10 results on '"Botros, M"'
Search Results
2. From the first selective non-peptide AT(2) receptor agonist to structurally related antagonists.
- Author
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Murugaiah AM, Wu X, Wallinder C, Mahalingam AK, Wan Y, Sköld C, Botros M, Guimond MO, Joshi A, Nyberg F, Gallo-Payet N, Hallberg A, and Alterman M
- Subjects
- Angiotensin II Type 2 Receptor Blockers chemistry, Angiotensin II Type 2 Receptor Blockers pharmacology, Animals, Carbamates chemistry, Carbamates pharmacology, Female, Imidazoles chemistry, Imidazoles pharmacology, In Vitro Techniques, Liver metabolism, Myometrium metabolism, Radioligand Assay, Rats, Receptor, Angiotensin, Type 2 agonists, Structure-Activity Relationship, Sulfonamides chemistry, Sulfonamides pharmacology, Swine, Thiophenes chemistry, Thiophenes pharmacology, Angiotensin II Type 2 Receptor Blockers chemical synthesis, Carbamates chemical synthesis, Imidazoles chemical synthesis, Receptor, Angiotensin, Type 2 metabolism, Sulfonamides chemical synthesis, Thiophenes chemical synthesis
- Abstract
A para substitution pattern of the phenyl ring is a characteristic feature of the first reported selective AT(2) receptor agonist M024/C21 (1) and all the nonpeptidic AT(2) receptor agonists described so far. Two series of compounds structurally related to 1 but with a meta substitution pattern have now been synthesized and biologically evaluated for their affinity to the AT(1) and AT(2) receptors. A high AT(2)/AT(1) receptor selectivity was obtained with all 41 compounds synthesized, and the majority exhibited K(i) ranging from 2 to 100 nM. Five compounds were evaluated for their functional activity at the AT(2) receptor, applying a neurite outgrowth assay in NG108-15 cells. Notably, four of the five compounds, with representatives from both series, acted as potent AT(2) receptor antagonists. These compounds were found to be considerably more effective than PD 123,319, the standard AT(2) receptor antagonist used in most laboratories. No AT(2) receptor antagonists were previously reported among the derivatives with a para substitution pattern. Hence, by a minor modification of the agonist 1 it could be transformed into the antagonist, compound 38. These compounds should serve as valuable tools in the assessment of the role of the AT(2) receptor in more complex physiological models.
- Published
- 2012
- Full Text
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3. Discovery of dipeptides with high affinity to the specific binding site for substance P1-7.
- Author
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Fransson R, Botros M, Sköld C, Nyberg F, Lindeberg G, Hallberg M, and Sandström A
- Subjects
- Amino Acid Sequence, Animals, Binding Sites, Binding, Competitive, Dipeptides chemical synthesis, Drug Discovery, Humans, Kinetics, Male, Molecular Structure, Peptide Fragments chemistry, Protein Binding, Radioligand Assay, Rats, Rats, Sprague-Dawley, Receptors, Neurokinin-1 metabolism, Receptors, Neurokinin-3 metabolism, Spinal Cord metabolism, Substance P chemistry, Dipeptides chemistry, Dipeptides metabolism, Peptide Fragments metabolism, Substance P metabolism
- Abstract
Substance P 1-7 (SP(1-7), H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH) is the major bioactive metabolite of substance P. The interest in this heptapeptide originates from the observation that it modulates, and in certain cases opposes the effects of the parent peptide, e.g., the nociceptive effect. The mu-opioid receptor agonist endomorphin-2 (EM-2, H-Tyr-Pro-Phe-Phe-NH(2)) has been found to also interact with the specific binding site of SP(1-7) with only a 10-fold lower affinity compared to the native peptide. Considering the smaller size of EM-2 compared to the target heptapeptide, it was selected as a lead compound in the development of low-molecular-weight ligands to the SP(1-7) binding site. An alanine scan and truncation study led to the unexpected discovery of the dipeptide H-Phe-Phe-NH(2) (K(i) = 1.5 nM), having equal affinity as the endogenous heptapeptide SP(1-7.) Moreover, the studies show that the C-terminal phenylalanine amide is crucial for the affinity of the dipeptide.
- Published
- 2010
- Full Text
- View/download PDF
4. Synthesis of a new class of druglike angiotensin II C-terminal mimics with affinity for the AT2 receptor.
- Author
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Georgsson J, Sköld C, Botros M, Lindeberg G, Nyberg F, Karlén A, Hallberg A, and Larhed M
- Subjects
- Animals, Female, In Vitro Techniques, Ligands, Liver metabolism, Models, Molecular, Molecular Mimicry, Myometrium metabolism, Oligopeptides chemistry, Oligopeptides pharmacology, Radioligand Assay, Rats, Structure-Activity Relationship, Swine, Angiotensin II chemistry, Oligopeptides chemical synthesis, Receptor, Angiotensin, Type 2 agonists
- Abstract
Four tripeptides corresponding to the C-terminal region of angiotensin II were synthesized. One of these peptides (Ac-His-Pro-Ile) showed moderate binding affinity for the AT2 receptor. Two aromatic histidine-related scaffolds were synthesized and introduced in the tripeptides to give eight new peptidomimetic structures. Three of the new peptide-derived druglike molecules exhibited selective, nanomolar affinity for the AT2 receptor. These ligands may become lead compounds in the future development of novel classes of selective AT2 receptor agonists.
- Published
- 2007
- Full Text
- View/download PDF
5. Selective angiotensin II AT2 receptor agonists: arylbenzylimidazole structure-activity relationships.
- Author
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Wu X, Wan Y, Mahalingam AK, Murugaiah AM, Plouffe B, Botros M, Karlén A, Hallberg M, Gallo-Payet N, and Alterman M
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- Animals, Benzimidazoles chemistry, Benzimidazoles pharmacology, Cell Differentiation drug effects, Cell Line, Tumor, Female, Ligands, Liver metabolism, Neurites drug effects, Neurites physiology, Radioligand Assay, Rats, Structure-Activity Relationship, Sulfonamides chemistry, Sulfonamides pharmacology, Swine, Thiophenes chemistry, Thiophenes pharmacology, Uterus metabolism, Benzimidazoles chemical synthesis, Receptor, Angiotensin, Type 2 agonists, Sulfonamides chemical synthesis, Thiophenes chemical synthesis
- Abstract
Structural alterations in the 2- and 5-positions of the first drug-like selective angiotensin II AT2 receptor agonist (1) have been performed. The imidazole ring system was proven to be a strong determinant for the AT2 selectivity, and with few exceptions all variations gave good AT2 receptor affinities and with retained high AT2/AT1 selectivities. On the contrary to the findings with AT1 receptor agonists, the impact of structural modifications in the 5-position of the AT2 selective compounds were less pronounced regarding activation of the AT2 receptor. The butyloxyphenyl (56) and the propylthienyl (50) derivatives were found to exert a high agonistic effect as deduced from their capacity to induce neurite elongation in neuronal cells, as does angiotensin II.
- Published
- 2006
- Full Text
- View/download PDF
6. Design, synthesis, and incorporation of a beta-turn mimetic in angiotensin II forming novel pseudopeptides with affinity for AT1 and AT2 receptors.
- Author
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Rosenström U, Sköld C, Lindeberg G, Botros M, Nyberg F, Karlén A, and Hallberg A
- Subjects
- Animals, Aorta, Thoracic drug effects, Aorta, Thoracic physiology, Benzodiazepines chemistry, Benzodiazepines pharmacology, Drug Design, Female, In Vitro Techniques, Ligands, Liver drug effects, Liver metabolism, Models, Molecular, Molecular Mimicry, Muscle Contraction drug effects, Muscle, Smooth, Vascular drug effects, Muscle, Smooth, Vascular physiology, Protein Structure, Secondary, Rabbits, Radioligand Assay, Rats, Receptor, Angiotensin, Type 1 metabolism, Receptor, Angiotensin, Type 2 metabolism, Swine, Uterus drug effects, Uterus metabolism, Angiotensin II chemistry, Benzodiazepines chemical synthesis, Peptides chemistry, Receptor, Angiotensin, Type 1 agonists, Receptor, Angiotensin, Type 2 agonists
- Abstract
A benzodiazepine-based beta-turn mimetic has been designed, synthesized, and incorporated into angiotensin II. Comparison of the mimetic with beta-turns in crystallized proteins showed that it most closely resembles a type II beta-turn. The compounds exhibited high to moderate binding affinity for the AT2 receptor, and one also displayed high affinity for the AT1 receptor. Molecular modeling showed that the high-affinity compounds could be incorporated into a previously derived model of AT2 receptor ligands.
- Published
- 2006
- Full Text
- View/download PDF
7. Angiotensin II pseudopeptides containing 1,3,5-trisubstituted benzene scaffolds with high AT2 receptor affinity.
- Author
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Georgsson J, Sköld C, Plouffe B, Lindeberg G, Botros M, Larhed M, Nyberg F, Gallo-Payet N, Gogoll A, Karlén A, and Hallberg A
- Subjects
- Angiotensin II chemical synthesis, Angiotensin II pharmacology, Animals, Aorta, Thoracic drug effects, Aorta, Thoracic physiology, Benzene Derivatives pharmacology, Cell Line, Tumor, Female, In Vitro Techniques, Ligands, Liver metabolism, Models, Molecular, Molecular Mimicry, Muscle Contraction drug effects, Muscle, Smooth, Vascular drug effects, Muscle, Smooth, Vascular physiology, Myometrium metabolism, Neurites drug effects, Neurites physiology, Oligopeptides pharmacology, Protein Structure, Secondary, Rabbits, Radioligand Assay, Rats, Receptor, Angiotensin, Type 1 agonists, Receptor, Angiotensin, Type 1 metabolism, Receptor, Angiotensin, Type 2 metabolism, Swine, Angiotensin II analogs & derivatives, Benzene Derivatives chemical synthesis, Oligopeptides chemical synthesis, Receptor, Angiotensin, Type 2 agonists
- Abstract
Two 1,3,5-trisubstituted aromatic scaffolds intended to serve as gamma-turn mimetics have been synthesized and incorporated in five pseudopeptide analogues of angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe), replacing Val-Tyr-Ile, Val-Tyr, or Tyr-Ile. All the tested compounds exhibited nanomolar affinity for the AT2 receptor with the best compound (3) having a K(i) of 1.85 nM. Four pseudopeptides were AT2 selective, while one (5) also exhibited good affinity for the AT1 receptor (K(i) = 30.3 nM). This pseudopeptide exerted full agonistic activity in an AT2 receptor induced neurite outgrowth assay but displayed no agonistic effect in an AT1 receptor functional assay. Molecular modeling, using the program DISCOtech, showed that the high-affinity ligands could interact similarly with the AT2 receptor as other ligands with high affinity for this receptor. A tentative agonist model is proposed for AT2 receptor activation by angiotensin II analogues. We conclude that the 1,3,5-trisubstituted benzene rings can be conveniently prepared and are suitable as gamma-turn mimics.
- Published
- 2005
- Full Text
- View/download PDF
8. New selective AT2 receptor ligands encompassing a gamma-turn mimetic replacing the amino acid residues 4-5 of angiotensin II act as agonists.
- Author
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Rosenström U, Sköld C, Plouffe B, Beaudry H, Lindeberg G, Botros M, Nyberg F, Wolf G, Karlén A, Gallo-Payet N, and Hallberg A
- Subjects
- Amino Acid Substitution, Angiotensin II Type 2 Receptor Blockers, Animals, Benzodiazepines chemistry, Benzodiazepines pharmacology, Cell Line, Tumor, Cell Proliferation drug effects, Enzyme Activation, Female, Imidazoles pharmacology, In Vitro Techniques, Ligands, Liver drug effects, Liver metabolism, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, Models, Molecular, Molecular Mimicry, Myometrium drug effects, Myometrium metabolism, Neurites drug effects, Neurites physiology, Protein Conformation, Pyridines pharmacology, Radioligand Assay, Rats, Receptor, Angiotensin, Type 1 metabolism, Receptor, Angiotensin, Type 2 chemistry, Swine, Angiotensin II chemistry, Benzodiazepines chemical synthesis, Receptor, Angiotensin, Type 2 agonists
- Abstract
New benzodiazepine-based gamma-turn mimetics with one or two amino acid side chains were synthesized. The gamma-turn mimetics were incorporated into angiotensin II (Ang II) replacing the Val(3)-Tyr(4)-Ile(5) or Tyr(4)-Ile(5) peptide segments. All of the resulting pseudopeptides displayed high AT(2)/AT(1) receptor selectivity and exhibited AT(2) receptor affinity in the low nanomolar range. Molecular modeling was used to investigate whether the compounds binding to the AT(2) receptor could position important structural elements in common areas. A previously described benzodiazepine-based gamma-turn mimetic with high affinity for the AT(2) receptor was also included in the modeling. It was found that the molecules, although being structurally quite different, could adopt the same binding mode/interaction pattern in agreement with the model hypothesis. The pseudopeptides selected for agonist studies were shown to act as AT(2) receptor agonists being able to induce outgrowth of neurite cells, stimulate p42/p44(mapk), and suppress proliferation of PC12 cells.
- Published
- 2005
- Full Text
- View/download PDF
9. First reported nonpeptide AT1 receptor agonist (L-162,313) acts as an AT2 receptor agonist in vivo.
- Author
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Wan Y, Wallinder C, Johansson B, Holm M, Mahalingam AK, Wu X, Botros M, Karlén A, Pettersson A, Nyberg F, Fändriks L, Hallberg A, and Alterman M
- Subjects
- Angiotensin II Type 1 Receptor Blockers, Angiotensin II Type 2 Receptor Blockers, Animals, Binding, Competitive, Duodenum drug effects, Duodenum metabolism, Female, In Vitro Techniques, Intestinal Mucosa drug effects, Intestinal Mucosa metabolism, Male, Myometrium metabolism, Pyridines pharmacology, Radioligand Assay, Rats, Rats, Sprague-Dawley, Receptor, Angiotensin, Type 1 agonists, Swine, Biphenyl Compounds pharmacology, Imidazoles pharmacology, Receptor, Angiotensin, Type 2 agonists
- Abstract
In this investigation, it is demonstrated that the first nonpeptide AT(1) receptor agonist L-162,313 (1), disclosed in 1994, also acts as an agonist at the AT(2) receptor. In anesthetized rats, administration of compound 1 intravenously or locally in the duodenum increased duodenal mucosal alkaline secretion, effects that were sensitive to the selective AT(2) receptor antagonist PD-123,319. The data strongly suggest that 1 is an AT(2) receptor agonist in vivo. To the best of our knowledge, this substance is the first nonpeptidic low-molecular weight compound with an agonistic effect mediated through the AT(2) receptor.
- Published
- 2004
- Full Text
- View/download PDF
10. A selective AT2 receptor ligand with a gamma-turn-like mimetic replacing the amino acid residues 4-5 of angiotensin II.
- Author
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Rosenström U, Sköld C, Lindeberg G, Botros M, Nyberg F, Karlén A, and Hallberg A
- Subjects
- Angiotensin II chemical synthesis, Angiotensin II pharmacology, Animals, Benzodiazepines pharmacology, Binding, Competitive, Female, Imidazoles pharmacology, In Vitro Techniques, Ligands, Liver metabolism, Membranes, Models, Molecular, Molecular Conformation, Molecular Mimicry, Myometrium metabolism, Radioligand Assay, Rats, Structure-Activity Relationship, Swine, Angiotensin II analogs & derivatives, Benzodiazepines chemical synthesis, Imidazoles chemical synthesis, Receptor, Angiotensin, Type 2 metabolism
- Abstract
Three angiotensin II (Ang II) analogues encompassing a benzodiazepine-based gamma-turn-like scaffold have been synthesized. Evaluation of the compounds in a radioligand binding assay showed that they had no affinity to the rat liver AT(1) receptor. However, one of the compounds displayed considerable affinity to the pig uterus AT(2) receptor (K(i) = 3.0 nM) while the other two lacked affinity to this receptor. It was hypothesized that the reason for the inactivity of one of these analogues to the AT(2) receptor was that the guanidino group of the Arg(2) residue and/or the N-terminal end of the pseudopeptide could not interact optimally with the receptor. To investigate this hypothesis, a conformational analysis was performed and a comparison was carried out with the monocyclic methylenedithioether analogue cyclo(S-CH(2)-S)[Cys(3,5)]Ang II which is known to bind with high affinity to the AT(2) receptor (K(i) = 0.62 nM). This comparison showed that, in the compounds with high AT(2) receptor affinity, the guanidino group of the Arg(2) residue and the N-terminal end could access common regions of space that were not accessible to the inactive compound. To examine the importance of the guanidino group for binding, the Arg side chain was removed by substituting Arg(2) for Ala(2) in the analogue having the high affinity. This analogue lacked affinity to AT(2) receptors, which supports the role of the guanidino group in receptor binding.
- Published
- 2004
- Full Text
- View/download PDF
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