypotensive activity in rats. These compounds, when dosed of 1.0 mg/kg iv in normotensive, anesthetized rats, significantly decreased systolic and diastolic pressure and their hypotensive effects lasted for longer than one hour.
|
Displacement of [125I] PIC from I1 imidazoline receptor in rat PC12 cells after 45 mins by gamma counting
|
Rattus norvegicus
|
14.1
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of 2-aryliminopyrrolidines as selective ligands for I1 imidazoline receptors: discovery of new sympatho-inhibitory hypotensive agents with potential beneficial effects in metabolic syndrome.
Year : 2015
Volume : 58
Issue : 2
First Page : 878
Last Page : 887
Authors : Gasparik V, Greney H, Schann S, Feldman J, Fellmann L, Ehrhardt JD, Bousquet P.
Abstract : New 2-aryliminopyrrolidines (1-18) were synthesized and tested for their binding properties on I1 imidazoline receptors vs α2-adrenergic receptors and their blood pressure effects after both systemic and intracerebral administrations. The purposes of this study were: (i) to analyze structure-activity and affinity relationships on I1 imdazoline receptors and (ii) to propose some leader compounds for the development of new sympatho-inhibitory drugs with potential applications in hypertension and/or metabolic syndrome, i.e., a cluster of cardiovascular (hypertension) and metabolic disorders. Our study highlights decisive arguments of SAR concerning both the affinity for I1Rs and the hypotensive activity of 2-aryliminopyrrolidines. Binding assays showed high affinity and selectivity of some compounds for I1 imidazoline receptors over α2-adreergic receptors. Compound 13 (laboratory reference LNP599; Ki = 3.2 nM on I1imidazoline receptors) is the prototype for the development of new centrally acting agents targeting specifically I1imidazoline receptors to be used in the management of hypertension and/or metabolic syndrome.
|
Displacement of [3H]RX821002 from human alpha2 adrenoceptor expressed in CHO cell membranes after 60 mins
|
Homo sapiens
|
3.8
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of 2-aryliminopyrrolidines as selective ligands for I1 imidazoline receptors: discovery of new sympatho-inhibitory hypotensive agents with potential beneficial effects in metabolic syndrome.
Year : 2015
Volume : 58
Issue : 2
First Page : 878
Last Page : 887
Authors : Gasparik V, Greney H, Schann S, Feldman J, Fellmann L, Ehrhardt JD, Bousquet P.
Abstract : New 2-aryliminopyrrolidines (1-18) were synthesized and tested for their binding properties on I1 imidazoline receptors vs α2-adrenergic receptors and their blood pressure effects after both systemic and intracerebral administrations. The purposes of this study were: (i) to analyze structure-activity and affinity relationships on I1 imdazoline receptors and (ii) to propose some leader compounds for the development of new sympatho-inhibitory drugs with potential applications in hypertension and/or metabolic syndrome, i.e., a cluster of cardiovascular (hypertension) and metabolic disorders. Our study highlights decisive arguments of SAR concerning both the affinity for I1Rs and the hypotensive activity of 2-aryliminopyrrolidines. Binding assays showed high affinity and selectivity of some compounds for I1 imidazoline receptors over α2-adreergic receptors. Compound 13 (laboratory reference LNP599; Ki = 3.2 nM on I1imidazoline receptors) is the prototype for the development of new centrally acting agents targeting specifically I1imidazoline receptors to be used in the management of hypertension and/or metabolic syndrome.
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Agonist activity at human recombinant Alpha-2 adrenergic receptor expressed in CHOK1 cells after 30 mins by [35S]GTPgammaS binding assay
|
Homo sapiens
|
35.3
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Transfer of SAR information from hypotensive indazole to indole derivatives acting at α-adrenergic receptors: In vitro and in vivo studies.
Year : 2016
Volume : 115
First Page : 406
Last Page : 415
Authors : Sączewski J, Hudson A, Scheinin M, Wasilewska A, Sączewski F, Rybczyńska A, Ferdousi M, Laurila JM, Boblewski K, Lehmann A, Watts H, Ma D.
Abstract : In a search for novel antihypertensive drugs we applied scaffold hopping from the previously described α1-adrenergic receptor antagonists, 1-[(imidazolin-2-yl)methyl]indazoles. The aim was to investigate whether the α-adrenergic properties of the indazole core were transferable to the indole core. The newly obtained 1-[(imidazolin-2-yl)methyl]indole analogues were screened in vitro for their binding affinities for α1-and α2-adrenoceptors, which allowed the identification of the target-based SAR transfer (T_SAR transfer) as well as structure-based SAR transfer (S_SAR transfer) events. However, when screened in vivo with use of anaesthetized male Wistar rats, the new indole ligands showed a different hemodynamic profile than expected. Instead of the immediate hypotensive effect characteristic of peripheral vasodilatator α1 blockers, a biphasic effect was observed, reminiscent of clonidine-like centrally acting antihypertensive agents. This was supported by subsequent in vitro functional studies in [(35)S]GTPγS binding assay, where the indole analogues displayed partial agonist properties at α2-adrenergic receptors. Since no correlation was found between the in vitro binding to α-adrenoceptors and the in vivo hemodynamic effects of the two series of indazole and indole bioisosteric compounds, in a search for new imidazoline-containing adrenergic drugs, the structure-based SAR transfer information obtained from in vitro binding studies should be treated with caution.
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Displacement of [3H]RS-79948-197 from recombinant human alpha2A adrenoreceptor expressed in CHOK1 cell membrane by scintillation counting method
|
Homo sapiens
|
28.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin.
Year : 2016
Volume : 24
Issue : 14
First Page : 3174
Last Page : 3183
Authors : Vucicevic J, Srdic-Rajic T, Pieroni M, Laurila JM, Perovic V, Tassini S, Azzali E, Costantino G, Glisic S, Agbaba D, Scheinin M, Nikolic K, Radi M, Veljkovic N.
Abstract : The clonidine-like central antihypertensive agent rilmenidine, which has high affinity for I1-type imidazoline receptors (I1-IR) was recently found to have cytotoxic effects on cultured cancer cell lines. However, due to its pharmacological effects resulting also from α2-adrenoceptor activation, rilmenidine cannot be considered a suitable anticancer drug candidate. Here, we report the identification of novel rilmenidine-derived compounds with anticancer potential and devoid of α2-adrenoceptor effects by means of ligand- and structure-based drug design approaches. Starting from a large virtual library, eleven compounds were selected, synthesized and submitted to biological evaluation. The most active compound 5 exhibited a cytotoxic profile similar to that of rilmenidine, but without appreciable affinity to α2-adrenoceptors. In addition, compound 5 significantly enhanced the apoptotic response to doxorubicin, and may thus represent an important tool for the development of better adjuvant chemotherapeutic strategies for doxorubicin-insensitive cancers.
|
Agonist activity at recombinant human alpha2A adrenoreceptor expressed in CHOK1 cell membrane incubated for 30 mins by [35S]GTPgammaS binding assay
|
Homo sapiens
|
30.2
nM
|
|
Journal : Bioorg. Med. Chem.
Title : A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin.
Year : 2016
Volume : 24
Issue : 14
First Page : 3174
Last Page : 3183
Authors : Vucicevic J, Srdic-Rajic T, Pieroni M, Laurila JM, Perovic V, Tassini S, Azzali E, Costantino G, Glisic S, Agbaba D, Scheinin M, Nikolic K, Radi M, Veljkovic N.
Abstract : The clonidine-like central antihypertensive agent rilmenidine, which has high affinity for I1-type imidazoline receptors (I1-IR) was recently found to have cytotoxic effects on cultured cancer cell lines. However, due to its pharmacological effects resulting also from α2-adrenoceptor activation, rilmenidine cannot be considered a suitable anticancer drug candidate. Here, we report the identification of novel rilmenidine-derived compounds with anticancer potential and devoid of α2-adrenoceptor effects by means of ligand- and structure-based drug design approaches. Starting from a large virtual library, eleven compounds were selected, synthesized and submitted to biological evaluation. The most active compound 5 exhibited a cytotoxic profile similar to that of rilmenidine, but without appreciable affinity to α2-adrenoceptors. In addition, compound 5 significantly enhanced the apoptotic response to doxorubicin, and may thus represent an important tool for the development of better adjuvant chemotherapeutic strategies for doxorubicin-insensitive cancers.
|
Displacement of [125I]PIC from Imidazoline-1 receptor in rat PC12 cell membrane incubated for 30 mins by gamma counting method
|
Rattus norvegicus
|
125.89
nM
|
|
Journal : Bioorg. Med. Chem.
Title : A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin.
Year : 2016
Volume : 24
Issue : 14
First Page : 3174
Last Page : 3183
Authors : Vucicevic J, Srdic-Rajic T, Pieroni M, Laurila JM, Perovic V, Tassini S, Azzali E, Costantino G, Glisic S, Agbaba D, Scheinin M, Nikolic K, Radi M, Veljkovic N.
Abstract : The clonidine-like central antihypertensive agent rilmenidine, which has high affinity for I1-type imidazoline receptors (I1-IR) was recently found to have cytotoxic effects on cultured cancer cell lines. However, due to its pharmacological effects resulting also from α2-adrenoceptor activation, rilmenidine cannot be considered a suitable anticancer drug candidate. Here, we report the identification of novel rilmenidine-derived compounds with anticancer potential and devoid of α2-adrenoceptor effects by means of ligand- and structure-based drug design approaches. Starting from a large virtual library, eleven compounds were selected, synthesized and submitted to biological evaluation. The most active compound 5 exhibited a cytotoxic profile similar to that of rilmenidine, but without appreciable affinity to α2-adrenoceptors. In addition, compound 5 significantly enhanced the apoptotic response to doxorubicin, and may thus represent an important tool for the development of better adjuvant chemotherapeutic strategies for doxorubicin-insensitive cancers.
|
Displacement of [3H]clonidine from alpha2 adrenergic receptor in rat brain cerebral cortex after 25 mins by microbeta scintillation counting method
|
Rattus norvegicus
|
2.7
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and activity of newly designed aroxyalkyl or aroxyethoxyethyl derivatives of piperazine on the cardiovascular and the central nervous systems.
Year : 2016
Volume : 26
Issue : 21
First Page : 5315
Last Page : 5321
Authors : Waszkielewicz AM, Kubacka M, Pańczyk K, Mogilski S, Siwek A, Głuch-Lutwin M, Gryboś A, Filipek B.
Abstract : In the search for new hypotensive agents some new aroxyalkyl or aroxyethoxyethyl derivatives of piperazine have been synthesized and evaluated for their pharmacological properties. Pharmacological tests included receptor binding assays toward adrenergic receptors α1, α2 and β1, additionally 5-HT1A, functional bioassay and in vivo evaluation of hypotensive activity as well as antidepressant-like potential. All the tested compounds exhibited α1-antagonistic properties, three of them possessed also hypotensive activity in rats. The most promising compound 3 1-[4-(2,6-dimethylphenoxy)butyl]-4-(2-methoxyphenyl)piperazine hydrochloride was a selective α1 receptor antagonist (Ki=23.5±1.3, α1/α2=15.77, pKB=8.538±0.109). It was active in all tested doses in vivo (1, 0.5, and 0.1mg/kg) and it reduced blood pressure by 10-13% at the dose of 1mg/kg (rats, i.v.). Compound 5 1-[2-(2,3-dimethylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine dihydrochloride exhibited the lowest dose for antidepressant-like activity 5mg/kgb.w. (mice, i.p.) without influence on spontaneous activity (mice, i.p.).
|
Agonist activity at human recombinant alpha-2A receptor expressed in PC12 cells assessed as inhibition of forskolin-stimulated intracellular cAMP accumulation measured after 10 mins by cAMP enzyme immunoassay
|
Homo sapiens
|
10.0
nM
|
|
Title : Novel methods for identifying improved, non-sedating alpha-2 agonists
Year : 2005
|
Agonist activity at human recombinant alpha-2C receptor expressed in PC12 cells assessed as inhibition of forskolin-stimulated intracellular cAMP accumulation measured after 10 mins by cAMP enzyme immunoassay
|
Homo sapiens
|
56.0
nM
|
|
Title : Novel methods for identifying improved, non-sedating alpha-2 agonists
Year : 2005
|
Agonist activity at bovine recombinant alpha-1A receptor expressed in HEK293 cells coexpressing Gag-pol assessed as increase in intracellular calcium measured after 60 mins by fluo-4 dye based FLIPR assay
|
Bos taurus
|
89.0
nM
|
|
Title : Novel methods for identifying improved, non-sedating alpha-2 agonists
Year : 2005
|
Agonist activity at hamster recombinant alpha-1B receptor expressed in HEK293 cells coexpressing Gag-pol assessed as increase in intracellular calcium measured after 60 mins by fluo-4 dye based FLIPR assay
|
Cricetinae
|
83.0
nM
|
|
Title : Novel methods for identifying improved, non-sedating alpha-2 agonists
Year : 2005
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
17.54
%
|
|
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
|
-0.02
%
|
|
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
|
-0.02
%
|
|
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.
