|
Functional activity against melatonin receptor in lightening Xenopus laevis tadpole skin
|
None
|
10.1
nM
|
|
Journal : J. Med. Chem.
Title : Melatonergic properties of the (+)- and (-)-enantiomers of N-(4-methoxy-2,3-dihydro-1H-phenalen-2-yl)amide derivatives.
Year : 1999
Volume : 42
Issue : 6
First Page : 1100
Last Page : 1105
Authors : Jellimann C, Mathé-Allainmat M, Andrieux J, Renard P, Delagrange P, Langlois M.
Abstract : N-(4-Methoxy-2,3-dihydro-1H-phenalen-2-yl)amide derivatives, conformationally restricted ligands for melatonin receptors, were synthesized by an alternative synthetic method from the corresponding 1,8-naphthalic anhydride which was transformed into the phenalenecarboxylic acid 7. A Curtius reaction on 7 gave the amino compound which was acylated to give compounds 4a-c. The (+)- and (-)-4a-c enantiomers were separated by semipreparative chiral HPLC. Compounds were evaluated for their affinity for chicken brain melatonin receptors in binding assays using 2-[125I]iodomelatonin and for their potency to lighten the skin of Xenopus laevis tadpoles. The butyramido derivative 4c was the most potent ligand (Ki = 1.7 nM). No enantioselectivity was observed with the enantiomers which were equipotent to the racemic mixture. In contrast to the reference compounds, melatonin, agomelatine (S 20098), and N-[2-(2, 7-dimethoxynaphth-1-yl)ethyl]acetamide, which were very potent at lightening the skin of X. laevis tadpoles, compounds 4a-c were inactive or weakly active (EC50 > 1 microM). In this bioassay, compound 4a was characterized as a putative antagonist of melatonin receptors.
|
Inhibition of 2-[125I]- iodomelatonin from chicken brain melatonin receptors
|
Gallus gallus
|
0.54
nM
|
|
Journal : J. Med. Chem.
Title : Melatonergic properties of the (+)- and (-)-enantiomers of N-(4-methoxy-2,3-dihydro-1H-phenalen-2-yl)amide derivatives.
Year : 1999
Volume : 42
Issue : 6
First Page : 1100
Last Page : 1105
Authors : Jellimann C, Mathé-Allainmat M, Andrieux J, Renard P, Delagrange P, Langlois M.
Abstract : N-(4-Methoxy-2,3-dihydro-1H-phenalen-2-yl)amide derivatives, conformationally restricted ligands for melatonin receptors, were synthesized by an alternative synthetic method from the corresponding 1,8-naphthalic anhydride which was transformed into the phenalenecarboxylic acid 7. A Curtius reaction on 7 gave the amino compound which was acylated to give compounds 4a-c. The (+)- and (-)-4a-c enantiomers were separated by semipreparative chiral HPLC. Compounds were evaluated for their affinity for chicken brain melatonin receptors in binding assays using 2-[125I]iodomelatonin and for their potency to lighten the skin of Xenopus laevis tadpoles. The butyramido derivative 4c was the most potent ligand (Ki = 1.7 nM). No enantioselectivity was observed with the enantiomers which were equipotent to the racemic mixture. In contrast to the reference compounds, melatonin, agomelatine (S 20098), and N-[2-(2, 7-dimethoxynaphth-1-yl)ethyl]acetamide, which were very potent at lightening the skin of X. laevis tadpoles, compounds 4a-c were inactive or weakly active (EC50 > 1 microM). In this bioassay, compound 4a was characterized as a putative antagonist of melatonin receptors.
|
Competitive binding by the displacement of 2-[125I]- Iodomelatonin binding from melatonin receptors in chicken brain membranes
|
None
|
0.54
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of new naphthalenic derivatives as ligands for 2-[125I]iodomelatonin binding sites.
Year : 1995
Volume : 38
Issue : 12
First Page : 2050
Last Page : 2060
Authors : Langlois M, Brémont B, Shen S, Poncet A, Andrieux J, Sicsic S, Serraz I, Mathé-Allainmat M, Renard P, Delagrange P.
Abstract : New melatonin-like agents were designed from the frameworks of 2,5-dimethoxyphenethylamine, an important structural moiety for the 5-HT receptor, and (2-methoxynaphthyl)-ethylamine. The compounds were synthesized by classical methods and evaluated in binding assays with chicken brain membranes using 2-[125I]iodomelatonin as the radioligand. Preliminary studies on the series of N-acyl-disubstituted phenethylamines showed the favorable role of the methoxy group in the ortho position of the side chain on the affinity for the receptor (Ki = 8 +/- 0.2 nM) for N-[2-(2-methoxy-5-bromophenyl)ethyl]propionamide (3o). This effect was confirmed in a series of the naphthalene derivatives, a bioisosteric moiety of the indole ring, and several potent ligands for melatonin binding sites were prepared such as N-[2-(2-methoxynaphthyl)ethyl]propionamide (4b) (Ki = 0.67 +/- 0.05 nM) and N-[2-(2,7-dimethoxynaphthyl)ethyl]cyclopropylformamide (Ki = 0.05 +/- 0.004 nM) (4k). Structure-activity relationships are discussed with regard to melatonin and bioisosteric naphthalenic compound 2. The Ki value for 4b was affected to a similar extent to that of melatonin by GTP-gamma-S or Mn2+ in competition experiments, suggesting an agonist profile for this compound.
|
Binding affinity against chicken brain melatonin receptors using 2-[125I]iodomelatonin as radioligand
|
None
|
0.537
nM
|
|
Journal : J. Med. Chem.
Title : Three-dimensional quantitative structure-activity relationship of melatonin receptor ligands: a comparative molecular field analysis study.
Year : 1997
Volume : 40
Issue : 5
First Page : 739
Last Page : 748
Authors : Sicsic S, Serraz I, Andrieux J, Brémont B, Mathé-Allainmat M, Poncet A, Shen S, Langlois M.
Abstract : A three-dimensional quantitative structure-activity relationship using the comparative molecular field analysis (CoMFA) paradigm applied to 57 melatonin receptor ligands belonging to diverse structural families was performed. The compounds studied which have been synthesized previously and reported to be active at chicken brain melatonin receptors were divided into a training set of 48 molecules and a test set of 9 molecules. As most of these compounds have a highly flexible ethylamido side chain, the alignments were based on the most sterically constrained molecule which contains a tricyclic phenalene structure. This tricyclic compound can adopt an axial and an equatorial conformation. Two different molecular superpositions representing possible positioning within the receptor site have been suggested previously. CoMFA was tentatively used to discriminate between alternate hypothetical biologically active conformation and between possible positionings. The best 3D quantitative structure-activity relationship model found yields significant cross-validated, conventional, and predictive r2 values equal to 0.798, 0.967, and 0.76, respectively, along with an average absolute error of prediction of 0.25 log units. These results suggest that the active conformation of the most flexible molecules including melatonin is in a folded form if we consider the spatial position of the ethylamido side chain relative to the aromatic ring.
|
Binding affinity is evaluated for chicken brain melatonin receptor using 2-[125I]iodomelatonin as radioligand
|
None
|
0.53
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of phenalene and acenaphthene derivatives as new conformationally restricted ligands for melatonin receptors.
Year : 2000
Volume : 43
Issue : 22
First Page : 4051
Last Page : 4062
Authors : Jellimann C, Mathé-Allainmat M, Andrieux J, Kloubert S, Boutin JA, Nicolas JP, Bennejean C, Delagrange P, Langlois M.
Abstract : Conformationally restricted phenalene and acenaphthene derivatives 5 were synthesized from phenalen-1-one and acenaphthen-1-one derivatives using the Horner-Emmons reaction. The amines were prepared through the corresponding isocyanates by the Curtius reaction on the acids or by the reduction of the nitriles. Amido derivatives (R(3) = Me, Et, n-Pr, c-Pr) were prepared by acylation of the amines with the appropriate anhydrides or acid chlorides or by the reductive acylation of the nitriles. The affinities of the compounds for melatonin binding sites were evaluated in vitro in binding assays using chicken brain melatonin and the human mt(1) and MT(2) receptors expressed in HEK-293 cells. The functionality of the compounds was determined by the potency to lighten the skin of Xenopus laevis tadpoles. Highly potent compounds were obtained. The data highlighted the role of the methoxy group located in the ortho position to the ethylamido chain as compounds with picomolar affinities such as 14c were obtained (chicken brain, hmt(1), hMT(2) K(i) values = 0.02, 0.008, 0.069 nM, respectively). Compound 14c was equipotent to the corresponding dimethoxy derivative 15c (chicken brain, hmt(1), hMT(2) K(i) values = 0.07, 0.016, 0.1 nM, respectively). On the other hand, the restricted conformation of the amido chain did not influence selectivity for the cloned hmt(1) and hMT(2) receptors. These compounds were also potent agonists of melanophore aggregation in X. laevis. 15a,c were several hundred fold more potent than melatonin (EC(50) = 0.025, 0.004 nM, respectively). Conformational studies indicated that the minimum energy folded conformation of the ethylamido chain could constitute the putative active form in the receptor site in agreement with previous results.
|
Monophasic inhibitory concentration against melatonin receptor was measured on ovine pars tuberalis membrane.
|
Ovis aries
|
0.0761
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands.
Year : 1994
Volume : 37
Issue : 20
First Page : 3231
Last Page : 3239
Authors : Depreux P, Lesieur D, Mansour HA, Morgan P, Howell HE, Renard P, Caignard DH, Pfeiffer B, Delagrange P, Guardiola B.
Abstract : A series of N-naphthylethyl amide derivatives were synthesized and evaluated as melatonin receptor ligands. The affinity of each compound for the melatonin receptor was determined by binding studies using [2-125I]iodomelatonin on ovine pars tuberalis membrane homogenates. Structure-activity relationships led to the conclusion that naphthalene is a bioisostere of the indole moiety of melatonin. Moreover it appears that the affinity is strongly affected by the size of the substituent of the nitrogen of the amidic function. Many of these ligands give biphasic dose-response curves which suggests that there may be two melatonin receptor subtypes within the ovine pars tuberalis cells. The replacement of naphthalene by benzofuran or benzothiophene did not strongly alter the affinity for the melatonin receptor. In contrast, the benzimidazole analogue was a poor ligand. Compound 7, the naphthalenic analogue of melatonin, a selective ligand of the melatonin receptor and an agonist derivative, has been selected for clinical development.
|
Binding affinity to melatonin receptor measured on ovine pars tuberalis membrane
|
Ovis aries
|
1e-10
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands.
Year : 1994
Volume : 37
Issue : 20
First Page : 3231
Last Page : 3239
Authors : Depreux P, Lesieur D, Mansour HA, Morgan P, Howell HE, Renard P, Caignard DH, Pfeiffer B, Delagrange P, Guardiola B.
Abstract : A series of N-naphthylethyl amide derivatives were synthesized and evaluated as melatonin receptor ligands. The affinity of each compound for the melatonin receptor was determined by binding studies using [2-125I]iodomelatonin on ovine pars tuberalis membrane homogenates. Structure-activity relationships led to the conclusion that naphthalene is a bioisostere of the indole moiety of melatonin. Moreover it appears that the affinity is strongly affected by the size of the substituent of the nitrogen of the amidic function. Many of these ligands give biphasic dose-response curves which suggests that there may be two melatonin receptor subtypes within the ovine pars tuberalis cells. The replacement of naphthalene by benzofuran or benzothiophene did not strongly alter the affinity for the melatonin receptor. In contrast, the benzimidazole analogue was a poor ligand. Compound 7, the naphthalenic analogue of melatonin, a selective ligand of the melatonin receptor and an agonist derivative, has been selected for clinical development.
|
Binding affinity against Melatonin receptor using ovine pars tuberalis membranes of the pituitary.
|
Ovis aries
|
1.0
l M-1
|
|
Journal : J. Med. Chem.
Title : Novel naphthalenic ligands with high affinity for the melatonin receptor.
Year : 1992
Volume : 35
Issue : 8
First Page : 1484
Last Page : 1486
Authors : Yous S, Andrieux J, Howell HE, Morgan PJ, Renard P, Pfeiffer B, Lesieur D, Guardiola-Lemaitre B.
|
Binding affinity against ovine pars tuberalis melatonin receptor using 2-[125I]- melatonin radioligand binding assay
|
Ovis aries
|
0.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological activity of conformationally restricted tricyclic analogs of the hormone melatonin
Year : 1996
Volume : 6
Issue : 10
First Page : 1071
Last Page : 1076
Authors : Leclerc V, Depreux P, Lesieur D, Caignard D, Renard P, Delagrange P, Guardiola-Lemaitre B, Morgan P
|
Binding affinity for human melatonin receptor type 1A, expressed in HEK293 cells (2-[125I]iodomelatonin is used as radioligand)
|
None
|
0.18
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of phenalene and acenaphthene derivatives as new conformationally restricted ligands for melatonin receptors.
Year : 2000
Volume : 43
Issue : 22
First Page : 4051
Last Page : 4062
Authors : Jellimann C, Mathé-Allainmat M, Andrieux J, Kloubert S, Boutin JA, Nicolas JP, Bennejean C, Delagrange P, Langlois M.
Abstract : Conformationally restricted phenalene and acenaphthene derivatives 5 were synthesized from phenalen-1-one and acenaphthen-1-one derivatives using the Horner-Emmons reaction. The amines were prepared through the corresponding isocyanates by the Curtius reaction on the acids or by the reduction of the nitriles. Amido derivatives (R(3) = Me, Et, n-Pr, c-Pr) were prepared by acylation of the amines with the appropriate anhydrides or acid chlorides or by the reductive acylation of the nitriles. The affinities of the compounds for melatonin binding sites were evaluated in vitro in binding assays using chicken brain melatonin and the human mt(1) and MT(2) receptors expressed in HEK-293 cells. The functionality of the compounds was determined by the potency to lighten the skin of Xenopus laevis tadpoles. Highly potent compounds were obtained. The data highlighted the role of the methoxy group located in the ortho position to the ethylamido chain as compounds with picomolar affinities such as 14c were obtained (chicken brain, hmt(1), hMT(2) K(i) values = 0.02, 0.008, 0.069 nM, respectively). Compound 14c was equipotent to the corresponding dimethoxy derivative 15c (chicken brain, hmt(1), hMT(2) K(i) values = 0.07, 0.016, 0.1 nM, respectively). On the other hand, the restricted conformation of the amido chain did not influence selectivity for the cloned hmt(1) and hMT(2) receptors. These compounds were also potent agonists of melanophore aggregation in X. laevis. 15a,c were several hundred fold more potent than melatonin (EC(50) = 0.025, 0.004 nM, respectively). Conformational studies indicated that the minimum energy folded conformation of the ethylamido chain could constitute the putative active form in the receptor site in agreement with previous results.
|
Agonist potency determined by [35S]GTP gamma-S binding assay using CHO cell lines for Melatonin receptor type 1A
|
Homo sapiens
|
1.56
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of naphthalenic dimers as selective MT1 melatoninergic ligands.
Year : 2003
Volume : 46
Issue : 7
First Page : 1127
Last Page : 1129
Authors : Descamps-François C, Yous S, Chavatte P, Audinot V, Bonnaud A, Boutin JA, Delagrange P, Bennejean C, Renard P, Lesieur D.
Abstract : We report the synthesis and binding properties at MT(1) and MT(2) receptors of the first example of agomelatine (N-[2-(7-methoxynaphth-1-yl)ethyl]acetamide) dimers in which two agomelatine moieties are linked together through their methoxy substituent by a polymethylene side chain according to the "bivalent ligand" approach. Some of these compounds behave as MT(1)-selective ligands. The most selective one (5) behaves as an antagonist.
|
Binding affinity for human Melatonin receptor type 1A stably transfected in human embryonic kidney cells (HEK 293) using 2-[125I]iodomelatonin as radioligand
|
Homo sapiens
|
0.06
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of naphthalenic dimers as selective MT1 melatoninergic ligands.
Year : 2003
Volume : 46
Issue : 7
First Page : 1127
Last Page : 1129
Authors : Descamps-François C, Yous S, Chavatte P, Audinot V, Bonnaud A, Boutin JA, Delagrange P, Bennejean C, Renard P, Lesieur D.
Abstract : We report the synthesis and binding properties at MT(1) and MT(2) receptors of the first example of agomelatine (N-[2-(7-methoxynaphth-1-yl)ethyl]acetamide) dimers in which two agomelatine moieties are linked together through their methoxy substituent by a polymethylene side chain according to the "bivalent ligand" approach. Some of these compounds behave as MT(1)-selective ligands. The most selective one (5) behaves as an antagonist.
|
Binding affinity for melatonin receptor type 1B, expressed in HEK293 cells (2-[125I]iodomelatonin is used as radioligand)
|
None
|
0.45
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of phenalene and acenaphthene derivatives as new conformationally restricted ligands for melatonin receptors.
Year : 2000
Volume : 43
Issue : 22
First Page : 4051
Last Page : 4062
Authors : Jellimann C, Mathé-Allainmat M, Andrieux J, Kloubert S, Boutin JA, Nicolas JP, Bennejean C, Delagrange P, Langlois M.
Abstract : Conformationally restricted phenalene and acenaphthene derivatives 5 were synthesized from phenalen-1-one and acenaphthen-1-one derivatives using the Horner-Emmons reaction. The amines were prepared through the corresponding isocyanates by the Curtius reaction on the acids or by the reduction of the nitriles. Amido derivatives (R(3) = Me, Et, n-Pr, c-Pr) were prepared by acylation of the amines with the appropriate anhydrides or acid chlorides or by the reductive acylation of the nitriles. The affinities of the compounds for melatonin binding sites were evaluated in vitro in binding assays using chicken brain melatonin and the human mt(1) and MT(2) receptors expressed in HEK-293 cells. The functionality of the compounds was determined by the potency to lighten the skin of Xenopus laevis tadpoles. Highly potent compounds were obtained. The data highlighted the role of the methoxy group located in the ortho position to the ethylamido chain as compounds with picomolar affinities such as 14c were obtained (chicken brain, hmt(1), hMT(2) K(i) values = 0.02, 0.008, 0.069 nM, respectively). Compound 14c was equipotent to the corresponding dimethoxy derivative 15c (chicken brain, hmt(1), hMT(2) K(i) values = 0.07, 0.016, 0.1 nM, respectively). On the other hand, the restricted conformation of the amido chain did not influence selectivity for the cloned hmt(1) and hMT(2) receptors. These compounds were also potent agonists of melanophore aggregation in X. laevis. 15a,c were several hundred fold more potent than melatonin (EC(50) = 0.025, 0.004 nM, respectively). Conformational studies indicated that the minimum energy folded conformation of the ethylamido chain could constitute the putative active form in the receptor site in agreement with previous results.
|
Agonist potency determined by [35S]GTP gamma-S binding assay using CHO cell lines for Melatonin receptor type 1B
|
Homo sapiens
|
0.1
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of naphthalenic dimers as selective MT1 melatoninergic ligands.
Year : 2003
Volume : 46
Issue : 7
First Page : 1127
Last Page : 1129
Authors : Descamps-François C, Yous S, Chavatte P, Audinot V, Bonnaud A, Boutin JA, Delagrange P, Bennejean C, Renard P, Lesieur D.
Abstract : We report the synthesis and binding properties at MT(1) and MT(2) receptors of the first example of agomelatine (N-[2-(7-methoxynaphth-1-yl)ethyl]acetamide) dimers in which two agomelatine moieties are linked together through their methoxy substituent by a polymethylene side chain according to the "bivalent ligand" approach. Some of these compounds behave as MT(1)-selective ligands. The most selective one (5) behaves as an antagonist.
|
Binding affinity for human Melatonin receptor type 1B stably transfected in human embryonic kidney cells (HEK 293) using 2-[125I]iodomelatonin as radioligand
|
Homo sapiens
|
0.27
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of naphthalenic dimers as selective MT1 melatoninergic ligands.
Year : 2003
Volume : 46
Issue : 7
First Page : 1127
Last Page : 1129
Authors : Descamps-François C, Yous S, Chavatte P, Audinot V, Bonnaud A, Boutin JA, Delagrange P, Bennejean C, Renard P, Lesieur D.
Abstract : We report the synthesis and binding properties at MT(1) and MT(2) receptors of the first example of agomelatine (N-[2-(7-methoxynaphth-1-yl)ethyl]acetamide) dimers in which two agomelatine moieties are linked together through their methoxy substituent by a polymethylene side chain according to the "bivalent ligand" approach. Some of these compounds behave as MT(1)-selective ligands. The most selective one (5) behaves as an antagonist.
|
Melanophore aggregation of the dermal melanocytes of Xenopus laevis tadpoles
|
None
|
0.53
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of phenalene and acenaphthene derivatives as new conformationally restricted ligands for melatonin receptors.
Year : 2000
Volume : 43
Issue : 22
First Page : 4051
Last Page : 4062
Authors : Jellimann C, Mathé-Allainmat M, Andrieux J, Kloubert S, Boutin JA, Nicolas JP, Bennejean C, Delagrange P, Langlois M.
Abstract : Conformationally restricted phenalene and acenaphthene derivatives 5 were synthesized from phenalen-1-one and acenaphthen-1-one derivatives using the Horner-Emmons reaction. The amines were prepared through the corresponding isocyanates by the Curtius reaction on the acids or by the reduction of the nitriles. Amido derivatives (R(3) = Me, Et, n-Pr, c-Pr) were prepared by acylation of the amines with the appropriate anhydrides or acid chlorides or by the reductive acylation of the nitriles. The affinities of the compounds for melatonin binding sites were evaluated in vitro in binding assays using chicken brain melatonin and the human mt(1) and MT(2) receptors expressed in HEK-293 cells. The functionality of the compounds was determined by the potency to lighten the skin of Xenopus laevis tadpoles. Highly potent compounds were obtained. The data highlighted the role of the methoxy group located in the ortho position to the ethylamido chain as compounds with picomolar affinities such as 14c were obtained (chicken brain, hmt(1), hMT(2) K(i) values = 0.02, 0.008, 0.069 nM, respectively). Compound 14c was equipotent to the corresponding dimethoxy derivative 15c (chicken brain, hmt(1), hMT(2) K(i) values = 0.07, 0.016, 0.1 nM, respectively). On the other hand, the restricted conformation of the amido chain did not influence selectivity for the cloned hmt(1) and hMT(2) receptors. These compounds were also potent agonists of melanophore aggregation in X. laevis. 15a,c were several hundred fold more potent than melatonin (EC(50) = 0.025, 0.004 nM, respectively). Conformational studies indicated that the minimum energy folded conformation of the ethylamido chain could constitute the putative active form in the receptor site in agreement with previous results.
|
Displacement of 2-[125I]iodomelatonin from human MT1 receptor expressed in HEK293 cells
|
Homo sapiens
|
0.06
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of 3-phenylnaphthalenic derivatives as new selective MT(2) melatoninergic ligands.
Year : 2008
Volume : 16
Issue : 18
First Page : 8339
Last Page : 8348
Authors : Poissonnier-Durieux S, Ettaoussi M, Pérès B, Boutin JA, Audinot V, Bennejean C, Delagrange P, Caignard DH, Renard P, Berthelot P, Lesieur D, Yous S.
Abstract : A series of naphthalenic analogues of melatonin were prepared and evaluated as melatonin receptor MT(2) selective ligands. Activity and MT(2) selectivity can be modulated with suitable variations of the C-3 phenyl and the acyl group on the C-1 side chain. Surprisingly, in contrast with what had been previously described in other series (2-benzylindoles, 2-benzylbenzofurans and 3-phenyltetralins), the presence of a C-3 phenyl with a functional group on the meta position seems to be primordial for MT(2) affinity and selectivity. Indeed, N-[2-(3-(3-hydroxymethylphenyl)-7-methoxynaphth-1-yl)ethyl]acetamide (21) is one of the best MT(2) selective ligands described until now and behaves as an antagonist.
|
Displacement of 2-[125I]iodomelatonin from human MT2 receptor expressed in CHO cells
|
Homo sapiens
|
0.27
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of 3-phenylnaphthalenic derivatives as new selective MT(2) melatoninergic ligands.
Year : 2008
Volume : 16
Issue : 18
First Page : 8339
Last Page : 8348
Authors : Poissonnier-Durieux S, Ettaoussi M, Pérès B, Boutin JA, Audinot V, Bennejean C, Delagrange P, Caignard DH, Renard P, Berthelot P, Lesieur D, Yous S.
Abstract : A series of naphthalenic analogues of melatonin were prepared and evaluated as melatonin receptor MT(2) selective ligands. Activity and MT(2) selectivity can be modulated with suitable variations of the C-3 phenyl and the acyl group on the C-1 side chain. Surprisingly, in contrast with what had been previously described in other series (2-benzylindoles, 2-benzylbenzofurans and 3-phenyltetralins), the presence of a C-3 phenyl with a functional group on the meta position seems to be primordial for MT(2) affinity and selectivity. Indeed, N-[2-(3-(3-hydroxymethylphenyl)-7-methoxynaphth-1-yl)ethyl]acetamide (21) is one of the best MT(2) selective ligands described until now and behaves as an antagonist.
|
Agonist activity at human MT2 receptor expressed in CHO cells by [35S]GTPgammaS binding assay
|
Homo sapiens
|
0.1
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of 3-phenylnaphthalenic derivatives as new selective MT(2) melatoninergic ligands.
Year : 2008
Volume : 16
Issue : 18
First Page : 8339
Last Page : 8348
Authors : Poissonnier-Durieux S, Ettaoussi M, Pérès B, Boutin JA, Audinot V, Bennejean C, Delagrange P, Caignard DH, Renard P, Berthelot P, Lesieur D, Yous S.
Abstract : A series of naphthalenic analogues of melatonin were prepared and evaluated as melatonin receptor MT(2) selective ligands. Activity and MT(2) selectivity can be modulated with suitable variations of the C-3 phenyl and the acyl group on the C-1 side chain. Surprisingly, in contrast with what had been previously described in other series (2-benzylindoles, 2-benzylbenzofurans and 3-phenyltetralins), the presence of a C-3 phenyl with a functional group on the meta position seems to be primordial for MT(2) affinity and selectivity. Indeed, N-[2-(3-(3-hydroxymethylphenyl)-7-methoxynaphth-1-yl)ethyl]acetamide (21) is one of the best MT(2) selective ligands described until now and behaves as an antagonist.
|
Agonist activity at human MT1 receptor expressed in CHO cells by [35S]GTPgamma binding assay
|
Homo sapiens
|
1.6
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and pharmacological evaluation of novel naphthalenic derivatives as selective MT(1) melatoninergic ligands.
Year : 2010
Volume : 18
Issue : 10
First Page : 3426
Last Page : 3436
Authors : Mésangeau C, Pérès B, Descamps-François C, Chavatte P, Audinot V, Coumailleau S, Boutin JA, Delagrange P, Bennejean C, Renard P, Caignard DH, Berthelot P, Yous S.
Abstract : Novel heterodimer analogues of melatonin were synthesized, when agomelatine (1) and various aryl units are linked via a linear alkyl chain through the methoxy group. The compounds were tested for their actions at melatonin receptors. Several of these ligands are MT(1)-selective with nanomolar or subnanomolar affinity. In addition, while most of the derivatives behave as partial agonists on one or both receptor subtypes, N-[2-(7-{4-[6-(1-methoxycarbonylethyl)naphthalen-2-yloxy]butoxy}naphthalen-1-yl)ethyl]acetamide (36), a subnanomolar MT(1) ligand with an 11-fold preference over MT(2) receptors, is a full antagonist on both receptors. Our results also confirm that the selectivity seen for the MT(1) receptor arises predominantly from steric factors and is not a consequence of the bridging of melatonin receptor dimers.
|
Agonist activity at human MT2 receptor expressed in CHO cells by [35S]GTPgamma binding assay
|
Homo sapiens
|
0.1
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and pharmacological evaluation of novel naphthalenic derivatives as selective MT(1) melatoninergic ligands.
Year : 2010
Volume : 18
Issue : 10
First Page : 3426
Last Page : 3436
Authors : Mésangeau C, Pérès B, Descamps-François C, Chavatte P, Audinot V, Coumailleau S, Boutin JA, Delagrange P, Bennejean C, Renard P, Caignard DH, Berthelot P, Yous S.
Abstract : Novel heterodimer analogues of melatonin were synthesized, when agomelatine (1) and various aryl units are linked via a linear alkyl chain through the methoxy group. The compounds were tested for their actions at melatonin receptors. Several of these ligands are MT(1)-selective with nanomolar or subnanomolar affinity. In addition, while most of the derivatives behave as partial agonists on one or both receptor subtypes, N-[2-(7-{4-[6-(1-methoxycarbonylethyl)naphthalen-2-yloxy]butoxy}naphthalen-1-yl)ethyl]acetamide (36), a subnanomolar MT(1) ligand with an 11-fold preference over MT(2) receptors, is a full antagonist on both receptors. Our results also confirm that the selectivity seen for the MT(1) receptor arises predominantly from steric factors and is not a consequence of the bridging of melatonin receptor dimers.
|
Binding affinity to rat MT1 receptor expressed in CHO-Galpha16 cells assessed as Ca2+ mobilization after 20 mins by FLIPR assay
|
Rattus norvegicus
|
2.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of 4-arylpiperidinyl amide and N-arylpiperdin-3-yl-cyclopropane carboxamide derivatives as novel melatonin receptor ligands.
Year : 2011
Volume : 21
Issue : 4
First Page : 1236
Last Page : 1242
Authors : Li G, Zhou H, Jiang Y, Keim H, Topiol SW, Poda SB, Ren Y, Chandrasena G, Doller D.
Abstract : Two series of 4-arylpiperidinyl amide and N-arylpiperdin-3-yl-cyclopropane carboxamide derivatives exhibiting diverse functionality at rat MT(1) and MT(2) receptors are reported. Compounds 11f and 18b (MT(1)/MT(2) agonist) have human microsomal intrinsic clearance comparable to ramelteon.
|
Binding affinity to rat MT2 receptor expressed in CHO-Galpha16 cells assessed as Ca2+ mobilization after 20 mins by FLIPR assay
|
Rattus norvegicus
|
1.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of 4-arylpiperidinyl amide and N-arylpiperdin-3-yl-cyclopropane carboxamide derivatives as novel melatonin receptor ligands.
Year : 2011
Volume : 21
Issue : 4
First Page : 1236
Last Page : 1242
Authors : Li G, Zhou H, Jiang Y, Keim H, Topiol SW, Poda SB, Ren Y, Chandrasena G, Doller D.
Abstract : Two series of 4-arylpiperidinyl amide and N-arylpiperdin-3-yl-cyclopropane carboxamide derivatives exhibiting diverse functionality at rat MT(1) and MT(2) receptors are reported. Compounds 11f and 18b (MT(1)/MT(2) agonist) have human microsomal intrinsic clearance comparable to ramelteon.
|
Displacement of [3H]melatonin from rat MT1 receptor expressed in CHO-Galpha16 cells
|
Rattus norvegicus
|
1.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of 4-arylpiperidinyl amide and N-arylpiperdin-3-yl-cyclopropane carboxamide derivatives as novel melatonin receptor ligands.
Year : 2011
Volume : 21
Issue : 4
First Page : 1236
Last Page : 1242
Authors : Li G, Zhou H, Jiang Y, Keim H, Topiol SW, Poda SB, Ren Y, Chandrasena G, Doller D.
Abstract : Two series of 4-arylpiperidinyl amide and N-arylpiperdin-3-yl-cyclopropane carboxamide derivatives exhibiting diverse functionality at rat MT(1) and MT(2) receptors are reported. Compounds 11f and 18b (MT(1)/MT(2) agonist) have human microsomal intrinsic clearance comparable to ramelteon.
|
Displacement of [3H]melatonin from rat MT2 receptor expressed in CHO-Galpha16 cells
|
Rattus norvegicus
|
0.14
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of 4-arylpiperidinyl amide and N-arylpiperdin-3-yl-cyclopropane carboxamide derivatives as novel melatonin receptor ligands.
Year : 2011
Volume : 21
Issue : 4
First Page : 1236
Last Page : 1242
Authors : Li G, Zhou H, Jiang Y, Keim H, Topiol SW, Poda SB, Ren Y, Chandrasena G, Doller D.
Abstract : Two series of 4-arylpiperidinyl amide and N-arylpiperdin-3-yl-cyclopropane carboxamide derivatives exhibiting diverse functionality at rat MT(1) and MT(2) receptors are reported. Compounds 11f and 18b (MT(1)/MT(2) agonist) have human microsomal intrinsic clearance comparable to ramelteon.
|
Displacement of [125I]iodomelatonin form human MT1 receptor expressed in CHO cells after 120 mins
|
Homo sapiens
|
0.1
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and pharmacological evaluation of new series of naphthalenic analogues as melatoninergic (MT1/MT2) and serotoninergic 5-HT2C dual ligands (I).
Year : 2012
Volume : 49
First Page : 310
Last Page : 323
Authors : Ettaoussi M, Sabaouni A, Rami M, Boutin JA, Delagrange P, Renard P, Spedding M, Caignard DH, Berthelot P, Yous S.
Abstract : As part of our ongoing interest in developing new melatoninergic ligands bearing the same pharmacological profile as agomelatine, we focused our attention on this compound as a lead. Several chemical modifications have been performed on positions C-3 and 8 of the naphthalene ring determined as primary targets for the agomelatine metabolism. Herein we report the modulation of the positions C-3 and 7 in addition of the amide side chain because of this later prominent role in the affinity profile of such ligands. Synthesized compounds were then biologically evaluated at human cloned melatoninergic and serotoninergic receptors and showed different binding affinity and intrinsic activity profiles. Compounds bearing fluoroacetamide group (compounds 4 and 5) showed a high melatoninergic binding affinity particularly towards MT(1) receptor subtype. Thus, the fluoroacetamide 4 exhibited a good melatoninergic (MT(1)/MT(2)) binding affinity (70 pM) higher than the lead. Moreover, other compounds (10a, 10e, 16, 17 and 18) issued from these modulations behaved as MT(1) and MT(2) agonists and exhibited a sub-nanomolar binding affinity towards these receptors. However, only compounds 10e, 17 and 18 showed a sub-nanomolar binding affinity at 5-HT(2C) higher than the agomelatine.
|
Displacement of [125I]iodomelatonin form human MT1 receptor expressed in HEK cells after 120 mins
|
Homo sapiens
|
0.1
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and pharmacological evaluation of new series of naphthalenic analogues as melatoninergic (MT1/MT2) and serotoninergic 5-HT2C dual ligands (I).
Year : 2012
Volume : 49
First Page : 310
Last Page : 323
Authors : Ettaoussi M, Sabaouni A, Rami M, Boutin JA, Delagrange P, Renard P, Spedding M, Caignard DH, Berthelot P, Yous S.
Abstract : As part of our ongoing interest in developing new melatoninergic ligands bearing the same pharmacological profile as agomelatine, we focused our attention on this compound as a lead. Several chemical modifications have been performed on positions C-3 and 8 of the naphthalene ring determined as primary targets for the agomelatine metabolism. Herein we report the modulation of the positions C-3 and 7 in addition of the amide side chain because of this later prominent role in the affinity profile of such ligands. Synthesized compounds were then biologically evaluated at human cloned melatoninergic and serotoninergic receptors and showed different binding affinity and intrinsic activity profiles. Compounds bearing fluoroacetamide group (compounds 4 and 5) showed a high melatoninergic binding affinity particularly towards MT(1) receptor subtype. Thus, the fluoroacetamide 4 exhibited a good melatoninergic (MT(1)/MT(2)) binding affinity (70 pM) higher than the lead. Moreover, other compounds (10a, 10e, 16, 17 and 18) issued from these modulations behaved as MT(1) and MT(2) agonists and exhibited a sub-nanomolar binding affinity towards these receptors. However, only compounds 10e, 17 and 18 showed a sub-nanomolar binding affinity at 5-HT(2C) higher than the agomelatine.
|
Displacement of [125I]iodomelatonin form human MT2 receptor expressed in CHO cells after 120 mins
|
Homo sapiens
|
0.12
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and pharmacological evaluation of new series of naphthalenic analogues as melatoninergic (MT1/MT2) and serotoninergic 5-HT2C dual ligands (I).
Year : 2012
Volume : 49
First Page : 310
Last Page : 323
Authors : Ettaoussi M, Sabaouni A, Rami M, Boutin JA, Delagrange P, Renard P, Spedding M, Caignard DH, Berthelot P, Yous S.
Abstract : As part of our ongoing interest in developing new melatoninergic ligands bearing the same pharmacological profile as agomelatine, we focused our attention on this compound as a lead. Several chemical modifications have been performed on positions C-3 and 8 of the naphthalene ring determined as primary targets for the agomelatine metabolism. Herein we report the modulation of the positions C-3 and 7 in addition of the amide side chain because of this later prominent role in the affinity profile of such ligands. Synthesized compounds were then biologically evaluated at human cloned melatoninergic and serotoninergic receptors and showed different binding affinity and intrinsic activity profiles. Compounds bearing fluoroacetamide group (compounds 4 and 5) showed a high melatoninergic binding affinity particularly towards MT(1) receptor subtype. Thus, the fluoroacetamide 4 exhibited a good melatoninergic (MT(1)/MT(2)) binding affinity (70 pM) higher than the lead. Moreover, other compounds (10a, 10e, 16, 17 and 18) issued from these modulations behaved as MT(1) and MT(2) agonists and exhibited a sub-nanomolar binding affinity towards these receptors. However, only compounds 10e, 17 and 18 showed a sub-nanomolar binding affinity at 5-HT(2C) higher than the agomelatine.
|
Displacement of [125I]iodomelatonin form human MT2 receptor expressed in HEK cells after 120 mins
|
Homo sapiens
|
0.12
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and pharmacological evaluation of new series of naphthalenic analogues as melatoninergic (MT1/MT2) and serotoninergic 5-HT2C dual ligands (I).
Year : 2012
Volume : 49
First Page : 310
Last Page : 323
Authors : Ettaoussi M, Sabaouni A, Rami M, Boutin JA, Delagrange P, Renard P, Spedding M, Caignard DH, Berthelot P, Yous S.
Abstract : As part of our ongoing interest in developing new melatoninergic ligands bearing the same pharmacological profile as agomelatine, we focused our attention on this compound as a lead. Several chemical modifications have been performed on positions C-3 and 8 of the naphthalene ring determined as primary targets for the agomelatine metabolism. Herein we report the modulation of the positions C-3 and 7 in addition of the amide side chain because of this later prominent role in the affinity profile of such ligands. Synthesized compounds were then biologically evaluated at human cloned melatoninergic and serotoninergic receptors and showed different binding affinity and intrinsic activity profiles. Compounds bearing fluoroacetamide group (compounds 4 and 5) showed a high melatoninergic binding affinity particularly towards MT(1) receptor subtype. Thus, the fluoroacetamide 4 exhibited a good melatoninergic (MT(1)/MT(2)) binding affinity (70 pM) higher than the lead. Moreover, other compounds (10a, 10e, 16, 17 and 18) issued from these modulations behaved as MT(1) and MT(2) agonists and exhibited a sub-nanomolar binding affinity towards these receptors. However, only compounds 10e, 17 and 18 showed a sub-nanomolar binding affinity at 5-HT(2C) higher than the agomelatine.
|
Agonist activity at human MT1 receptor expressed in CHO cells after 1 hr by [35S]GTPgammaS binding assay
|
Homo sapiens
|
1.29
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and pharmacological evaluation of new series of naphthalenic analogues as melatoninergic (MT1/MT2) and serotoninergic 5-HT2C dual ligands (I).
Year : 2012
Volume : 49
First Page : 310
Last Page : 323
Authors : Ettaoussi M, Sabaouni A, Rami M, Boutin JA, Delagrange P, Renard P, Spedding M, Caignard DH, Berthelot P, Yous S.
Abstract : As part of our ongoing interest in developing new melatoninergic ligands bearing the same pharmacological profile as agomelatine, we focused our attention on this compound as a lead. Several chemical modifications have been performed on positions C-3 and 8 of the naphthalene ring determined as primary targets for the agomelatine metabolism. Herein we report the modulation of the positions C-3 and 7 in addition of the amide side chain because of this later prominent role in the affinity profile of such ligands. Synthesized compounds were then biologically evaluated at human cloned melatoninergic and serotoninergic receptors and showed different binding affinity and intrinsic activity profiles. Compounds bearing fluoroacetamide group (compounds 4 and 5) showed a high melatoninergic binding affinity particularly towards MT(1) receptor subtype. Thus, the fluoroacetamide 4 exhibited a good melatoninergic (MT(1)/MT(2)) binding affinity (70 pM) higher than the lead. Moreover, other compounds (10a, 10e, 16, 17 and 18) issued from these modulations behaved as MT(1) and MT(2) agonists and exhibited a sub-nanomolar binding affinity towards these receptors. However, only compounds 10e, 17 and 18 showed a sub-nanomolar binding affinity at 5-HT(2C) higher than the agomelatine.
|
Agonist activity at human MT2 receptor expressed in CHO cells after 1 hr by [35S]GTPgammaS binding assay
|
Homo sapiens
|
2.72
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and pharmacological evaluation of new series of naphthalenic analogues as melatoninergic (MT1/MT2) and serotoninergic 5-HT2C dual ligands (I).
Year : 2012
Volume : 49
First Page : 310
Last Page : 323
Authors : Ettaoussi M, Sabaouni A, Rami M, Boutin JA, Delagrange P, Renard P, Spedding M, Caignard DH, Berthelot P, Yous S.
Abstract : As part of our ongoing interest in developing new melatoninergic ligands bearing the same pharmacological profile as agomelatine, we focused our attention on this compound as a lead. Several chemical modifications have been performed on positions C-3 and 8 of the naphthalene ring determined as primary targets for the agomelatine metabolism. Herein we report the modulation of the positions C-3 and 7 in addition of the amide side chain because of this later prominent role in the affinity profile of such ligands. Synthesized compounds were then biologically evaluated at human cloned melatoninergic and serotoninergic receptors and showed different binding affinity and intrinsic activity profiles. Compounds bearing fluoroacetamide group (compounds 4 and 5) showed a high melatoninergic binding affinity particularly towards MT(1) receptor subtype. Thus, the fluoroacetamide 4 exhibited a good melatoninergic (MT(1)/MT(2)) binding affinity (70 pM) higher than the lead. Moreover, other compounds (10a, 10e, 16, 17 and 18) issued from these modulations behaved as MT(1) and MT(2) agonists and exhibited a sub-nanomolar binding affinity towards these receptors. However, only compounds 10e, 17 and 18 showed a sub-nanomolar binding affinity at 5-HT(2C) higher than the agomelatine.
|
Displacement of [3H]mesulergine from human 5HT2C receptor expressed in CHO cells after 60 mins
|
Homo sapiens
|
708.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and pharmacological evaluation of new series of naphthalenic analogues as melatoninergic (MT1/MT2) and serotoninergic 5-HT2C dual ligands (I).
Year : 2012
Volume : 49
First Page : 310
Last Page : 323
Authors : Ettaoussi M, Sabaouni A, Rami M, Boutin JA, Delagrange P, Renard P, Spedding M, Caignard DH, Berthelot P, Yous S.
Abstract : As part of our ongoing interest in developing new melatoninergic ligands bearing the same pharmacological profile as agomelatine, we focused our attention on this compound as a lead. Several chemical modifications have been performed on positions C-3 and 8 of the naphthalene ring determined as primary targets for the agomelatine metabolism. Herein we report the modulation of the positions C-3 and 7 in addition of the amide side chain because of this later prominent role in the affinity profile of such ligands. Synthesized compounds were then biologically evaluated at human cloned melatoninergic and serotoninergic receptors and showed different binding affinity and intrinsic activity profiles. Compounds bearing fluoroacetamide group (compounds 4 and 5) showed a high melatoninergic binding affinity particularly towards MT(1) receptor subtype. Thus, the fluoroacetamide 4 exhibited a good melatoninergic (MT(1)/MT(2)) binding affinity (70 pM) higher than the lead. Moreover, other compounds (10a, 10e, 16, 17 and 18) issued from these modulations behaved as MT(1) and MT(2) agonists and exhibited a sub-nanomolar binding affinity towards these receptors. However, only compounds 10e, 17 and 18 showed a sub-nanomolar binding affinity at 5-HT(2C) higher than the agomelatine.
|
Displacement of [125I]2-iodomelatonin from melatonin receptor in chicken brain membranes after 60 mins by gamma counting
|
Gallus gallus
|
0.67
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of new N-(arylcyclopropyl)acetamides and N-(arylvinyl)acetamides as conformationally-restricted ligands for melatonin receptors.
Year : 2013
Volume : 23
Issue : 2
First Page : 430
Last Page : 434
Authors : Morellato L, Lefas-Le Gall M, Langlois M, Caignard DH, Renard P, Delagrange P, Mathé-Allainmat M.
Abstract : N-(Arylcyclopropyl)acetamides and N-(arylvinyl)acetamides or methyl ureas have been prepared as constrained analogues of melatonin. The affinity of these new compounds for chicken brain melatonin receptors and recombinant human MT(1) and MT(2) receptors was evaluated using 2-[(125)I]-iodomelatonin as radioligand. Strict ethylenic or cyclopropyl analogues of the commercialized agonist agomelatine (Valdoxan®) were equipotent to agomelatine in binding bioassays. However, the ethylenic analogue was more effective than the cyclopropyl one in the melanophore aggregation bioassay, but was still less potent than the disubstituted 2,7-dimethoxy-naphtalenic compounds.
|
Antimelanogenic activity in Xenopus laevis tadpoles assessed as melanophore aggregation by microscopy
|
Xenopus laevis
|
0.35
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of new N-(arylcyclopropyl)acetamides and N-(arylvinyl)acetamides as conformationally-restricted ligands for melatonin receptors.
Year : 2013
Volume : 23
Issue : 2
First Page : 430
Last Page : 434
Authors : Morellato L, Lefas-Le Gall M, Langlois M, Caignard DH, Renard P, Delagrange P, Mathé-Allainmat M.
Abstract : N-(Arylcyclopropyl)acetamides and N-(arylvinyl)acetamides or methyl ureas have been prepared as constrained analogues of melatonin. The affinity of these new compounds for chicken brain melatonin receptors and recombinant human MT(1) and MT(2) receptors was evaluated using 2-[(125)I]-iodomelatonin as radioligand. Strict ethylenic or cyclopropyl analogues of the commercialized agonist agomelatine (Valdoxan®) were equipotent to agomelatine in binding bioassays. However, the ethylenic analogue was more effective than the cyclopropyl one in the melanophore aggregation bioassay, but was still less potent than the disubstituted 2,7-dimethoxy-naphtalenic compounds.
|
Displacement of [125I]2-iodomelatonin from human recombinant MT1 receptor expressed in HEK293 cells after 2 hrs by gamma counting
|
Homo sapiens
|
0.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of new N-(arylcyclopropyl)acetamides and N-(arylvinyl)acetamides as conformationally-restricted ligands for melatonin receptors.
Year : 2013
Volume : 23
Issue : 2
First Page : 430
Last Page : 434
Authors : Morellato L, Lefas-Le Gall M, Langlois M, Caignard DH, Renard P, Delagrange P, Mathé-Allainmat M.
Abstract : N-(Arylcyclopropyl)acetamides and N-(arylvinyl)acetamides or methyl ureas have been prepared as constrained analogues of melatonin. The affinity of these new compounds for chicken brain melatonin receptors and recombinant human MT(1) and MT(2) receptors was evaluated using 2-[(125)I]-iodomelatonin as radioligand. Strict ethylenic or cyclopropyl analogues of the commercialized agonist agomelatine (Valdoxan®) were equipotent to agomelatine in binding bioassays. However, the ethylenic analogue was more effective than the cyclopropyl one in the melanophore aggregation bioassay, but was still less potent than the disubstituted 2,7-dimethoxy-naphtalenic compounds.
|
Displacement of [125I]2-iodomelatonin from human recombinant MT2 receptor expressed in HEK293 cells after 2 hrs by gamma counting
|
Homo sapiens
|
0.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of new N-(arylcyclopropyl)acetamides and N-(arylvinyl)acetamides as conformationally-restricted ligands for melatonin receptors.
Year : 2013
Volume : 23
Issue : 2
First Page : 430
Last Page : 434
Authors : Morellato L, Lefas-Le Gall M, Langlois M, Caignard DH, Renard P, Delagrange P, Mathé-Allainmat M.
Abstract : N-(Arylcyclopropyl)acetamides and N-(arylvinyl)acetamides or methyl ureas have been prepared as constrained analogues of melatonin. The affinity of these new compounds for chicken brain melatonin receptors and recombinant human MT(1) and MT(2) receptors was evaluated using 2-[(125)I]-iodomelatonin as radioligand. Strict ethylenic or cyclopropyl analogues of the commercialized agonist agomelatine (Valdoxan®) were equipotent to agomelatine in binding bioassays. However, the ethylenic analogue was more effective than the cyclopropyl one in the melanophore aggregation bioassay, but was still less potent than the disubstituted 2,7-dimethoxy-naphtalenic compounds.
|
Cytotoxicity against human L02 cells assessed as inhibitory rate at 80 uM after 24 hrs by MTT assay
|
Homo sapiens
|
20.2
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of amide side-chain modified Agomelatine analogues as potential antidepressant-like agents.
Year : 2014
Volume : 24
Issue : 7
First Page : 1672
Last Page : 1676
Authors : Chang Y, Pi W, Ang W, Liu Y, Li C, Zheng J, Xiong L, Yang T, Luo Y.
Abstract : In this work, nineteen analogues of Agomelatine were readily synthesized through structural modification of the acetamide side-chain starting from the key common intermediate 2-(7-methoxynaphthalen-1-yl) ethanamine (3), which was prepared from commercially available compound 2-(7-methoxynaphthalen-1-yl) acetonitrile (2) in two steps. Corticosterone-induced PC12 pheochromocytoma cells phenotypic in vitro model was utilized to evaluate their potential antidepression activities. Imide compound 4a and acylamino carboxylic acid analogue 5b showed good protective effects on traumatic PC12 cells with protection rates of 34.2% and 23.2%, respectively. Further in vivo assessments in C57 mice FST (forced swim test) model demonstrated that compound 4a significantly reduced the immobility time of the tested subjects, indicating antidepressant-like activity. Preliminary toxicity assays conducted on human normal liver L02 cells and embryonic kidney 293 cells suggested a relatively low safety risk for compound 4a compared with the marketed drugs Agomelatine and Fluoxetine. The promising antidepressant-like efficacy of compound 4a, together with the relatively low toxicity to the normal tested cells and high liability of diffusion through the blood-brain barrier (BBB), presents us insights of exploration of me-better drug candidates of Agomelatine.
|
Cytotoxicity against human HEK293 cells assessed as inhibitory rate at 80 uM after 24 hrs by MTT assay
|
Homo sapiens
|
26.6
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of amide side-chain modified Agomelatine analogues as potential antidepressant-like agents.
Year : 2014
Volume : 24
Issue : 7
First Page : 1672
Last Page : 1676
Authors : Chang Y, Pi W, Ang W, Liu Y, Li C, Zheng J, Xiong L, Yang T, Luo Y.
Abstract : In this work, nineteen analogues of Agomelatine were readily synthesized through structural modification of the acetamide side-chain starting from the key common intermediate 2-(7-methoxynaphthalen-1-yl) ethanamine (3), which was prepared from commercially available compound 2-(7-methoxynaphthalen-1-yl) acetonitrile (2) in two steps. Corticosterone-induced PC12 pheochromocytoma cells phenotypic in vitro model was utilized to evaluate their potential antidepression activities. Imide compound 4a and acylamino carboxylic acid analogue 5b showed good protective effects on traumatic PC12 cells with protection rates of 34.2% and 23.2%, respectively. Further in vivo assessments in C57 mice FST (forced swim test) model demonstrated that compound 4a significantly reduced the immobility time of the tested subjects, indicating antidepressant-like activity. Preliminary toxicity assays conducted on human normal liver L02 cells and embryonic kidney 293 cells suggested a relatively low safety risk for compound 4a compared with the marketed drugs Agomelatine and Fluoxetine. The promising antidepressant-like efficacy of compound 4a, together with the relatively low toxicity to the normal tested cells and high liability of diffusion through the blood-brain barrier (BBB), presents us insights of exploration of me-better drug candidates of Agomelatine.
|
Cytotoxicity against human L02 cells as inhibition of cell viability at 80 uM after 24 hrs by MTT assay
|
Homo sapiens
|
20.2
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of novel naphthalene compounds as potential antidepressant agents.
Year : 2014
Volume : 82
First Page : 263
Last Page : 273
Authors : Ang W, Chen G, Xiong L, Chang Y, Pi W, Liu Y, Li C, Zheng J, Zhou L, Yang B, Deng Y, Yang S, Luo Y, Wei Y.
Abstract : In this study, a series of novel naphthalene compounds were synthesized and screened for their antidepressant-like activities in vitro and in vivo. Their values for two descriptors (ClogP, tPSA) of the blood-brain barrier (BBB) were calculated for early assessment of the central nervous system (CNS) drug-likeness. Seven of them (6d, 6i, 6k, 6o, 6p, 6s and 6t) demonstrated potential protective effects on corticosterone-induced lesion of PC12 cells although they cannot repair the irreversible oxidant injury to PC12 cells by hydrogen peroxide. Compounds with promising neurorestorative activities (6k, 6o and 6p) were further evaluated for their in vivo effects by forced swim test (FST) and open field test (OFT) in C57 mice models. The FST results showed that compounds 6k, 6o and 6p remarkably reduced the immobility time of the tested mice. Among them, compound 6k was the most potent one, much more effective than Agomelatine and comparable to Fluoxetine. The OFT results showed that mice treated with compound 6k traveled a longer distance than those treated with Agomelatine or Fluoxetine, indicating a better general locomotor activity. The paper also proposed a possible binding mode of compound 6k with glucocorticoid receptor by docking study. The in vitro cytotoxicity data on HEK293 and L02 cells suggested compound 6k to be a promising antidepressant candidate for subsequent investigation.
|
Cytotoxicity against human HEK293 cells as inhibition of cell viability at 80 uM after 24 hrs by MTT assay
|
Homo sapiens
|
26.6
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of novel naphthalene compounds as potential antidepressant agents.
Year : 2014
Volume : 82
First Page : 263
Last Page : 273
Authors : Ang W, Chen G, Xiong L, Chang Y, Pi W, Liu Y, Li C, Zheng J, Zhou L, Yang B, Deng Y, Yang S, Luo Y, Wei Y.
Abstract : In this study, a series of novel naphthalene compounds were synthesized and screened for their antidepressant-like activities in vitro and in vivo. Their values for two descriptors (ClogP, tPSA) of the blood-brain barrier (BBB) were calculated for early assessment of the central nervous system (CNS) drug-likeness. Seven of them (6d, 6i, 6k, 6o, 6p, 6s and 6t) demonstrated potential protective effects on corticosterone-induced lesion of PC12 cells although they cannot repair the irreversible oxidant injury to PC12 cells by hydrogen peroxide. Compounds with promising neurorestorative activities (6k, 6o and 6p) were further evaluated for their in vivo effects by forced swim test (FST) and open field test (OFT) in C57 mice models. The FST results showed that compounds 6k, 6o and 6p remarkably reduced the immobility time of the tested mice. Among them, compound 6k was the most potent one, much more effective than Agomelatine and comparable to Fluoxetine. The OFT results showed that mice treated with compound 6k traveled a longer distance than those treated with Agomelatine or Fluoxetine, indicating a better general locomotor activity. The paper also proposed a possible binding mode of compound 6k with glucocorticoid receptor by docking study. The in vitro cytotoxicity data on HEK293 and L02 cells suggested compound 6k to be a promising antidepressant candidate for subsequent investigation.
|
Antidepressant-like activity in C57 mouse assessed as reduction in immobility time at 32 mg/kg, ip administered from day 2 to 15 measured on 2nd and 15th day 30 mins after drug challenge by forced swim test
|
Mus musculus
|
8.4
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of novel naphthalene compounds as potential antidepressant agents.
Year : 2014
Volume : 82
First Page : 263
Last Page : 273
Authors : Ang W, Chen G, Xiong L, Chang Y, Pi W, Liu Y, Li C, Zheng J, Zhou L, Yang B, Deng Y, Yang S, Luo Y, Wei Y.
Abstract : In this study, a series of novel naphthalene compounds were synthesized and screened for their antidepressant-like activities in vitro and in vivo. Their values for two descriptors (ClogP, tPSA) of the blood-brain barrier (BBB) were calculated for early assessment of the central nervous system (CNS) drug-likeness. Seven of them (6d, 6i, 6k, 6o, 6p, 6s and 6t) demonstrated potential protective effects on corticosterone-induced lesion of PC12 cells although they cannot repair the irreversible oxidant injury to PC12 cells by hydrogen peroxide. Compounds with promising neurorestorative activities (6k, 6o and 6p) were further evaluated for their in vivo effects by forced swim test (FST) and open field test (OFT) in C57 mice models. The FST results showed that compounds 6k, 6o and 6p remarkably reduced the immobility time of the tested mice. Among them, compound 6k was the most potent one, much more effective than Agomelatine and comparable to Fluoxetine. The OFT results showed that mice treated with compound 6k traveled a longer distance than those treated with Agomelatine or Fluoxetine, indicating a better general locomotor activity. The paper also proposed a possible binding mode of compound 6k with glucocorticoid receptor by docking study. The in vitro cytotoxicity data on HEK293 and L02 cells suggested compound 6k to be a promising antidepressant candidate for subsequent investigation.
|
Intrinsic activity at human MT2 receptor expressed in CHO cell membranes after 1 hr by [35S]GTPgammaS binding assay
|
Homo sapiens
|
0.18
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Melatonergic ligands: Design, synthesis and pharmacological evaluation of novel series of naphthofuranic derivatives.
Year : 2016
Volume : 109
First Page : 360
Last Page : 370
Authors : Landagaray E, Ettaoussi M, Duroux R, Boutin JA, Caignard DH, Delagrange P, Melnyk P, Berthelot P, Yous S.
Abstract : Following our research for new melatonergic ligands, herein we report the design, synthesis and biological evaluation of new series of naphthofuranic derivatives as MT1 and MT2 ligands. Binding affinity results of the prepared compounds revealed good binding affinities at both melatonin receptor subtypes. Particularly, compound 6a behaved as an MT1 partial agonist and MT2 full agonist and exhibited an excellent binding affinity at MT2 (Ki = 0.09 nM). In addition, lateral chain displacement from position 1 to 2 of the furan core had no effect on the binding affinity at both MT1 and MT2, while elongation of this side chain, led to decreased melatonergic binding affinities.
|
Intrinsic activity at human MT1 receptor expressed in CHO cell membranes after 1 hr by [35S]GTPgammaS binding assay
|
Homo sapiens
|
1.4
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Melatonergic ligands: Design, synthesis and pharmacological evaluation of novel series of naphthofuranic derivatives.
Year : 2016
Volume : 109
First Page : 360
Last Page : 370
Authors : Landagaray E, Ettaoussi M, Duroux R, Boutin JA, Caignard DH, Delagrange P, Melnyk P, Berthelot P, Yous S.
Abstract : Following our research for new melatonergic ligands, herein we report the design, synthesis and biological evaluation of new series of naphthofuranic derivatives as MT1 and MT2 ligands. Binding affinity results of the prepared compounds revealed good binding affinities at both melatonin receptor subtypes. Particularly, compound 6a behaved as an MT1 partial agonist and MT2 full agonist and exhibited an excellent binding affinity at MT2 (Ki = 0.09 nM). In addition, lateral chain displacement from position 1 to 2 of the furan core had no effect on the binding affinity at both MT1 and MT2, while elongation of this side chain, led to decreased melatonergic binding affinities.
|
Displacement of 2-[125I]iodomelatonin from human MT2 receptor expressed in CHO cell membranes after 120 mins
|
Homo sapiens
|
0.21
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Melatonergic ligands: Design, synthesis and pharmacological evaluation of novel series of naphthofuranic derivatives.
Year : 2016
Volume : 109
First Page : 360
Last Page : 370
Authors : Landagaray E, Ettaoussi M, Duroux R, Boutin JA, Caignard DH, Delagrange P, Melnyk P, Berthelot P, Yous S.
Abstract : Following our research for new melatonergic ligands, herein we report the design, synthesis and biological evaluation of new series of naphthofuranic derivatives as MT1 and MT2 ligands. Binding affinity results of the prepared compounds revealed good binding affinities at both melatonin receptor subtypes. Particularly, compound 6a behaved as an MT1 partial agonist and MT2 full agonist and exhibited an excellent binding affinity at MT2 (Ki = 0.09 nM). In addition, lateral chain displacement from position 1 to 2 of the furan core had no effect on the binding affinity at both MT1 and MT2, while elongation of this side chain, led to decreased melatonergic binding affinities.
|
Displacement of 2-[125I]iodomelatonin from human MT1 receptor expressed in CHO cell membranes after 120 mins
|
Homo sapiens
|
0.12
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Melatonergic ligands: Design, synthesis and pharmacological evaluation of novel series of naphthofuranic derivatives.
Year : 2016
Volume : 109
First Page : 360
Last Page : 370
Authors : Landagaray E, Ettaoussi M, Duroux R, Boutin JA, Caignard DH, Delagrange P, Melnyk P, Berthelot P, Yous S.
Abstract : Following our research for new melatonergic ligands, herein we report the design, synthesis and biological evaluation of new series of naphthofuranic derivatives as MT1 and MT2 ligands. Binding affinity results of the prepared compounds revealed good binding affinities at both melatonin receptor subtypes. Particularly, compound 6a behaved as an MT1 partial agonist and MT2 full agonist and exhibited an excellent binding affinity at MT2 (Ki = 0.09 nM). In addition, lateral chain displacement from position 1 to 2 of the furan core had no effect on the binding affinity at both MT1 and MT2, while elongation of this side chain, led to decreased melatonergic binding affinities.
|
Binding affinity to 5-HT2C receptor (unknown origin)
|
Homo sapiens
|
630.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Melatonergic ligands: Design, synthesis and pharmacological evaluation of novel series of naphthofuranic derivatives.
Year : 2016
Volume : 109
First Page : 360
Last Page : 370
Authors : Landagaray E, Ettaoussi M, Duroux R, Boutin JA, Caignard DH, Delagrange P, Melnyk P, Berthelot P, Yous S.
Abstract : Following our research for new melatonergic ligands, herein we report the design, synthesis and biological evaluation of new series of naphthofuranic derivatives as MT1 and MT2 ligands. Binding affinity results of the prepared compounds revealed good binding affinities at both melatonin receptor subtypes. Particularly, compound 6a behaved as an MT1 partial agonist and MT2 full agonist and exhibited an excellent binding affinity at MT2 (Ki = 0.09 nM). In addition, lateral chain displacement from position 1 to 2 of the furan core had no effect on the binding affinity at both MT1 and MT2, while elongation of this side chain, led to decreased melatonergic binding affinities.
|
Displacement of 2-[125I]iodomelatonin from human MT1 receptor expressed in HEK or CHO cell membranes after 120 mins
|
Homo sapiens
|
0.1
nM
|
|
Journal : Eur J Med Chem
Title : New quinolinic derivatives as melatonergic ligands: Synthesis and pharmacological evaluation.
Year : 2017
Volume : 127
First Page : 621
Last Page : 631
Authors : Landagaray E, Ettaoussi M, Rami M, Boutin JA, Caignard DH, Delagrange P, Melnyk P, Berthelot P, Yous S.
Abstract : New series of melatonergic ligands issued from two methoxy-quinolinic scaffolds (2-MQ and 3-MQ), were designed and synthesized. Herein we report the synthetic scheme and pharmacological results of the new prepared compounds. Investigation of compound 11a, the strict 2-MQ analogue, revealed the promising potential of this series. Therefore, pharmacomodulation of the acetamide function of 11a has led to compounds with different pharmacological profiles and the emergence of an MT2 selectivity. Besides, sulphonamide 11b showed the most important MT2 selectivity of this series (167 folds) while methyl and ethyl-ureas 11f and 11g represented the most potent melatonergic ligands of this study.
|
Displacement of 2-[125I]iodomelatonin from human MT2 receptor expressed in HEK or CHO cell membranes after 120 mins
|
Homo sapiens
|
0.2
nM
|
|
Journal : Eur J Med Chem
Title : New quinolinic derivatives as melatonergic ligands: Synthesis and pharmacological evaluation.
Year : 2017
Volume : 127
First Page : 621
Last Page : 631
Authors : Landagaray E, Ettaoussi M, Rami M, Boutin JA, Caignard DH, Delagrange P, Melnyk P, Berthelot P, Yous S.
Abstract : New series of melatonergic ligands issued from two methoxy-quinolinic scaffolds (2-MQ and 3-MQ), were designed and synthesized. Herein we report the synthetic scheme and pharmacological results of the new prepared compounds. Investigation of compound 11a, the strict 2-MQ analogue, revealed the promising potential of this series. Therefore, pharmacomodulation of the acetamide function of 11a has led to compounds with different pharmacological profiles and the emergence of an MT2 selectivity. Besides, sulphonamide 11b showed the most important MT2 selectivity of this series (167 folds) while methyl and ethyl-ureas 11f and 11g represented the most potent melatonergic ligands of this study.
|
Intrinsic activity at human MT1 receptor expressed in CHO cell membranes after 1 hr by [35S]GTPgammaS binding assay
|
Homo sapiens
|
1.4
nM
|
|
Journal : Eur J Med Chem
Title : New quinolinic derivatives as melatonergic ligands: Synthesis and pharmacological evaluation.
Year : 2017
Volume : 127
First Page : 621
Last Page : 631
Authors : Landagaray E, Ettaoussi M, Rami M, Boutin JA, Caignard DH, Delagrange P, Melnyk P, Berthelot P, Yous S.
Abstract : New series of melatonergic ligands issued from two methoxy-quinolinic scaffolds (2-MQ and 3-MQ), were designed and synthesized. Herein we report the synthetic scheme and pharmacological results of the new prepared compounds. Investigation of compound 11a, the strict 2-MQ analogue, revealed the promising potential of this series. Therefore, pharmacomodulation of the acetamide function of 11a has led to compounds with different pharmacological profiles and the emergence of an MT2 selectivity. Besides, sulphonamide 11b showed the most important MT2 selectivity of this series (167 folds) while methyl and ethyl-ureas 11f and 11g represented the most potent melatonergic ligands of this study.
|
Intrinsic activity at human MT2 receptor expressed in CHO cell membranes after 1 hr by [35S]GTPgammaS binding assay
|
Homo sapiens
|
0.18
nM
|
|
Journal : Eur J Med Chem
Title : New quinolinic derivatives as melatonergic ligands: Synthesis and pharmacological evaluation.
Year : 2017
Volume : 127
First Page : 621
Last Page : 631
Authors : Landagaray E, Ettaoussi M, Rami M, Boutin JA, Caignard DH, Delagrange P, Melnyk P, Berthelot P, Yous S.
Abstract : New series of melatonergic ligands issued from two methoxy-quinolinic scaffolds (2-MQ and 3-MQ), were designed and synthesized. Herein we report the synthetic scheme and pharmacological results of the new prepared compounds. Investigation of compound 11a, the strict 2-MQ analogue, revealed the promising potential of this series. Therefore, pharmacomodulation of the acetamide function of 11a has led to compounds with different pharmacological profiles and the emergence of an MT2 selectivity. Besides, sulphonamide 11b showed the most important MT2 selectivity of this series (167 folds) while methyl and ethyl-ureas 11f and 11g represented the most potent melatonergic ligands of this study.
|
Displacement of 2-[125I]Iodomelatonin from human MT1 receptor expressed in CHO cell membranes after 120 mins
|
Homo sapiens
|
0.1202
nM
|
|
Journal : MedChemComm
Year : 2014
Volume : 5
Issue : 9
First Page : 1303
Last Page : 1308
|
Displacement of 2-[125I]Iodomelatonin from human MT2 receptor expressed in CHO cell membranes after 120 mins
|
Homo sapiens
|
0.3802
nM
|
|
Journal : MedChemComm
Year : 2014
Volume : 5
Issue : 9
First Page : 1303
Last Page : 1308
|
Displacement of [3H]mesulergine from human 5HT2C (VSV) receptor expressed in CHO cell membranes after 60 mins by scintillation counting method
|
Homo sapiens
|
707.95
nM
|
|
Journal : MedChemComm
Year : 2014
Volume : 5
Issue : 9
First Page : 1303
Last Page : 1308
|
Agonist activity at human MT1 receptor expressed in CHO cells after 1 hr by [35S]GTPgammaS binding assay
|
Homo sapiens
|
0.1995
nM
|
|
Journal : MedChemComm
Year : 2014
Volume : 5
Issue : 9
First Page : 1303
Last Page : 1308
|
Agonist activity at human MT2 receptor expressed in CHO cells after 1 hr by [35S]GTPgammaS binding assay
|
Homo sapiens
|
0.06918
nM
|
|
Journal : MedChemComm
Year : 2014
Volume : 5
Issue : 9
First Page : 1303
Last Page : 1308
|
Displacement of 2-[125I]iodomelatonin from human MT1 receptor expressed in CHO cell membranes after 120 mins by filter binding method
|
Homo sapiens
|
0.1
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of new naphtho- and quinolinocyclopentane derivatives as potent melatoninergic (MT1/MT2) and serotoninergic (5-HT2C) dual ligands.
Year : 2017
Volume : 141
First Page : 552
Last Page : 566
Authors : Duroux R, Rami M, Landagaray E, Ettaoussi M, Caignard DH, Delagrange P, Melnyk P, Yous S.
Abstract : We recently reported a series of naphthofuranic compounds as constrained agomelatine analogues. Herein, in order to explore alternative ethyl amide side chain rigidification, naphthocyclopentane and quinolinocyclopentane derivatives with various acetamide modulations were synthesized and evaluated at both melatonin (MT1, MT2) and serotonin (5-HT2C) receptors. These modifications has led to compounds with promising dual affinity and high MTs receptors agonist activity. Enantiomeric separation was then performed on selected compounds allowing us to identify levogyre enantiomers (-)-17g and (-)-17k as the highest (MT1, MT2)/5-HT2C dual ligands described nowadays.
|
Displacement of 2-[125I]iodomelatonin from human MT2 receptor expressed in CHO cell membranes after 120 mins by filter binding method
|
Homo sapiens
|
0.2
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of new naphtho- and quinolinocyclopentane derivatives as potent melatoninergic (MT1/MT2) and serotoninergic (5-HT2C) dual ligands.
Year : 2017
Volume : 141
First Page : 552
Last Page : 566
Authors : Duroux R, Rami M, Landagaray E, Ettaoussi M, Caignard DH, Delagrange P, Melnyk P, Yous S.
Abstract : We recently reported a series of naphthofuranic compounds as constrained agomelatine analogues. Herein, in order to explore alternative ethyl amide side chain rigidification, naphthocyclopentane and quinolinocyclopentane derivatives with various acetamide modulations were synthesized and evaluated at both melatonin (MT1, MT2) and serotonin (5-HT2C) receptors. These modifications has led to compounds with promising dual affinity and high MTs receptors agonist activity. Enantiomeric separation was then performed on selected compounds allowing us to identify levogyre enantiomers (-)-17g and (-)-17k as the highest (MT1, MT2)/5-HT2C dual ligands described nowadays.
|
Displacement of [3H]-mesulergine from human 5-HT2C receptor expressed in CHO cell membranes after 60 mins by TopCount scintillation counting method
|
Homo sapiens
|
708.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of new naphtho- and quinolinocyclopentane derivatives as potent melatoninergic (MT1/MT2) and serotoninergic (5-HT2C) dual ligands.
Year : 2017
Volume : 141
First Page : 552
Last Page : 566
Authors : Duroux R, Rami M, Landagaray E, Ettaoussi M, Caignard DH, Delagrange P, Melnyk P, Yous S.
Abstract : We recently reported a series of naphthofuranic compounds as constrained agomelatine analogues. Herein, in order to explore alternative ethyl amide side chain rigidification, naphthocyclopentane and quinolinocyclopentane derivatives with various acetamide modulations were synthesized and evaluated at both melatonin (MT1, MT2) and serotonin (5-HT2C) receptors. These modifications has led to compounds with promising dual affinity and high MTs receptors agonist activity. Enantiomeric separation was then performed on selected compounds allowing us to identify levogyre enantiomers (-)-17g and (-)-17k as the highest (MT1, MT2)/5-HT2C dual ligands described nowadays.
|
Agonist activity at human MT2 receptor expressed in CHO cell membranes after 1 hr by [35S]GTPgammaS binding assay
|
Homo sapiens
|
0.18
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of new naphtho- and quinolinocyclopentane derivatives as potent melatoninergic (MT1/MT2) and serotoninergic (5-HT2C) dual ligands.
Year : 2017
Volume : 141
First Page : 552
Last Page : 566
Authors : Duroux R, Rami M, Landagaray E, Ettaoussi M, Caignard DH, Delagrange P, Melnyk P, Yous S.
Abstract : We recently reported a series of naphthofuranic compounds as constrained agomelatine analogues. Herein, in order to explore alternative ethyl amide side chain rigidification, naphthocyclopentane and quinolinocyclopentane derivatives with various acetamide modulations were synthesized and evaluated at both melatonin (MT1, MT2) and serotonin (5-HT2C) receptors. These modifications has led to compounds with promising dual affinity and high MTs receptors agonist activity. Enantiomeric separation was then performed on selected compounds allowing us to identify levogyre enantiomers (-)-17g and (-)-17k as the highest (MT1, MT2)/5-HT2C dual ligands described nowadays.
|
Agonist activity at human MT1 receptor expressed in CHO cell membranes after 1 hr by [35S]GTPgammaS binding assay
|
Homo sapiens
|
1.4
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of new naphtho- and quinolinocyclopentane derivatives as potent melatoninergic (MT1/MT2) and serotoninergic (5-HT2C) dual ligands.
Year : 2017
Volume : 141
First Page : 552
Last Page : 566
Authors : Duroux R, Rami M, Landagaray E, Ettaoussi M, Caignard DH, Delagrange P, Melnyk P, Yous S.
Abstract : We recently reported a series of naphthofuranic compounds as constrained agomelatine analogues. Herein, in order to explore alternative ethyl amide side chain rigidification, naphthocyclopentane and quinolinocyclopentane derivatives with various acetamide modulations were synthesized and evaluated at both melatonin (MT1, MT2) and serotonin (5-HT2C) receptors. These modifications has led to compounds with promising dual affinity and high MTs receptors agonist activity. Enantiomeric separation was then performed on selected compounds allowing us to identify levogyre enantiomers (-)-17g and (-)-17k as the highest (MT1, MT2)/5-HT2C dual ligands described nowadays.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
42.24
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
21.04
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
14.2
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-4.536
%
|
|
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
|
-0.06
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.03
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.06
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.28
%
|
|
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
|
-0.03
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Displacement of 2-[125l]-lodomelatonin from human MT1 expressed in CHO cells incubated for 120 mins by radioligand binding assay
|
Homo sapiens
|
0.12
nM
|
|
Journal : Eur J Med Chem
Title : Quinazoline and phthalazine derivatives as novel melatonin receptor ligands analogues of agomelatine.
Year : 2020
Volume : 189
First Page : 112078
Last Page : 112078
Authors : Bolteau R,Descamps F,Ettaoussi M,Caignard DH,Delagrange P,Melnyk P,Yous S
Abstract : For further development of successors of Agomelatine through modulation of its pharmacokinetic properties, we report herein the design, synthesis and pharmacological results of a new family of melatonin receptor ligands. Issued from the introduction of quinazoline and phthalazine scaffolds carrying an ethyl amide lateral chain and a methoxy group as bioisosteric ligands analogues of previously developed Agomelatine. The biological activity of the prepared analogues was compared with that of Agomelatine. Quinazoline and phthalazine rings proved to be a versatile scaffold for easy feasible MT and MT ligands. Potent agonists with sub-micromolar binding affinity were obtained. However, the presence of two nitrogen atoms resulted in compounds with lower affinity for both MT and MT, in comparison with the parent compound, balanced by the exhibition of good pharmacokinetic properties.
|
Displacement of 2-[125l]-lodomelatonin from human MT2 expressed in CHO cells incubated for 120 mins by radioligand binding assay
|
Homo sapiens
|
0.21
nM
|
|
Journal : Eur J Med Chem
Title : Quinazoline and phthalazine derivatives as novel melatonin receptor ligands analogues of agomelatine.
Year : 2020
Volume : 189
First Page : 112078
Last Page : 112078
Authors : Bolteau R,Descamps F,Ettaoussi M,Caignard DH,Delagrange P,Melnyk P,Yous S
Abstract : For further development of successors of Agomelatine through modulation of its pharmacokinetic properties, we report herein the design, synthesis and pharmacological results of a new family of melatonin receptor ligands. Issued from the introduction of quinazoline and phthalazine scaffolds carrying an ethyl amide lateral chain and a methoxy group as bioisosteric ligands analogues of previously developed Agomelatine. The biological activity of the prepared analogues was compared with that of Agomelatine. Quinazoline and phthalazine rings proved to be a versatile scaffold for easy feasible MT and MT ligands. Potent agonists with sub-micromolar binding affinity were obtained. However, the presence of two nitrogen atoms resulted in compounds with lower affinity for both MT and MT, in comparison with the parent compound, balanced by the exhibition of good pharmacokinetic properties.
|
Agonist activity at human MT1 expressed in CHO cell membrane incubated for 1 hr by [35S]GTPgammaS binding assay
|
Homo sapiens
|
1.56
nM
|
|
Journal : Eur J Med Chem
Title : Quinazoline and phthalazine derivatives as novel melatonin receptor ligands analogues of agomelatine.
Year : 2020
Volume : 189
First Page : 112078
Last Page : 112078
Authors : Bolteau R,Descamps F,Ettaoussi M,Caignard DH,Delagrange P,Melnyk P,Yous S
Abstract : For further development of successors of Agomelatine through modulation of its pharmacokinetic properties, we report herein the design, synthesis and pharmacological results of a new family of melatonin receptor ligands. Issued from the introduction of quinazoline and phthalazine scaffolds carrying an ethyl amide lateral chain and a methoxy group as bioisosteric ligands analogues of previously developed Agomelatine. The biological activity of the prepared analogues was compared with that of Agomelatine. Quinazoline and phthalazine rings proved to be a versatile scaffold for easy feasible MT and MT ligands. Potent agonists with sub-micromolar binding affinity were obtained. However, the presence of two nitrogen atoms resulted in compounds with lower affinity for both MT and MT, in comparison with the parent compound, balanced by the exhibition of good pharmacokinetic properties.
|
Agonist activity at human MT2 expressed in CHO cell membrane incubated for 1 hr by [35S]GTPgammaS binding assay
|
Homo sapiens
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0.21
nM
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|
Journal : Eur J Med Chem
Title : Quinazoline and phthalazine derivatives as novel melatonin receptor ligands analogues of agomelatine.
Year : 2020
Volume : 189
First Page : 112078
Last Page : 112078
Authors : Bolteau R,Descamps F,Ettaoussi M,Caignard DH,Delagrange P,Melnyk P,Yous S
Abstract : For further development of successors of Agomelatine through modulation of its pharmacokinetic properties, we report herein the design, synthesis and pharmacological results of a new family of melatonin receptor ligands. Issued from the introduction of quinazoline and phthalazine scaffolds carrying an ethyl amide lateral chain and a methoxy group as bioisosteric ligands analogues of previously developed Agomelatine. The biological activity of the prepared analogues was compared with that of Agomelatine. Quinazoline and phthalazine rings proved to be a versatile scaffold for easy feasible MT and MT ligands. Potent agonists with sub-micromolar binding affinity were obtained. However, the presence of two nitrogen atoms resulted in compounds with lower affinity for both MT and MT, in comparison with the parent compound, balanced by the exhibition of good pharmacokinetic properties.
