|
In vitro ability to displace [3H]oxotremorine-M (OXO-M) from rat cerebral cortex muscarinic receptor.
|
None
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Substituent variation in azabicyclic triazole- and tetrazole-based muscarinic receptor ligands.
Year : 1992
Volume : 35
Issue : 13
First Page : 2392
Last Page : 2406
Authors : Jenkins SM, Wadsworth HJ, Bromidge S, Orlek BS, Wyman PA, Riley GJ, Hawkins J.
Abstract : The effect of variation of the 1-azabicyclic substituent on the novel 1,2,3-triazol-4-yl-, 1,2,4-triazol-1-yl, tetrazol-5-yl-, and tetrazol-2-yl-based muscarinic receptor ligands has been studied, and the exo-azabicyclic[2.2.1]hept-3-yl substituent was found to give the most potent and efficacious compounds. In addition, variation of the second substituent on 1,2,4-triazol-1-yl- and tetrazol-2-yl-based muscarinic receptor ligands has yielded a series of novel compounds with high potencies and efficacies, ranging from full agonists to antagonists. Small lipophilic electron withdrawing substituents give potent but low efficacy compounds, while small polar electron donating substituents give potent and efficacious compounds. The activity of these compounds is described in terms of a model of the receptor involving lipophilic and hydrogen bonding interactions. These compounds provide muscarinic ligands with high potency and a range of efficacies suitable for testing as candidate drugs in the treatment of Alzheimer's disease.
|
Compound was tested in vitro for its binding affinity to muscarinic acetylcholine receptor from rat cortical homogenates using [3H]OXO-M as radioligand
|
None
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and muscarinic activities of quinuclidin-3-yltriazole and -tetrazole derivatives.
Year : 1992
Volume : 35
Issue : 7
First Page : 1280
Last Page : 1290
Authors : Wadsworth HJ, Jenkins SM, Orlek BS, Cassidy F, Clark MS, Brown F, Riley GJ, Graves D, Hawkins J, Naylor CB.
Abstract : The synthesis of 15 methyl or unsubstituted 1,2,3-triazoles, 1,2,4-triazoles, and tetrazoles additionally substituted with a 1-azabicyclo[2.2.2]octan-3-yl group is described. The potency and efficacy of these compounds as muscarinic ligands were determined in radioligand binding assays using [3H]oxotremorine and [3H]quinuclidinyl benzilate. Potency and efficacy were found in compounds in which the azole moiety was attached to the azabicyclic ring either through a carbon atom or a nitrogen atom. Electrostatic potential maps of both the C-linked and the novel N-linked series of compounds were calculated. A relationship between position and depth of the electrostatic minima relative to the azabicyclic ring and the potency and efficacy of the compounds was determined.
|
The compound was tested in vitro for central muscarinic acetylcholine receptor affinity to displace [3H]oxotremorine-M from rat cerebral cortex; Value ranges from 7-20
|
None
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Comparison of azabicyclic esters and oxadiazoles as ligands for the muscarinic receptor.
Year : 1991
Volume : 34
Issue : 9
First Page : 2726
Last Page : 2735
Authors : Orlek BS, Blaney FE, Brown F, Clark MS, Hadley MS, Hatcher J, Riley GJ, Rosenberg HE, Wadsworth HJ, Wyman P.
Abstract : The link between the cognitive deficit associated with Alzheimer type dementia and the loss of cholinergic function in the disease provides a basis for examining muscarinic agonists as potential therapeutic agents. This paper describes the design and synthesis of novel azabicyclic methyl esters as ligands for the muscarinic receptor. Replacement of the methyl ester by a 3-methyl-1,2,4-oxadiazole ring produces potent metabolically more stable muscarinic agonists capable of penetrating the central nervous system. These compounds generally show improved affinity relative to the corresponding methyl esters. 3-Methyl-1,2,4-oxadiazole 7b has an affinity 4 times that of acetylcholine. Receptor affinity is discussed in relation to the size and geometry of the azabicyclic ring and the electronic properties of the heteroaromatic ring.
|
Agonistic activity against muscarinic acetylcholine receptor M5 expressed in NIH 3T3 cells.
|
None
|
630.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological characterization of bivalent 1-methyl-1,2,5,6-tetrahydropyridyl-1,2,5-thiadiazole derivatives as selective muscarinic agonists.
Year : 2001
Volume : 44
Issue : 26
First Page : 4563
Last Page : 4576
Authors : Rajeswaran WG, Cao Y, Huang XP, Wroblewski ME, Colclough T, Lee S, Liu F, Nagy PI, Ellis J, Levine BA, Nocka KH, Messer WS.
Abstract : Selective muscarinic agonists could be useful in the treatment of neurological disorders such as Alzheimer's disease, schizophrenia, and chronic pain. Many muscarinic agonists have been developed, yet most exhibit at best limited functional selectivity for a given receptor subtype perhaps because of the high degree of sequence homology within the putative binding site, which appears to be buried within the transmembrane domains. Bivalent compounds containing essentially two agonist pharmacophores within the same molecule were synthesized and tested for receptor binding affinity and muscarinic agonist activity. A series of bis-1,2,5-thiadiazole derivatives of 1,2,5,6-tetrahydropyridine linked by an alkyloxy moiety exhibited very high affinity (K(i) < 1 nM) and strong agonist activity. The degree of activity depended on the length of the linking alkyl group, which could be replaced by a poly(ethylene glycol) moiety, resulting in improved water solubility, binding affinity, and agonist potency.
|
Binding affinity towards rat forebrain nicotinic acetylcholine receptor using [3H]EB as radioligand
|
Rattus norvegicus
|
43.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pharmacology of the agonist binding sites of rat neuronal nicotinic receptor subtypes expressed in HEK 293 cells.
Year : 2004
Volume : 14
Issue : 8
First Page : 1845
Last Page : 1848
Authors : Xiao Y, Baydyuk M, Wang HP, Davis HE, Kellar KJ.
Abstract : The binding affinities of agonists at heteromeric nicotinic receptors composed of rat alpha2, alpha3 and alpha4 subunits in combination with beta2 or beta4 subunits were examined in stably transfected HEK 293 cells. In most cases, the affinities of agonists were higher at receptors composed of an alpha subunit in combination with the beta2 subunit than the beta4 subunit, and in some cases this difference was quite large (>250 times), suggesting the possibility of developing subtype-selective ligands and therapeutically useful drugs.
|
Binding affinity towards rat nicotinic acetylcholine receptor alpha2-beta2 expressed in HEK293 cells using [3H]EB as radioligand
|
Rattus norvegicus
|
11.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pharmacology of the agonist binding sites of rat neuronal nicotinic receptor subtypes expressed in HEK 293 cells.
Year : 2004
Volume : 14
Issue : 8
First Page : 1845
Last Page : 1848
Authors : Xiao Y, Baydyuk M, Wang HP, Davis HE, Kellar KJ.
Abstract : The binding affinities of agonists at heteromeric nicotinic receptors composed of rat alpha2, alpha3 and alpha4 subunits in combination with beta2 or beta4 subunits were examined in stably transfected HEK 293 cells. In most cases, the affinities of agonists were higher at receptors composed of an alpha subunit in combination with the beta2 subunit than the beta4 subunit, and in some cases this difference was quite large (>250 times), suggesting the possibility of developing subtype-selective ligands and therapeutically useful drugs.
|
Binding affinity towards rat Nicotinic acetylcholine receptor alpha3-beta2 expressed in HEK293 cells using [3H]EB as radioligand
|
Rattus norvegicus
|
41.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pharmacology of the agonist binding sites of rat neuronal nicotinic receptor subtypes expressed in HEK 293 cells.
Year : 2004
Volume : 14
Issue : 8
First Page : 1845
Last Page : 1848
Authors : Xiao Y, Baydyuk M, Wang HP, Davis HE, Kellar KJ.
Abstract : The binding affinities of agonists at heteromeric nicotinic receptors composed of rat alpha2, alpha3 and alpha4 subunits in combination with beta2 or beta4 subunits were examined in stably transfected HEK 293 cells. In most cases, the affinities of agonists were higher at receptors composed of an alpha subunit in combination with the beta2 subunit than the beta4 subunit, and in some cases this difference was quite large (>250 times), suggesting the possibility of developing subtype-selective ligands and therapeutically useful drugs.
|
Binding affinity towards rat Nicotinic acetylcholine receptor alpha3-beta4 expressed in HEK293 cells using [3H]EB as radioligand
|
Rattus norvegicus
|
820.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pharmacology of the agonist binding sites of rat neuronal nicotinic receptor subtypes expressed in HEK 293 cells.
Year : 2004
Volume : 14
Issue : 8
First Page : 1845
Last Page : 1848
Authors : Xiao Y, Baydyuk M, Wang HP, Davis HE, Kellar KJ.
Abstract : The binding affinities of agonists at heteromeric nicotinic receptors composed of rat alpha2, alpha3 and alpha4 subunits in combination with beta2 or beta4 subunits were examined in stably transfected HEK 293 cells. In most cases, the affinities of agonists were higher at receptors composed of an alpha subunit in combination with the beta2 subunit than the beta4 subunit, and in some cases this difference was quite large (>250 times), suggesting the possibility of developing subtype-selective ligands and therapeutically useful drugs.
|
Binding affinity towards rat Nicotinic acetylcholine receptor alpha4-beta2 expressed in HEK293 cells using [3H]EB as radioligand
|
Rattus norvegicus
|
45.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pharmacology of the agonist binding sites of rat neuronal nicotinic receptor subtypes expressed in HEK 293 cells.
Year : 2004
Volume : 14
Issue : 8
First Page : 1845
Last Page : 1848
Authors : Xiao Y, Baydyuk M, Wang HP, Davis HE, Kellar KJ.
Abstract : The binding affinities of agonists at heteromeric nicotinic receptors composed of rat alpha2, alpha3 and alpha4 subunits in combination with beta2 or beta4 subunits were examined in stably transfected HEK 293 cells. In most cases, the affinities of agonists were higher at receptors composed of an alpha subunit in combination with the beta2 subunit than the beta4 subunit, and in some cases this difference was quite large (>250 times), suggesting the possibility of developing subtype-selective ligands and therapeutically useful drugs.
|
Binding affinity towards rat Nicotinic acetylcholine receptor alpha4-beta4 expressed in HEK293 cells using [3H]EB as radioligand
|
Rattus norvegicus
|
83.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pharmacology of the agonist binding sites of rat neuronal nicotinic receptor subtypes expressed in HEK 293 cells.
Year : 2004
Volume : 14
Issue : 8
First Page : 1845
Last Page : 1848
Authors : Xiao Y, Baydyuk M, Wang HP, Davis HE, Kellar KJ.
Abstract : The binding affinities of agonists at heteromeric nicotinic receptors composed of rat alpha2, alpha3 and alpha4 subunits in combination with beta2 or beta4 subunits were examined in stably transfected HEK 293 cells. In most cases, the affinities of agonists were higher at receptors composed of an alpha subunit in combination with the beta2 subunit than the beta4 subunit, and in some cases this difference was quite large (>250 times), suggesting the possibility of developing subtype-selective ligands and therapeutically useful drugs.
|
Binding affinity towards rat alpha2-beta4 nACh receptor expressed in HEK293 cells using [3H]EB as radioligand
|
Rattus norvegicus
|
180.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pharmacology of the agonist binding sites of rat neuronal nicotinic receptor subtypes expressed in HEK 293 cells.
Year : 2004
Volume : 14
Issue : 8
First Page : 1845
Last Page : 1848
Authors : Xiao Y, Baydyuk M, Wang HP, Davis HE, Kellar KJ.
Abstract : The binding affinities of agonists at heteromeric nicotinic receptors composed of rat alpha2, alpha3 and alpha4 subunits in combination with beta2 or beta4 subunits were examined in stably transfected HEK 293 cells. In most cases, the affinities of agonists were higher at receptors composed of an alpha subunit in combination with the beta2 subunit than the beta4 subunit, and in some cases this difference was quite large (>250 times), suggesting the possibility of developing subtype-selective ligands and therapeutically useful drugs.
|
Displacement of [3H]-cytisine from Alpha4-beta2 Nicotinic acetylcholine receptor of rat brain homogenates
|
Rattus norvegicus
|
7.6
nM
|
|
Journal : J. Med. Chem.
Title : Ligand selectivity for the acetylcholine binding site of the rat alpha4beta2 and alpha3beta4 nicotinic subtypes investigated by molecular docking.
Year : 2005
Volume : 48
Issue : 16
First Page : 5123
Last Page : 5130
Authors : Bisson WH, Scapozza L, Westera G, Mu L, Schubiger PA.
Abstract : The homology models of the extracellular domains of the neuronal alpha4beta2 (pdb code: 1ole) and ganglionic alpha3beta4 (pdb code: 1olf) rat nicotinic acetylcholine receptor (nAChR) subtypes were refined and energetically minimized. In this work, a series of nAChR ligands (1-15) were docked into the modeled binding cavity of both receptors. High-affinity, toxic ligands such as epibatidine (1) and dechloroepibatidine (2) docked into cluster 1 with the charged tertiary amino group, forming a pi-cation interaction with Trp 147 on the (+) side of the alpha4 subunit and establishing a characteristic H-bond with the Lys 77 on the (-) side of the beta2 subunit. The nontoxic ligands such as 33bMet (3), (S)-A-85380 (4), and acetylcholine (6) docked into cluster 2 with the same pi-cation interaction but with the rest of the molecule occupying a different moiety of the binding pocket. Molecular docking into the alpha3beta4 subtype showed that both enantiomers of 1 (1a and 1b) are representative templates for ligands with affinity toward this ganglionic nAChR subtype. The ranking scores of the docked molecules confirm the existence of structure-dependent subtype selectivity and shed light on the design of specific and selective alpha4beta2 nAChR subtype ligands.
|
Displacement of [3H]epibatidine from Alpha3 Beta4 Nicotinic acetylcholine receptor of rat brain homogenates
|
Rattus norvegicus
|
881.0
nM
|
|
Journal : J. Med. Chem.
Title : Ligand selectivity for the acetylcholine binding site of the rat alpha4beta2 and alpha3beta4 nicotinic subtypes investigated by molecular docking.
Year : 2005
Volume : 48
Issue : 16
First Page : 5123
Last Page : 5130
Authors : Bisson WH, Scapozza L, Westera G, Mu L, Schubiger PA.
Abstract : The homology models of the extracellular domains of the neuronal alpha4beta2 (pdb code: 1ole) and ganglionic alpha3beta4 (pdb code: 1olf) rat nicotinic acetylcholine receptor (nAChR) subtypes were refined and energetically minimized. In this work, a series of nAChR ligands (1-15) were docked into the modeled binding cavity of both receptors. High-affinity, toxic ligands such as epibatidine (1) and dechloroepibatidine (2) docked into cluster 1 with the charged tertiary amino group, forming a pi-cation interaction with Trp 147 on the (+) side of the alpha4 subunit and establishing a characteristic H-bond with the Lys 77 on the (-) side of the beta2 subunit. The nontoxic ligands such as 33bMet (3), (S)-A-85380 (4), and acetylcholine (6) docked into cluster 2 with the same pi-cation interaction but with the rest of the molecule occupying a different moiety of the binding pocket. Molecular docking into the alpha3beta4 subtype showed that both enantiomers of 1 (1a and 1b) are representative templates for ligands with affinity toward this ganglionic nAChR subtype. The ranking scores of the docked molecules confirm the existence of structure-dependent subtype selectivity and shed light on the design of specific and selective alpha4beta2 nAChR subtype ligands.
|
Displacement of [3H]NMS from human cloned muscarinic M2 receptor expressed in CHO cells
|
Homo sapiens
|
158.49
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Rapid novel divergent synthesis and muscarinic agonist profile of all four optical isomers of N,N,N-trimethyl(6-methyl-1,4-dioxan-2-yl)methanaminium iodide.
Year : 2008
Volume : 18
Issue : 2
First Page : 614
Last Page : 618
Authors : Piergentili A, Quaglia W, Giannella M, Del Bello F, Buccioni M, Nesi M, Matucci R.
Abstract : Two stereoselective parallel divergent four-step procedures to obtain all four enantiomeric forms of N,N,N-trimethyl(6-methyl-1,4-dioxan-2-yl)methanaminium iodide were developed. Enantiomeric purity was determined by quantitative (1)H NMR spectroscopy in the presence of the chiral shift reagent (+)-MTPA. The biological profile of the obtained compounds was evaluated at all muscarinic receptor subtypes by binding and functional assays.
|
Displacement of [3H]cystisine from nicotinic alpha-4-beta-2 receptor in rat brain
|
Rattus norvegicus
|
39.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Preparation and affinity profile of novel nicotinic ligands.
Year : 2008
Volume : 18
Issue : 6
First Page : 2188
Last Page : 2193
Authors : Charton Y, Guillonneau C, Lockhart B, Lestage P, Goldstein S.
Abstract : Novel nicotinic ligands, characterized by the presence of an amino substituted cyclopropane ring connected to a pyridine nucleus, are described. Pharmacological investigation revealed that these compounds exhibit highest affinity for the rat alpha4beta2 subtype of the nicotinic receptor with no affinity for the muscarinic receptor. No appreciable affinity for the muscular or for the ganglionic nicotinic receptor was observed at concentrations up to 10 microM. The increase in cortical ACh release as well as a positive effect on memory in a social recognition test in rat are exemplified.
|
Displacement of [3H]oxotremorine from muscarinic receptor in rat brain
|
Rattus norvegicus
|
85.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Preparation and affinity profile of novel nicotinic ligands.
Year : 2008
Volume : 18
Issue : 6
First Page : 2188
Last Page : 2193
Authors : Charton Y, Guillonneau C, Lockhart B, Lestage P, Goldstein S.
Abstract : Novel nicotinic ligands, characterized by the presence of an amino substituted cyclopropane ring connected to a pyridine nucleus, are described. Pharmacological investigation revealed that these compounds exhibit highest affinity for the rat alpha4beta2 subtype of the nicotinic receptor with no affinity for the muscarinic receptor. No appreciable affinity for the muscular or for the ganglionic nicotinic receptor was observed at concentrations up to 10 microM. The increase in cortical ACh release as well as a positive effect on memory in a social recognition test in rat are exemplified.
|
Agonist activity at human muscarinic M1 receptor expressed in CHO-K1 cells assessed as increase of acetylcholine-induced calcium flux by FLIPR assay
|
Homo sapiens
|
1.1
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 receptor agonist with unprecedented selectivity and procognitive potential.
Year : 2010
Volume : 53
Issue : 17
First Page : 6386
Last Page : 6397
Authors : Sams AG, Hentzer M, Mikkelsen GK, Larsen K, Bundgaard C, Plath N, Christoffersen CT, Bang-Andersen B.
Abstract : The discovery and structure-activity relationship (SAR) of a series of allosteric muscarinic M(1) receptor agonists are described. Compound 17 (Lu AE51090) was identified as a representative compound from the series, based on its high selectivity as an agonist at the muscarinic M(1) receptor across a panel of muscarinic receptor subtypes. Furthermore, 17 displayed a high degree of selectivity when tested in a broad panel of G-protein-coupled receptors, ion channels, transporters, and enzymes, and 17 showed an acceptable pharmacokinetic profile and sufficient brain exposure in rodents in order to characterize the compound in vivo. Hence, in a rodent model of learning and memory, 17 reversed delay-induced natural forgetting, suggesting a procognitive potential of 17.
|
Agonist activity at human muscarinic M2 receptor expressed in CHO-K1 cells coexpressing Galpha16 subunit assessed as increase of acetylcholine-induced calcium flux by FLIPR assay
|
Homo sapiens
|
220.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 receptor agonist with unprecedented selectivity and procognitive potential.
Year : 2010
Volume : 53
Issue : 17
First Page : 6386
Last Page : 6397
Authors : Sams AG, Hentzer M, Mikkelsen GK, Larsen K, Bundgaard C, Plath N, Christoffersen CT, Bang-Andersen B.
Abstract : The discovery and structure-activity relationship (SAR) of a series of allosteric muscarinic M(1) receptor agonists are described. Compound 17 (Lu AE51090) was identified as a representative compound from the series, based on its high selectivity as an agonist at the muscarinic M(1) receptor across a panel of muscarinic receptor subtypes. Furthermore, 17 displayed a high degree of selectivity when tested in a broad panel of G-protein-coupled receptors, ion channels, transporters, and enzymes, and 17 showed an acceptable pharmacokinetic profile and sufficient brain exposure in rodents in order to characterize the compound in vivo. Hence, in a rodent model of learning and memory, 17 reversed delay-induced natural forgetting, suggesting a procognitive potential of 17.
|
Agonist activity at human muscarinic M3 receptor expressed in BHK-21 cells assessed as increase of acetylcholine-induced calcium flux by FLIPR assay
|
Homo sapiens
|
3.2
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 receptor agonist with unprecedented selectivity and procognitive potential.
Year : 2010
Volume : 53
Issue : 17
First Page : 6386
Last Page : 6397
Authors : Sams AG, Hentzer M, Mikkelsen GK, Larsen K, Bundgaard C, Plath N, Christoffersen CT, Bang-Andersen B.
Abstract : The discovery and structure-activity relationship (SAR) of a series of allosteric muscarinic M(1) receptor agonists are described. Compound 17 (Lu AE51090) was identified as a representative compound from the series, based on its high selectivity as an agonist at the muscarinic M(1) receptor across a panel of muscarinic receptor subtypes. Furthermore, 17 displayed a high degree of selectivity when tested in a broad panel of G-protein-coupled receptors, ion channels, transporters, and enzymes, and 17 showed an acceptable pharmacokinetic profile and sufficient brain exposure in rodents in order to characterize the compound in vivo. Hence, in a rodent model of learning and memory, 17 reversed delay-induced natural forgetting, suggesting a procognitive potential of 17.
|
Agonist activity at human muscarinic M4 receptor expressed in BHK-21 cells coexpressing Galpha16 subunit assessed as increase of acetylcholine-induced calcium flux by FLIPR assay
|
Homo sapiens
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 receptor agonist with unprecedented selectivity and procognitive potential.
Year : 2010
Volume : 53
Issue : 17
First Page : 6386
Last Page : 6397
Authors : Sams AG, Hentzer M, Mikkelsen GK, Larsen K, Bundgaard C, Plath N, Christoffersen CT, Bang-Andersen B.
Abstract : The discovery and structure-activity relationship (SAR) of a series of allosteric muscarinic M(1) receptor agonists are described. Compound 17 (Lu AE51090) was identified as a representative compound from the series, based on its high selectivity as an agonist at the muscarinic M(1) receptor across a panel of muscarinic receptor subtypes. Furthermore, 17 displayed a high degree of selectivity when tested in a broad panel of G-protein-coupled receptors, ion channels, transporters, and enzymes, and 17 showed an acceptable pharmacokinetic profile and sufficient brain exposure in rodents in order to characterize the compound in vivo. Hence, in a rodent model of learning and memory, 17 reversed delay-induced natural forgetting, suggesting a procognitive potential of 17.
|
Agonist activity at human muscarinic M5 receptor expressed in BHK-21 cells assessed as increase of acetylcholine-induced calcium flux by FLIPR assay
|
Homo sapiens
|
1.2
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 receptor agonist with unprecedented selectivity and procognitive potential.
Year : 2010
Volume : 53
Issue : 17
First Page : 6386
Last Page : 6397
Authors : Sams AG, Hentzer M, Mikkelsen GK, Larsen K, Bundgaard C, Plath N, Christoffersen CT, Bang-Andersen B.
Abstract : The discovery and structure-activity relationship (SAR) of a series of allosteric muscarinic M(1) receptor agonists are described. Compound 17 (Lu AE51090) was identified as a representative compound from the series, based on its high selectivity as an agonist at the muscarinic M(1) receptor across a panel of muscarinic receptor subtypes. Furthermore, 17 displayed a high degree of selectivity when tested in a broad panel of G-protein-coupled receptors, ion channels, transporters, and enzymes, and 17 showed an acceptable pharmacokinetic profile and sufficient brain exposure in rodents in order to characterize the compound in vivo. Hence, in a rodent model of learning and memory, 17 reversed delay-induced natural forgetting, suggesting a procognitive potential of 17.
|
Displacement of [3H]epibatidine from rat alpha3beta4 nAChR expressed in HEK292 cells after 3 hrs
|
Rattus norvegicus
|
620.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel α3β4 nicotinic acetylcholine receptor-selective ligands. Discovery, structure-activity studies, and pharmacological evaluation.
Year : 2010
Volume : 53
Issue : 22
First Page : 8187
Last Page : 8191
Authors : Zaveri N, Jiang F, Olsen C, Polgar W, Toll L.
Abstract : Antagonist activity at the α3β4 nicotinic acetylcholine receptor (nAChR) is thought to contribute to the antiaddictive properties of several compounds. However, truly selective ligands for the α3β4 nAChR have not been available. We report the discovery and SAR of a novel class of compounds that bind to the α3β4 nAChR and have no measurable affinity for the α4β2 or α7 subtype. In functional assays the lead compound antagonized epibatidine-induced Ca(2+) flux in α3β4-transfected cells in a noncompetitive manner.
|
Displacement of [3H]epibatidine from rat alpha4beta2 nAChR expressed in HEK292 cells after 3 hrs
|
Rattus norvegicus
|
37.7
nM
|
|
Journal : J. Med. Chem.
Title : Novel α3β4 nicotinic acetylcholine receptor-selective ligands. Discovery, structure-activity studies, and pharmacological evaluation.
Year : 2010
Volume : 53
Issue : 22
First Page : 8187
Last Page : 8191
Authors : Zaveri N, Jiang F, Olsen C, Polgar W, Toll L.
Abstract : Antagonist activity at the α3β4 nicotinic acetylcholine receptor (nAChR) is thought to contribute to the antiaddictive properties of several compounds. However, truly selective ligands for the α3β4 nAChR have not been available. We report the discovery and SAR of a novel class of compounds that bind to the α3β4 nAChR and have no measurable affinity for the α4β2 or α7 subtype. In functional assays the lead compound antagonized epibatidine-induced Ca(2+) flux in α3β4-transfected cells in a noncompetitive manner.
|
Agonist activity at human M1 receptor expressed in CHO-K1 cells assessed as calcium mobilization for 6 mins by Calcium4-based staining
|
Homo sapiens
|
1.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Hit-to-lead investigation of a series of novel combined dopamine D2 and muscarinic M1 receptor ligands with putative antipsychotic and pro-cognitive potential.
Year : 2012
Volume : 22
Issue : 15
First Page : 5134
Last Page : 5140
Authors : Sams AG, Larsen K, Mikkelsen GK, Hentzer M, Christoffersen CT, Jensen KG, Frederiksen K, Bang-Andersen B.
Abstract : We describe the discovery of a series of compounds based on 1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3,4-dihydro-1H-quinolin-2-one (3), showing combined D(2) receptor affinity and M(1) receptor agonism. Based on a strategy of controlling logP, we herein describe a hit-to-lead investigation with the aim of retaining the combined D(2)/M(1) profile, while removing the propensity of the compounds to inhibit the hERG channel, as well as at obtaining acceptable pharmacokinetic properties. Although a SAR was evident for all four parameters in question, it was not possible to separate hERG channel inhibition and D(2) receptor affinity by this effort; whilst it was feasible to obtain compounds with M(1) receptor agonism, acceptable clearance, and weak hERG inhibition.
|
Agonist activity at human muscarinic M5 receptor expressed in BHK-21 cells assessed as calcium mobilization for 6 mins by Calcium4-based staining
|
Homo sapiens
|
1.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Hit-to-lead investigation of a series of novel combined dopamine D2 and muscarinic M1 receptor ligands with putative antipsychotic and pro-cognitive potential.
Year : 2012
Volume : 22
Issue : 15
First Page : 5134
Last Page : 5140
Authors : Sams AG, Larsen K, Mikkelsen GK, Hentzer M, Christoffersen CT, Jensen KG, Frederiksen K, Bang-Andersen B.
Abstract : We describe the discovery of a series of compounds based on 1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3,4-dihydro-1H-quinolin-2-one (3), showing combined D(2) receptor affinity and M(1) receptor agonism. Based on a strategy of controlling logP, we herein describe a hit-to-lead investigation with the aim of retaining the combined D(2)/M(1) profile, while removing the propensity of the compounds to inhibit the hERG channel, as well as at obtaining acceptable pharmacokinetic properties. Although a SAR was evident for all four parameters in question, it was not possible to separate hERG channel inhibition and D(2) receptor affinity by this effort; whilst it was feasible to obtain compounds with M(1) receptor agonism, acceptable clearance, and weak hERG inhibition.
|
Agonist activity at muscarinic human M4 receptor expressed in BHK-21 cells assessed as calcium mobilization for 6 mins by Calcium4-based staining
|
Homo sapiens
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Hit-to-lead investigation of a series of novel combined dopamine D2 and muscarinic M1 receptor ligands with putative antipsychotic and pro-cognitive potential.
Year : 2012
Volume : 22
Issue : 15
First Page : 5134
Last Page : 5140
Authors : Sams AG, Larsen K, Mikkelsen GK, Hentzer M, Christoffersen CT, Jensen KG, Frederiksen K, Bang-Andersen B.
Abstract : We describe the discovery of a series of compounds based on 1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3,4-dihydro-1H-quinolin-2-one (3), showing combined D(2) receptor affinity and M(1) receptor agonism. Based on a strategy of controlling logP, we herein describe a hit-to-lead investigation with the aim of retaining the combined D(2)/M(1) profile, while removing the propensity of the compounds to inhibit the hERG channel, as well as at obtaining acceptable pharmacokinetic properties. Although a SAR was evident for all four parameters in question, it was not possible to separate hERG channel inhibition and D(2) receptor affinity by this effort; whilst it was feasible to obtain compounds with M(1) receptor agonism, acceptable clearance, and weak hERG inhibition.
|
Agonist activity at human muscarinic M3 receptor expressed in BHK-21 cells assessed as calcium mobilization for 6 mins by Calcium4-based staining
|
Homo sapiens
|
3.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Hit-to-lead investigation of a series of novel combined dopamine D2 and muscarinic M1 receptor ligands with putative antipsychotic and pro-cognitive potential.
Year : 2012
Volume : 22
Issue : 15
First Page : 5134
Last Page : 5140
Authors : Sams AG, Larsen K, Mikkelsen GK, Hentzer M, Christoffersen CT, Jensen KG, Frederiksen K, Bang-Andersen B.
Abstract : We describe the discovery of a series of compounds based on 1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3,4-dihydro-1H-quinolin-2-one (3), showing combined D(2) receptor affinity and M(1) receptor agonism. Based on a strategy of controlling logP, we herein describe a hit-to-lead investigation with the aim of retaining the combined D(2)/M(1) profile, while removing the propensity of the compounds to inhibit the hERG channel, as well as at obtaining acceptable pharmacokinetic properties. Although a SAR was evident for all four parameters in question, it was not possible to separate hERG channel inhibition and D(2) receptor affinity by this effort; whilst it was feasible to obtain compounds with M(1) receptor agonism, acceptable clearance, and weak hERG inhibition.
|
Agonist activity at human muscarinic M2 receptor expressed in CHO-K1 cells assessed as calcium mobilization for 6 mins by Calcium4-based staining
|
Homo sapiens
|
220.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Hit-to-lead investigation of a series of novel combined dopamine D2 and muscarinic M1 receptor ligands with putative antipsychotic and pro-cognitive potential.
Year : 2012
Volume : 22
Issue : 15
First Page : 5134
Last Page : 5140
Authors : Sams AG, Larsen K, Mikkelsen GK, Hentzer M, Christoffersen CT, Jensen KG, Frederiksen K, Bang-Andersen B.
Abstract : We describe the discovery of a series of compounds based on 1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3,4-dihydro-1H-quinolin-2-one (3), showing combined D(2) receptor affinity and M(1) receptor agonism. Based on a strategy of controlling logP, we herein describe a hit-to-lead investigation with the aim of retaining the combined D(2)/M(1) profile, while removing the propensity of the compounds to inhibit the hERG channel, as well as at obtaining acceptable pharmacokinetic properties. Although a SAR was evident for all four parameters in question, it was not possible to separate hERG channel inhibition and D(2) receptor affinity by this effort; whilst it was feasible to obtain compounds with M(1) receptor agonism, acceptable clearance, and weak hERG inhibition.
|
Displacement of [3H]epibatidine from chimeric human alpha7-5-HT3A receptor expressed in HEK293 cells after 2 hrs by scintillation counter analysis
|
Homo sapiens
|
501.19
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Identification of novel α7 nicotinic receptor ligands by in silico screening against the crystal structure of a chimeric α7 receptor ligand binding domain.
Year : 2012
Volume : 20
Issue : 19
First Page : 5992
Last Page : 6002
Authors : Akdemir A, Edink E, Thompson AJ, Lummis SC, Kooistra AJ, de Graaf C, de Esch IJ.
Abstract : A hierarchical in silico screening procedure using the crystal structure of an agonist bound chimeric α7/Ls-AChBP protein was successfully applied to both proprietary and commercial databases containing drug-like molecules. An overall hit rate of 26% (pK(i) ≥5.0) was obtained, with an even better hit rate of 35% for the commercial compound collection. Structurally novel and diverse ligands were identified. Binding studies with [(3)H]epibatidine on chimeric α7/5-HT(3) receptors yielded submicromolar inhibition constants for identified hits. Compared to a previous screening procedure that utilized the wild type Ls-AChBP crystal structure, the current study shows that the recently obtained α7/Ls-AChBP chimeric protein crystal structure is a better template for the identification of novel α7 receptor ligands.
|
Displacement of [3H]epibatidine from rat recombinant alpha4beta4 nAChR expressed in HEK293 cells after 4 hrs by scintillation counting analysis
|
Rattus norvegicus
|
57.54
nM
|
|
Displacement of [3H]epibatidine from rat recombinant alpha4beta4 nAChR expressed in HEK293 cells after 4 hrs by scintillation counting analysis
|
Rattus norvegicus
|
58.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, pharmacology, and biostructural characterization of novel α4β2 nicotinic acetylcholine receptor agonists.
Year : 2013
Volume : 56
Issue : 3
First Page : 940
Last Page : 951
Authors : Ussing CA, Hansen CP, Petersen JG, Jensen AA, Rohde LA, Ahring PK, Nielsen EØ, Kastrup JS, Gajhede M, Frølund B, Balle T.
Abstract : In our search for selective agonists for the α(4)β(2) subtype of the nicotinic acetylcholine receptors (nAChRs), we have synthesized and characterized a series of novel heterocyclic analogues of 3-(dimethylamino)butyl dimethylcarbamate (DMABC, 4). All new heterocyclic analogues, especially N,N-dimethyl-4-(1-methyl-1H-imidazol-2-yloxy)butan-2-amine (7), showed an improved binding selectivity profile in favor of α(4)β(2) over other nAChR subtypes, primarily due to impaired binding at β(4) containing receptors. This observation can be rationalized based on cocrystal structures of (R)-4 and (R)-7 bound to acetylcholine binding protein from Lymnaea stagnalis. Functional characterization at both (α(4))(2)(β(2))(3) and (α(4))(3)(β(2))(2) receptors using two-electrode voltage clamp techniques in Xenopus laevis oocytes indicates that the investigated compounds interact differently with the two receptor stoichiometries. Compound 7 is an efficacious agonist at both α(4)-β(2) and α(4)-α(4) binding sites, while the close analogue N,N-dimethyl-4-(1,4-dimethyl-1H-imidazol-2-yloxy)butan-2-amine (9) primarily activates via α(4)-β(2) binding sites. The results suggest that it may be possible to rationally design compounds with specific stoichiometry preferences.
|
Displacement of [3H]epibatidine from rat recombinant alpha3beta4 nAChR expressed in HEK293 cells after 4 hrs by scintillation counting analysis
|
Rattus norvegicus
|
616.6
nM
|
|
Displacement of [3H]epibatidine from rat recombinant alpha3beta4 nAChR expressed in HEK293 cells after 4 hrs by scintillation counting analysis
|
Rattus norvegicus
|
620.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, pharmacology, and biostructural characterization of novel α4β2 nicotinic acetylcholine receptor agonists.
Year : 2013
Volume : 56
Issue : 3
First Page : 940
Last Page : 951
Authors : Ussing CA, Hansen CP, Petersen JG, Jensen AA, Rohde LA, Ahring PK, Nielsen EØ, Kastrup JS, Gajhede M, Frølund B, Balle T.
Abstract : In our search for selective agonists for the α(4)β(2) subtype of the nicotinic acetylcholine receptors (nAChRs), we have synthesized and characterized a series of novel heterocyclic analogues of 3-(dimethylamino)butyl dimethylcarbamate (DMABC, 4). All new heterocyclic analogues, especially N,N-dimethyl-4-(1-methyl-1H-imidazol-2-yloxy)butan-2-amine (7), showed an improved binding selectivity profile in favor of α(4)β(2) over other nAChR subtypes, primarily due to impaired binding at β(4) containing receptors. This observation can be rationalized based on cocrystal structures of (R)-4 and (R)-7 bound to acetylcholine binding protein from Lymnaea stagnalis. Functional characterization at both (α(4))(2)(β(2))(3) and (α(4))(3)(β(2))(2) receptors using two-electrode voltage clamp techniques in Xenopus laevis oocytes indicates that the investigated compounds interact differently with the two receptor stoichiometries. Compound 7 is an efficacious agonist at both α(4)-β(2) and α(4)-α(4) binding sites, while the close analogue N,N-dimethyl-4-(1,4-dimethyl-1H-imidazol-2-yloxy)butan-2-amine (9) primarily activates via α(4)-β(2) binding sites. The results suggest that it may be possible to rationally design compounds with specific stoichiometry preferences.
|
Displacement of [3H]epibatidine from rat recombinant alpha4beta2 nAChR expressed in HEK293 cells after 4 hrs by scintillation counting analysis
|
Rattus norvegicus
|
33.11
nM
|
|
Displacement of [3H]epibatidine from rat recombinant alpha4beta2 nAChR expressed in HEK293 cells after 4 hrs by scintillation counting analysis
|
Rattus norvegicus
|
33.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, pharmacology, and biostructural characterization of novel α4β2 nicotinic acetylcholine receptor agonists.
Year : 2013
Volume : 56
Issue : 3
First Page : 940
Last Page : 951
Authors : Ussing CA, Hansen CP, Petersen JG, Jensen AA, Rohde LA, Ahring PK, Nielsen EØ, Kastrup JS, Gajhede M, Frølund B, Balle T.
Abstract : In our search for selective agonists for the α(4)β(2) subtype of the nicotinic acetylcholine receptors (nAChRs), we have synthesized and characterized a series of novel heterocyclic analogues of 3-(dimethylamino)butyl dimethylcarbamate (DMABC, 4). All new heterocyclic analogues, especially N,N-dimethyl-4-(1-methyl-1H-imidazol-2-yloxy)butan-2-amine (7), showed an improved binding selectivity profile in favor of α(4)β(2) over other nAChR subtypes, primarily due to impaired binding at β(4) containing receptors. This observation can be rationalized based on cocrystal structures of (R)-4 and (R)-7 bound to acetylcholine binding protein from Lymnaea stagnalis. Functional characterization at both (α(4))(2)(β(2))(3) and (α(4))(3)(β(2))(2) receptors using two-electrode voltage clamp techniques in Xenopus laevis oocytes indicates that the investigated compounds interact differently with the two receptor stoichiometries. Compound 7 is an efficacious agonist at both α(4)-β(2) and α(4)-α(4) binding sites, while the close analogue N,N-dimethyl-4-(1,4-dimethyl-1H-imidazol-2-yloxy)butan-2-amine (9) primarily activates via α(4)-β(2) binding sites. The results suggest that it may be possible to rationally design compounds with specific stoichiometry preferences.
|
Activation of alpha4beta2* nAChR low affinity site (unknown origin) expressed in xenopus oocytes by electrophysiology method
|
Homo sapiens
|
73.0
nM
|
|
Journal : J. Med. Chem.
Title : Recent developments in novel antidepressants targeting α4β2-nicotinic acetylcholine receptors.
Year : 2014
Volume : 57
Issue : 20
First Page : 8204
Last Page : 8223
Authors : Yu LF, Zhang HK, Caldarone BJ, Eaton JB, Lukas RJ, Kozikowski AP.
Abstract : Nicotinic acetylcholine receptors (nAChRs) have been investigated for developing drugs that can potentially treat various central nervous system disorders. Considerable evidence supports the hypothesis that modulation of the cholinergic system through activation and/or desensitization/inactivation of nAChR holds promise for the development of new antidepressants. The introductory portion of this Miniperspective discusses the basic pharmacology that underpins the involvement of α4β2-nAChRs in depression, along with the structural features that are essential to ligand recognition by the α4β2-nAChRs. The remainder of this Miniperspective analyzes reported nicotinic ligands in terms of drug design considerations and their potency and selectivity, with a particular focus on compounds exhibiting antidepressant-like effects in preclinical or clinical studies. This Miniperspective aims to provide an in-depth analysis of the potential for using nicotinic ligands in the treatment of depression, which may hold some promise in addressing an unmet clinical need by providing relief from depressive symptoms in refractory patients.
|
Activation of alpha4beta2* nAChR high affinity site (unknown origin) expressed in xenopus oocytes by electrophysiology method
|
Homo sapiens
|
1.7
nM
|
|
Journal : J. Med. Chem.
Title : Recent developments in novel antidepressants targeting α4β2-nicotinic acetylcholine receptors.
Year : 2014
Volume : 57
Issue : 20
First Page : 8204
Last Page : 8223
Authors : Yu LF, Zhang HK, Caldarone BJ, Eaton JB, Lukas RJ, Kozikowski AP.
Abstract : Nicotinic acetylcholine receptors (nAChRs) have been investigated for developing drugs that can potentially treat various central nervous system disorders. Considerable evidence supports the hypothesis that modulation of the cholinergic system through activation and/or desensitization/inactivation of nAChR holds promise for the development of new antidepressants. The introductory portion of this Miniperspective discusses the basic pharmacology that underpins the involvement of α4β2-nAChRs in depression, along with the structural features that are essential to ligand recognition by the α4β2-nAChRs. The remainder of this Miniperspective analyzes reported nicotinic ligands in terms of drug design considerations and their potency and selectivity, with a particular focus on compounds exhibiting antidepressant-like effects in preclinical or clinical studies. This Miniperspective aims to provide an in-depth analysis of the potential for using nicotinic ligands in the treatment of depression, which may hold some promise in addressing an unmet clinical need by providing relief from depressive symptoms in refractory patients.
|
Partial agonist activity at human muscarinic M1 acetylcholine receptor expressed in CHO cells assessed as increase in IP1 accumulation incubated for 30 mins by FRET based HTRF assay
|
Homo sapiens
|
371.54
nM
|
|
Journal : J. Med. Chem.
Title : Rational design of partial agonists for the muscarinic m1 acetylcholine receptor.
Year : 2015
Volume : 58
Issue : 2
First Page : 560
Last Page : 576
Authors : Chen X, Klöckner J, Holze J, Zimmermann C, Seemann WK, Schrage R, Bock A, Mohr K, Tränkle C, Holzgrabe U, Decker M.
Abstract : Aiming to design partial agonists for a G-protein-coupled receptor based on dynamic ligand binding, we synthesized three different series of bipharmacophoric ligands composed of the orthosteric building blocks iperoxo and 1 linked to allosteric modulators (BQCA-derived compounds, BQCAd; TBPB-derived compound, TBPBd). Their interactions were studied with the human muscarinic acetylcholine M1-receptor (hM1) with respect to receptor binding and Gq-protein signaling. Results demonstrate that iperoxo/BQCAd (2, 3) and 1/BQCAd hybrids (4) act as M1 partial agonists, whereas 1/TBPBd hybrids (5) did not activate M1-receptors. Among the iperoxo/BQCAd-hybrids, spacer length in conjunction with the pattern of substitution tuned efficacy. Most interestingly, a model of dynamic ligand binding revealed that the spacer length of 2a and 3a controlled the probability of switch between the inactive purely allosteric and the active bitopic orthosteric/allosteric binding pose. In summary, dynamic ligand binding can be exploited in M1 receptors to design partial agonists with graded efficacy.
|
Agonist activity at human alpha4beta2 nAChR high affinity form expressed in rat GH4C1 cells assessed as induction of peak current amplitude at holding potential of -70 mV by whole-cell patch clamp assay
|
Homo sapiens
|
400.0
nM
|
|
Journal : J. Med. Chem.
Title : Chemistry and Pharmacology of a Series of Unichiral Analogues of 2-(2-Pyrrolidinyl)-1,4-benzodioxane, Prolinol Phenyl Ether, and Prolinol 3-Pyridyl Ether Designed as α4β2-Nicotinic Acetylcholine Receptor Agonists.
Year : 2015
Volume : 58
Issue : 16
First Page : 6665
Last Page : 6677
Authors : Bolchi C, Valoti E, Gotti C, Fasoli F, Ruggeri P, Fumagalli L, Binda M, Mucchietto V, Sciaccaluga M, Budriesi R, Fucile S, Pallavicini M.
Abstract : Some unichiral analogues of 2R,2'S-2-(1'-methyl-2'-pyrrolidinyl)-7-hydroxy-1,4-benzodioxane, a potent and selective α4β2-nAChR partial agonist, were designed by opening dioxane and replacing hydroxyl carbon with nitrogen. The resulting 3-pyridyl and m-hydroxyphenyl ethers have high α4β2 affinity and good subtype selectivity, which get lost if OH is removed from phenyl or the position of pyridine nitrogen is changed. High α4β2 affinity and selectivity are also attained by meta hydroxylating the 3-pyridyl and the phenyl ethers of (S)-N-methylprolinol and the phenyl ether of (S)-2-azetidinemethanol, known α4β2 agonists, although the interaction mode of the aryloxymethylene substructure cannot be assimilated to that of benzodioxane. Indeed, the α4β2 and α3β4 functional tests well differentiate behaviors that the binding tests homologize: both the 3-hydroxyphenyl and the 5-hydroxy-3-pyridyl ether of N-methylprolinol are α4β2 full agonists, but only the latter is highly α4β2/α3β4 selective, while potent and selective partial α4β2 agonism characterizes the hydroxybenzodioxane derivative and its two opened semirigid analogues.
|
Agonist activity at human muscarinic M1 receptor expressed in CHO cells after 30 mins by GTPgamma35S binding assay
|
Homo sapiens
|
25.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of N-[6-(Substituted Aminoethylideneamino)-2-Hydroxyindan-1-yl]arylamides as selective and potent muscarinic M₁ agonists.
Year : 2015
Volume : 25
Issue : 19
First Page : 4158
Last Page : 4163
Authors : Liu B, Croy CH, Hitchcock SA, Allen JR, Rao Z, Evans D, Bures MG, McKinzie DL, Watt ML, Stuart Gregory G, Hansen MM, Hoogestraat PJ, Jamison JA, Okha-Mokube FM, Stratford RE, Turner W, Bymaster F, Felder CC.
Abstract : The observation that cholinergic deafferentation of circuits projecting from forebrain basal nuclei to frontal and hippocampal circuits occurs in Alzheimer's disease has led to drug-targeting of muscarinic M1 receptors to alleviate cognitive symptoms. The high homology within the acetylcholine binding domain of this family however has made receptor-selective ligand development challenging. This work presents the synthesis scheme, pharmacokinetic and structure-activity-relationship study findings for M1-selective ligand, LY593093. Pharmacologically the compound acts as an orthosteric ligand. The homology modeling work presented however will illustrate that compound binding spans from the acetylcholine pocket to the extracellular loops of the receptor, a common allosteric vestibule for the muscarinic protein family. Altogether LY593093 represents a growing class of multi-topic ligands which interact with the receptors in both the ortho- and allosteric binding sites, but which exert their activation mechanism as an orthosteric ligand.
|
Agonist activity at human muscarinic M2 receptor expressed in CHO cells after 30 mins by GTPgamma35S binding assay
|
Homo sapiens
|
7.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of N-[6-(Substituted Aminoethylideneamino)-2-Hydroxyindan-1-yl]arylamides as selective and potent muscarinic M₁ agonists.
Year : 2015
Volume : 25
Issue : 19
First Page : 4158
Last Page : 4163
Authors : Liu B, Croy CH, Hitchcock SA, Allen JR, Rao Z, Evans D, Bures MG, McKinzie DL, Watt ML, Stuart Gregory G, Hansen MM, Hoogestraat PJ, Jamison JA, Okha-Mokube FM, Stratford RE, Turner W, Bymaster F, Felder CC.
Abstract : The observation that cholinergic deafferentation of circuits projecting from forebrain basal nuclei to frontal and hippocampal circuits occurs in Alzheimer's disease has led to drug-targeting of muscarinic M1 receptors to alleviate cognitive symptoms. The high homology within the acetylcholine binding domain of this family however has made receptor-selective ligand development challenging. This work presents the synthesis scheme, pharmacokinetic and structure-activity-relationship study findings for M1-selective ligand, LY593093. Pharmacologically the compound acts as an orthosteric ligand. The homology modeling work presented however will illustrate that compound binding spans from the acetylcholine pocket to the extracellular loops of the receptor, a common allosteric vestibule for the muscarinic protein family. Altogether LY593093 represents a growing class of multi-topic ligands which interact with the receptors in both the ortho- and allosteric binding sites, but which exert their activation mechanism as an orthosteric ligand.
|
Agonist activity at human muscarinic M3 receptor expressed in CHO cells after 30 mins by GTPgamma35S binding assay
|
Homo sapiens
|
205.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of N-[6-(Substituted Aminoethylideneamino)-2-Hydroxyindan-1-yl]arylamides as selective and potent muscarinic M₁ agonists.
Year : 2015
Volume : 25
Issue : 19
First Page : 4158
Last Page : 4163
Authors : Liu B, Croy CH, Hitchcock SA, Allen JR, Rao Z, Evans D, Bures MG, McKinzie DL, Watt ML, Stuart Gregory G, Hansen MM, Hoogestraat PJ, Jamison JA, Okha-Mokube FM, Stratford RE, Turner W, Bymaster F, Felder CC.
Abstract : The observation that cholinergic deafferentation of circuits projecting from forebrain basal nuclei to frontal and hippocampal circuits occurs in Alzheimer's disease has led to drug-targeting of muscarinic M1 receptors to alleviate cognitive symptoms. The high homology within the acetylcholine binding domain of this family however has made receptor-selective ligand development challenging. This work presents the synthesis scheme, pharmacokinetic and structure-activity-relationship study findings for M1-selective ligand, LY593093. Pharmacologically the compound acts as an orthosteric ligand. The homology modeling work presented however will illustrate that compound binding spans from the acetylcholine pocket to the extracellular loops of the receptor, a common allosteric vestibule for the muscarinic protein family. Altogether LY593093 represents a growing class of multi-topic ligands which interact with the receptors in both the ortho- and allosteric binding sites, but which exert their activation mechanism as an orthosteric ligand.
|
Agonist activity at human muscarinic M4 receptor expressed in CHO cells after 30 mins by GTPgamma35S binding assay
|
Homo sapiens
|
48.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of N-[6-(Substituted Aminoethylideneamino)-2-Hydroxyindan-1-yl]arylamides as selective and potent muscarinic M₁ agonists.
Year : 2015
Volume : 25
Issue : 19
First Page : 4158
Last Page : 4163
Authors : Liu B, Croy CH, Hitchcock SA, Allen JR, Rao Z, Evans D, Bures MG, McKinzie DL, Watt ML, Stuart Gregory G, Hansen MM, Hoogestraat PJ, Jamison JA, Okha-Mokube FM, Stratford RE, Turner W, Bymaster F, Felder CC.
Abstract : The observation that cholinergic deafferentation of circuits projecting from forebrain basal nuclei to frontal and hippocampal circuits occurs in Alzheimer's disease has led to drug-targeting of muscarinic M1 receptors to alleviate cognitive symptoms. The high homology within the acetylcholine binding domain of this family however has made receptor-selective ligand development challenging. This work presents the synthesis scheme, pharmacokinetic and structure-activity-relationship study findings for M1-selective ligand, LY593093. Pharmacologically the compound acts as an orthosteric ligand. The homology modeling work presented however will illustrate that compound binding spans from the acetylcholine pocket to the extracellular loops of the receptor, a common allosteric vestibule for the muscarinic protein family. Altogether LY593093 represents a growing class of multi-topic ligands which interact with the receptors in both the ortho- and allosteric binding sites, but which exert their activation mechanism as an orthosteric ligand.
|
Agonist activity at human muscarinic M5 receptor expressed in CHO cells after 30 mins by GTPgamma35S binding assay
|
Homo sapiens
|
19.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of N-[6-(Substituted Aminoethylideneamino)-2-Hydroxyindan-1-yl]arylamides as selective and potent muscarinic M₁ agonists.
Year : 2015
Volume : 25
Issue : 19
First Page : 4158
Last Page : 4163
Authors : Liu B, Croy CH, Hitchcock SA, Allen JR, Rao Z, Evans D, Bures MG, McKinzie DL, Watt ML, Stuart Gregory G, Hansen MM, Hoogestraat PJ, Jamison JA, Okha-Mokube FM, Stratford RE, Turner W, Bymaster F, Felder CC.
Abstract : The observation that cholinergic deafferentation of circuits projecting from forebrain basal nuclei to frontal and hippocampal circuits occurs in Alzheimer's disease has led to drug-targeting of muscarinic M1 receptors to alleviate cognitive symptoms. The high homology within the acetylcholine binding domain of this family however has made receptor-selective ligand development challenging. This work presents the synthesis scheme, pharmacokinetic and structure-activity-relationship study findings for M1-selective ligand, LY593093. Pharmacologically the compound acts as an orthosteric ligand. The homology modeling work presented however will illustrate that compound binding spans from the acetylcholine pocket to the extracellular loops of the receptor, a common allosteric vestibule for the muscarinic protein family. Altogether LY593093 represents a growing class of multi-topic ligands which interact with the receptors in both the ortho- and allosteric binding sites, but which exert their activation mechanism as an orthosteric ligand.
|
Displacement of [3H]epibatidine from rat alpha4beta2 nAChR expressed in HEK293 cells after 4 hrs by scintillation counting assay
|
Rattus norvegicus
|
33.0
nM
|
|
Displacement of [3H]epibatidine from rat alpha4beta2 nAChR expressed in HEK293 cells after 4 hrs by scintillation counting assay
|
Rattus norvegicus
|
33.11
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Exploration of the molecular architecture of the orthosteric binding site in the α4β2 nicotinic acetylcholine receptor with analogs of 3-(dimethylamino)butyl dimethylcarbamate (DMABC) and 1-(pyridin-3-yl)-1,4-diazepane.
Year : 2015
Volume : 102
First Page : 425
Last Page : 444
Authors : Bach TB, Jensen AA, Petersen JG, Sørensen TE, Della Volpe S, Liu J, Blaazer AR, van Muijlwijk-Koezen JE, Balle T, Frølund B.
Abstract : X-ray crystal structures of acetylcholine binding proteins (AChBPs) have revealed two different possible extensions to the classical ligand binding pocket known to accommodate various nicotinic agonists. One of the pockets is limited in size while the other is of considerable dimensions and protrudes along the interfacial cleft between subunits. To probe these putative extensions in functional nicotinic acetylcholine receptors (nAChRs), elongated analogs of 3-(dimethylamino)butyl dimethylcarbamate (DMABC) and 1-(pyridine-3-yl)-1,4-diazepane were prepared and characterized pharmacologically at neuronal heteromeric nAChRs. Although the new analogs, relative to parent compounds, displayed lower binding affinities, functional characterization of selected compounds revealed that they had retained partial α4β2 nAChR agonist activity. The structure-activity relationship data did not indicate an upper limit to the size of substituents as would have been expected if the ligand was bound in the smaller pocket. The data were better in agreement with a binding mode in which substituents protrude along the interfacial cleft of the receptor. This was further supported by docking into a homology model of the α4-β2 nAChR interface and by surface plasmon resonance biosensor analysis of binding of the compounds to acetylcholine-binding proteins, where they exhibit preference for Lymnaea stagnalis ACh binding protein (Ls-AChBP) over the Aplysia california ACh binding protein (Ac-AChBP). These results suggest new opportunities for expanding chemical space in the development of partial agonist and may be of interest in relation to development of novel smoking cessation aids.
|
Displacement of [3H]epibatidine from rat alpha4beta4 nACHR expressed in HEK293 cells after 4 hrs by scintillation counting assay
|
Rattus norvegicus
|
58.0
nM
|
|
Displacement of [3H]epibatidine from rat alpha4beta4 nACHR expressed in HEK293 cells after 4 hrs by scintillation counting assay
|
Rattus norvegicus
|
57.54
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Exploration of the molecular architecture of the orthosteric binding site in the α4β2 nicotinic acetylcholine receptor with analogs of 3-(dimethylamino)butyl dimethylcarbamate (DMABC) and 1-(pyridin-3-yl)-1,4-diazepane.
Year : 2015
Volume : 102
First Page : 425
Last Page : 444
Authors : Bach TB, Jensen AA, Petersen JG, Sørensen TE, Della Volpe S, Liu J, Blaazer AR, van Muijlwijk-Koezen JE, Balle T, Frølund B.
Abstract : X-ray crystal structures of acetylcholine binding proteins (AChBPs) have revealed two different possible extensions to the classical ligand binding pocket known to accommodate various nicotinic agonists. One of the pockets is limited in size while the other is of considerable dimensions and protrudes along the interfacial cleft between subunits. To probe these putative extensions in functional nicotinic acetylcholine receptors (nAChRs), elongated analogs of 3-(dimethylamino)butyl dimethylcarbamate (DMABC) and 1-(pyridine-3-yl)-1,4-diazepane were prepared and characterized pharmacologically at neuronal heteromeric nAChRs. Although the new analogs, relative to parent compounds, displayed lower binding affinities, functional characterization of selected compounds revealed that they had retained partial α4β2 nAChR agonist activity. The structure-activity relationship data did not indicate an upper limit to the size of substituents as would have been expected if the ligand was bound in the smaller pocket. The data were better in agreement with a binding mode in which substituents protrude along the interfacial cleft of the receptor. This was further supported by docking into a homology model of the α4-β2 nAChR interface and by surface plasmon resonance biosensor analysis of binding of the compounds to acetylcholine-binding proteins, where they exhibit preference for Lymnaea stagnalis ACh binding protein (Ls-AChBP) over the Aplysia california ACh binding protein (Ac-AChBP). These results suggest new opportunities for expanding chemical space in the development of partial agonist and may be of interest in relation to development of novel smoking cessation aids.
|
Displacement of [3H]epibatidine from rat alpha3beta4 nACHR expressed in HEK293 cells after 4 hrs by scintillation counting assay
|
Rattus norvegicus
|
620.0
nM
|
|
Displacement of [3H]epibatidine from rat alpha3beta4 nACHR expressed in HEK293 cells after 4 hrs by scintillation counting assay
|
Rattus norvegicus
|
616.6
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Exploration of the molecular architecture of the orthosteric binding site in the α4β2 nicotinic acetylcholine receptor with analogs of 3-(dimethylamino)butyl dimethylcarbamate (DMABC) and 1-(pyridin-3-yl)-1,4-diazepane.
Year : 2015
Volume : 102
First Page : 425
Last Page : 444
Authors : Bach TB, Jensen AA, Petersen JG, Sørensen TE, Della Volpe S, Liu J, Blaazer AR, van Muijlwijk-Koezen JE, Balle T, Frølund B.
Abstract : X-ray crystal structures of acetylcholine binding proteins (AChBPs) have revealed two different possible extensions to the classical ligand binding pocket known to accommodate various nicotinic agonists. One of the pockets is limited in size while the other is of considerable dimensions and protrudes along the interfacial cleft between subunits. To probe these putative extensions in functional nicotinic acetylcholine receptors (nAChRs), elongated analogs of 3-(dimethylamino)butyl dimethylcarbamate (DMABC) and 1-(pyridine-3-yl)-1,4-diazepane were prepared and characterized pharmacologically at neuronal heteromeric nAChRs. Although the new analogs, relative to parent compounds, displayed lower binding affinities, functional characterization of selected compounds revealed that they had retained partial α4β2 nAChR agonist activity. The structure-activity relationship data did not indicate an upper limit to the size of substituents as would have been expected if the ligand was bound in the smaller pocket. The data were better in agreement with a binding mode in which substituents protrude along the interfacial cleft of the receptor. This was further supported by docking into a homology model of the α4-β2 nAChR interface and by surface plasmon resonance biosensor analysis of binding of the compounds to acetylcholine-binding proteins, where they exhibit preference for Lymnaea stagnalis ACh binding protein (Ls-AChBP) over the Aplysia california ACh binding protein (Ac-AChBP). These results suggest new opportunities for expanding chemical space in the development of partial agonist and may be of interest in relation to development of novel smoking cessation aids.
|
Displacement of [3H]N-methyl-scopolamine bromide from human recombinant muscarinic M2 receptor expressed in HEK293T cell membranes after 1 hr by liquid scintillation counting method
|
Homo sapiens
|
390.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Design and Discovery of New M2 Receptor Agonists.
Year : 2017
Volume : 60
Issue : 22
First Page : 9239
Last Page : 9250
Authors : Fish I, Stößel A, Eitel K, Valant C, Albold S, Huebner H, Möller D, Clark MJ, Sunahara RK, Christopoulos A, Shoichet BK, Gmeiner P.
Abstract : Muscarinic receptor agonists are characterized by apparently strict restraints on their tertiary or quaternary amine and their distance to an ester or related center. On the basis of the active state crystal structure of the muscarinic M2 receptor in complex with iperoxo, we explored potential agonists that lacked the highly conserved functionalities of previously known ligands. Using structure-guided pharmacophore design followed by docking, we found two agonists (compounds 3 and 17), out of 19 docked and synthesized compounds, that fit the receptor well and were predicted to form a hydrogen-bond conserved among known agonists. Structural optimization led to compound 28, which was 4-fold more potent than its parent 3. Fortified by the discovery of this new scaffold, we sought a broader range of chemotypes by docking 2.2 million fragments, which revealed another three micromolar agonists unrelated either to 28 or known muscarinics. Even pockets as tightly defined and as deeply studied as that of the muscarinic reveal opportunities for the structure-based design and the discovery of new chemotypes.
|
Agonist activity at human recombinant muscarinic M2 receptor co-expressed with Galphaqi5-HA in African green monkey COS7 cells assessed as IP accumulation after 2 hrs in presence of myo-[3H]inositol by liquid scintillation counting method
|
Homo sapiens
|
56.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Design and Discovery of New M2 Receptor Agonists.
Year : 2017
Volume : 60
Issue : 22
First Page : 9239
Last Page : 9250
Authors : Fish I, Stößel A, Eitel K, Valant C, Albold S, Huebner H, Möller D, Clark MJ, Sunahara RK, Christopoulos A, Shoichet BK, Gmeiner P.
Abstract : Muscarinic receptor agonists are characterized by apparently strict restraints on their tertiary or quaternary amine and their distance to an ester or related center. On the basis of the active state crystal structure of the muscarinic M2 receptor in complex with iperoxo, we explored potential agonists that lacked the highly conserved functionalities of previously known ligands. Using structure-guided pharmacophore design followed by docking, we found two agonists (compounds 3 and 17), out of 19 docked and synthesized compounds, that fit the receptor well and were predicted to form a hydrogen-bond conserved among known agonists. Structural optimization led to compound 28, which was 4-fold more potent than its parent 3. Fortified by the discovery of this new scaffold, we sought a broader range of chemotypes by docking 2.2 million fragments, which revealed another three micromolar agonists unrelated either to 28 or known muscarinics. Even pockets as tightly defined and as deeply studied as that of the muscarinic reveal opportunities for the structure-based design and the discovery of new chemotypes.
|
Displacement of [3H]N-methyl-scopolamine from human recombinant muscarinic M2 receptor expressed in CHO-FlpIn cells after 6 hrs by liquid scintillation counting method
|
Homo sapiens
|
380.19
nM
|
|
Displacement of [3H]N-methyl-scopolamine from human recombinant muscarinic M2 receptor expressed in CHO-FlpIn cells after 6 hrs by liquid scintillation counting method
|
Homo sapiens
|
380.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Design and Discovery of New M2 Receptor Agonists.
Year : 2017
Volume : 60
Issue : 22
First Page : 9239
Last Page : 9250
Authors : Fish I, Stößel A, Eitel K, Valant C, Albold S, Huebner H, Möller D, Clark MJ, Sunahara RK, Christopoulos A, Shoichet BK, Gmeiner P.
Abstract : Muscarinic receptor agonists are characterized by apparently strict restraints on their tertiary or quaternary amine and their distance to an ester or related center. On the basis of the active state crystal structure of the muscarinic M2 receptor in complex with iperoxo, we explored potential agonists that lacked the highly conserved functionalities of previously known ligands. Using structure-guided pharmacophore design followed by docking, we found two agonists (compounds 3 and 17), out of 19 docked and synthesized compounds, that fit the receptor well and were predicted to form a hydrogen-bond conserved among known agonists. Structural optimization led to compound 28, which was 4-fold more potent than its parent 3. Fortified by the discovery of this new scaffold, we sought a broader range of chemotypes by docking 2.2 million fragments, which revealed another three micromolar agonists unrelated either to 28 or known muscarinics. Even pockets as tightly defined and as deeply studied as that of the muscarinic reveal opportunities for the structure-based design and the discovery of new chemotypes.
|
Agonist activity at Gq/11 coupled recombinant human muscarinic M1 AChR expressed in CHO-FlpIn cells assessed as IP-one accumulation after 40 mins by HTRF assay
|
Homo sapiens
|
616.6
nM
|
|
Agonist activity at Gq/11 coupled recombinant human muscarinic M1 AChR expressed in CHO-FlpIn cells assessed as IP-one accumulation after 40 mins by HTRF assay
|
Homo sapiens
|
620.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Design and Discovery of New M2 Receptor Agonists.
Year : 2017
Volume : 60
Issue : 22
First Page : 9239
Last Page : 9250
Authors : Fish I, Stößel A, Eitel K, Valant C, Albold S, Huebner H, Möller D, Clark MJ, Sunahara RK, Christopoulos A, Shoichet BK, Gmeiner P.
Abstract : Muscarinic receptor agonists are characterized by apparently strict restraints on their tertiary or quaternary amine and their distance to an ester or related center. On the basis of the active state crystal structure of the muscarinic M2 receptor in complex with iperoxo, we explored potential agonists that lacked the highly conserved functionalities of previously known ligands. Using structure-guided pharmacophore design followed by docking, we found two agonists (compounds 3 and 17), out of 19 docked and synthesized compounds, that fit the receptor well and were predicted to form a hydrogen-bond conserved among known agonists. Structural optimization led to compound 28, which was 4-fold more potent than its parent 3. Fortified by the discovery of this new scaffold, we sought a broader range of chemotypes by docking 2.2 million fragments, which revealed another three micromolar agonists unrelated either to 28 or known muscarinics. Even pockets as tightly defined and as deeply studied as that of the muscarinic reveal opportunities for the structure-based design and the discovery of new chemotypes.
|
Agonist activity at Gq/11 coupled recombinant human muscarinic M3 AChR expressed in CHO-FlpIn cells assessed as IP-one accumulation after 40 mins by HTRF assay
|
Homo sapiens
|
239.88
nM
|
|
Agonist activity at Gq/11 coupled recombinant human muscarinic M3 AChR expressed in CHO-FlpIn cells assessed as IP-one accumulation after 40 mins by HTRF assay
|
Homo sapiens
|
240.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Design and Discovery of New M2 Receptor Agonists.
Year : 2017
Volume : 60
Issue : 22
First Page : 9239
Last Page : 9250
Authors : Fish I, Stößel A, Eitel K, Valant C, Albold S, Huebner H, Möller D, Clark MJ, Sunahara RK, Christopoulos A, Shoichet BK, Gmeiner P.
Abstract : Muscarinic receptor agonists are characterized by apparently strict restraints on their tertiary or quaternary amine and their distance to an ester or related center. On the basis of the active state crystal structure of the muscarinic M2 receptor in complex with iperoxo, we explored potential agonists that lacked the highly conserved functionalities of previously known ligands. Using structure-guided pharmacophore design followed by docking, we found two agonists (compounds 3 and 17), out of 19 docked and synthesized compounds, that fit the receptor well and were predicted to form a hydrogen-bond conserved among known agonists. Structural optimization led to compound 28, which was 4-fold more potent than its parent 3. Fortified by the discovery of this new scaffold, we sought a broader range of chemotypes by docking 2.2 million fragments, which revealed another three micromolar agonists unrelated either to 28 or known muscarinics. Even pockets as tightly defined and as deeply studied as that of the muscarinic reveal opportunities for the structure-based design and the discovery of new chemotypes.
|
Agonist activity at Gi/o protein-coupled recombinant human muscarinic M2 receptor expressed in CHO-FlpIn cells preincubated for 60 mins followed by [35S]GTPgammaS addition measured after 30 mins by liquid scintillation counting method
|
Homo sapiens
|
512.86
nM
|
|
Agonist activity at Gi/o protein-coupled recombinant human muscarinic M2 receptor expressed in CHO-FlpIn cells preincubated for 60 mins followed by [35S]GTPgammaS addition measured after 30 mins by liquid scintillation counting method
|
Homo sapiens
|
510.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Design and Discovery of New M2 Receptor Agonists.
Year : 2017
Volume : 60
Issue : 22
First Page : 9239
Last Page : 9250
Authors : Fish I, Stößel A, Eitel K, Valant C, Albold S, Huebner H, Möller D, Clark MJ, Sunahara RK, Christopoulos A, Shoichet BK, Gmeiner P.
Abstract : Muscarinic receptor agonists are characterized by apparently strict restraints on their tertiary or quaternary amine and their distance to an ester or related center. On the basis of the active state crystal structure of the muscarinic M2 receptor in complex with iperoxo, we explored potential agonists that lacked the highly conserved functionalities of previously known ligands. Using structure-guided pharmacophore design followed by docking, we found two agonists (compounds 3 and 17), out of 19 docked and synthesized compounds, that fit the receptor well and were predicted to form a hydrogen-bond conserved among known agonists. Structural optimization led to compound 28, which was 4-fold more potent than its parent 3. Fortified by the discovery of this new scaffold, we sought a broader range of chemotypes by docking 2.2 million fragments, which revealed another three micromolar agonists unrelated either to 28 or known muscarinics. Even pockets as tightly defined and as deeply studied as that of the muscarinic reveal opportunities for the structure-based design and the discovery of new chemotypes.
|
Agonist activity at recombinant human muscarinic M2 receptor expressed in HEK293 cells assessed as inhibition of forskolin-mediated cAMP accumulation after 10 mins by FRET assay
|
Homo sapiens
|
48.98
nM
|
|
Agonist activity at recombinant human muscarinic M2 receptor expressed in HEK293 cells assessed as inhibition of forskolin-mediated cAMP accumulation after 10 mins by FRET assay
|
Homo sapiens
|
49.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Design and Discovery of New M2 Receptor Agonists.
Year : 2017
Volume : 60
Issue : 22
First Page : 9239
Last Page : 9250
Authors : Fish I, Stößel A, Eitel K, Valant C, Albold S, Huebner H, Möller D, Clark MJ, Sunahara RK, Christopoulos A, Shoichet BK, Gmeiner P.
Abstract : Muscarinic receptor agonists are characterized by apparently strict restraints on their tertiary or quaternary amine and their distance to an ester or related center. On the basis of the active state crystal structure of the muscarinic M2 receptor in complex with iperoxo, we explored potential agonists that lacked the highly conserved functionalities of previously known ligands. Using structure-guided pharmacophore design followed by docking, we found two agonists (compounds 3 and 17), out of 19 docked and synthesized compounds, that fit the receptor well and were predicted to form a hydrogen-bond conserved among known agonists. Structural optimization led to compound 28, which was 4-fold more potent than its parent 3. Fortified by the discovery of this new scaffold, we sought a broader range of chemotypes by docking 2.2 million fragments, which revealed another three micromolar agonists unrelated either to 28 or known muscarinics. Even pockets as tightly defined and as deeply studied as that of the muscarinic reveal opportunities for the structure-based design and the discovery of new chemotypes.
|
Agonist activity at recombinant human muscarinic M1 receptor expressed in CHO cells assessed as upregulation in ERK1/2 phosphorylation after 5 mins by alphascreen assay
|
Homo sapiens
|
46.77
nM
|
|
Agonist activity at recombinant human muscarinic M1 receptor expressed in CHO cells assessed as upregulation in ERK1/2 phosphorylation after 5 mins by alphascreen assay
|
Homo sapiens
|
47.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Design and Discovery of New M2 Receptor Agonists.
Year : 2017
Volume : 60
Issue : 22
First Page : 9239
Last Page : 9250
Authors : Fish I, Stößel A, Eitel K, Valant C, Albold S, Huebner H, Möller D, Clark MJ, Sunahara RK, Christopoulos A, Shoichet BK, Gmeiner P.
Abstract : Muscarinic receptor agonists are characterized by apparently strict restraints on their tertiary or quaternary amine and their distance to an ester or related center. On the basis of the active state crystal structure of the muscarinic M2 receptor in complex with iperoxo, we explored potential agonists that lacked the highly conserved functionalities of previously known ligands. Using structure-guided pharmacophore design followed by docking, we found two agonists (compounds 3 and 17), out of 19 docked and synthesized compounds, that fit the receptor well and were predicted to form a hydrogen-bond conserved among known agonists. Structural optimization led to compound 28, which was 4-fold more potent than its parent 3. Fortified by the discovery of this new scaffold, we sought a broader range of chemotypes by docking 2.2 million fragments, which revealed another three micromolar agonists unrelated either to 28 or known muscarinics. Even pockets as tightly defined and as deeply studied as that of the muscarinic reveal opportunities for the structure-based design and the discovery of new chemotypes.
|
Agonist activity at recombinant human muscarinic M2 receptor expressed in CHO cells assessed as upregulation in ERK1/2 phosphorylation after 5 mins by alphascreen assay
|
Homo sapiens
|
12.59
nM
|
|
Agonist activity at recombinant human muscarinic M2 receptor expressed in CHO cells assessed as upregulation in ERK1/2 phosphorylation after 5 mins by alphascreen assay
|
Homo sapiens
|
13.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Design and Discovery of New M2 Receptor Agonists.
Year : 2017
Volume : 60
Issue : 22
First Page : 9239
Last Page : 9250
Authors : Fish I, Stößel A, Eitel K, Valant C, Albold S, Huebner H, Möller D, Clark MJ, Sunahara RK, Christopoulos A, Shoichet BK, Gmeiner P.
Abstract : Muscarinic receptor agonists are characterized by apparently strict restraints on their tertiary or quaternary amine and their distance to an ester or related center. On the basis of the active state crystal structure of the muscarinic M2 receptor in complex with iperoxo, we explored potential agonists that lacked the highly conserved functionalities of previously known ligands. Using structure-guided pharmacophore design followed by docking, we found two agonists (compounds 3 and 17), out of 19 docked and synthesized compounds, that fit the receptor well and were predicted to form a hydrogen-bond conserved among known agonists. Structural optimization led to compound 28, which was 4-fold more potent than its parent 3. Fortified by the discovery of this new scaffold, we sought a broader range of chemotypes by docking 2.2 million fragments, which revealed another three micromolar agonists unrelated either to 28 or known muscarinics. Even pockets as tightly defined and as deeply studied as that of the muscarinic reveal opportunities for the structure-based design and the discovery of new chemotypes.
|
Agonist activity at recombinant human muscarinic M3 receptor expressed in CHO cells assessed as upregulation in ERK1/2 phosphorylation after 5 mins by alphascreen assay
|
Homo sapiens
|
22.91
nM
|
|
Agonist activity at recombinant human muscarinic M3 receptor expressed in CHO cells assessed as upregulation in ERK1/2 phosphorylation after 5 mins by alphascreen assay
|
Homo sapiens
|
23.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Design and Discovery of New M2 Receptor Agonists.
Year : 2017
Volume : 60
Issue : 22
First Page : 9239
Last Page : 9250
Authors : Fish I, Stößel A, Eitel K, Valant C, Albold S, Huebner H, Möller D, Clark MJ, Sunahara RK, Christopoulos A, Shoichet BK, Gmeiner P.
Abstract : Muscarinic receptor agonists are characterized by apparently strict restraints on their tertiary or quaternary amine and their distance to an ester or related center. On the basis of the active state crystal structure of the muscarinic M2 receptor in complex with iperoxo, we explored potential agonists that lacked the highly conserved functionalities of previously known ligands. Using structure-guided pharmacophore design followed by docking, we found two agonists (compounds 3 and 17), out of 19 docked and synthesized compounds, that fit the receptor well and were predicted to form a hydrogen-bond conserved among known agonists. Structural optimization led to compound 28, which was 4-fold more potent than its parent 3. Fortified by the discovery of this new scaffold, we sought a broader range of chemotypes by docking 2.2 million fragments, which revealed another three micromolar agonists unrelated either to 28 or known muscarinics. Even pockets as tightly defined and as deeply studied as that of the muscarinic reveal opportunities for the structure-based design and the discovery of new chemotypes.
|
Agonist activity at human Muscarinic acetylcholine receptor M4 expressed in HEK cells co-expressing Glosensor construct assessed as decrease in isoproterenol-induced cAMP accumulation incubated for 7 mins in presence of isoproterenol by Glosensor cAMP reagent/plate reader based luminescence assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of Selective M4 Muscarinic Acetylcholine Receptor Agonists with Novel Carbamate Isosteres.
Year : 2019
Volume : 10
Issue : 6
First Page : 941
Last Page : 948
Authors : Yang Q, Lachapelle EA, Kablaoui NM, Webb D, Popiolek M, Grimwood S, Kozak R, O'Connor RE, Lazzaro JT, Butler CR, Zhang L.
Abstract : It has been hypothesized that selective muscarinic acetylcholine receptor (mAChR) M4 subtype activation could provide therapeutic benefits to a number of neurological disorders while minimizing unwanted cholinergic side effects observed due to nonselective mAChR activation. Given the high sequence and structural homology of the orthosteric binding sites among mAChRs, achieving M4 subtype-selective activation has been challenging. Herein, we describe the discovery of a series of M4 subtype-selective agonists bearing novel carbamate isosteres. Comparison of the isosteres' electrostatic potential isosurface sheds light on key structural features for M4 subtype-selective activation. The identified key features were further illustrated in a proposed receptor-agonist interaction mode.
|
Positive allosteric modulatory activity at human Muscarinic acetylcholine receptor M4 expressed in HEK cells co-expressing Glosensor construct assessed as as increase in acteylcholine-induced cAMP accumulation incubated for 7 mins in presence of isoproterenol/acetylcholine by Glosensor cAMP reagent/plate reader based luminescence assay
|
Homo sapiens
|
57.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of Selective M4 Muscarinic Acetylcholine Receptor Agonists with Novel Carbamate Isosteres.
Year : 2019
Volume : 10
Issue : 6
First Page : 941
Last Page : 948
Authors : Yang Q, Lachapelle EA, Kablaoui NM, Webb D, Popiolek M, Grimwood S, Kozak R, O'Connor RE, Lazzaro JT, Butler CR, Zhang L.
Abstract : It has been hypothesized that selective muscarinic acetylcholine receptor (mAChR) M4 subtype activation could provide therapeutic benefits to a number of neurological disorders while minimizing unwanted cholinergic side effects observed due to nonselective mAChR activation. Given the high sequence and structural homology of the orthosteric binding sites among mAChRs, achieving M4 subtype-selective activation has been challenging. Herein, we describe the discovery of a series of M4 subtype-selective agonists bearing novel carbamate isosteres. Comparison of the isosteres' electrostatic potential isosurface sheds light on key structural features for M4 subtype-selective activation. The identified key features were further illustrated in a proposed receptor-agonist interaction mode.
|
Agonist activity at human muscarinic M1 receptor expressed in HEK293T cells co-expressing Galpha subunit and PLC-beta3 by split luciferase complementation assay
|
Homo sapiens
|
134.9
nM
|
|
Journal : J Med Chem
Title : Fluorination of Photoswitchable Muscarinic Agonists Tunes Receptor Pharmacology and Photochromic Properties.
Year : 2019
Volume : 62
Issue : 6
First Page : 3009
Last Page : 3020
Authors : Agnetta L, Bermudez M, Riefolo F, Matera C, Claro E, Messerer R, Littmann T, Wolber G, Holzgrabe U, Decker M.
Abstract : Red-shifted azobenzene scaffolds have emerged as useful molecular photoswitches to expand potential applications of photopharmacological tool compounds. As one of them, tetra- ortho-fluoro azobenzene is well compatible for the design of visible-light-responsive systems, providing stable and bidirectional photoconversions and tissue-compatible characteristics. Using the unsubstituted azobenzene core and its tetra- ortho-fluorinated analogue, we have developed a set of uni- and bivalent photoswitchable toolbox derivatives of the highly potent muscarinic acetylcholine receptor agonist iperoxo. We investigated the impact of the substitution pattern on receptor activity and evaluated the different binding modes. Compounds 9b and 15b show excellent photochemical properties and biological activity as fluorination of the azobenzene core alters not only the photochromic behavior but also the pharmacological profile at the muscarinic M1 receptor. These findings demonstrate that incorporation of fluorinated azobenzenes not just may alter photophysical properties but can exhibit a considerably different biological profile that has to be carefully investigated.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
17.96
%
|
|
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
|
-0.28
%
|
|
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
|
-0.28
%
|
|
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.
