| 1. |
- Andappan, Murugaiah M. S., et al.
(författare)
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From the First Selective Non-Peptide AT(2) Receptor Agonist to Structurally Related Antagonists
- 2012
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:5, s. 2265-2278
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Tidskriftsartikel (refereegranskat)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.
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| 2. |
- Botros, Milad, 1951-
(författare)
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Characterization of Substance P (SP) Aminoterminal SP (1-7) Binding in Brain Regions and Spinal Cord of the Male Rat : Studies on the Interaction with Opioid Related Pathways
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Binding sites for substance P(1-7), SP(1-7) have been identified and characterized for the first time in crude membrane fraction from rat CNS using tritiated ([3H]) SP(1-7) as tracer. These putative receptors were investigated in relation to their affinity for tachykinins, opioid peptides and sigma receptor ligands. [3H]-SP(1-7) specifically binds to high affinity binding sites identified as receptor targets for the heptapeptide SP (1-7). Two distinct binding sites were observed in the spinal cord. One site is recognized by high affinity for SP(1-7) with a Kd of 0.5 nM, whereas the other site showed low affinity for the heptapeptide (Kd=12 nM). In the brain, the binding of SP(1-7) fitted a single site binding model with a Kd of 4.4 nM and a Ki of 4.2 nM. Further, using the spinal cord membranes the binding of [3H]-SP (1-7) was weakly displaced by SP and other N-terminal fragments thereof and no or negligible affinity was observed for ligands of the NK-1, NK-2 and NK-3 tachykinin receptors, C-terminal SP(5-11), Tyr-w-MIF-1 or the mu-opioid receptor antagonists naloxone and naloxonazine. On the other hand it was significantly displaced by endomorphin-2, DAMGO, and Try-MIF-1 and exhibit some affinity for MIF-1, ß-casomorphin and endomorphin-1. However, only endomorphin-2, DAMGO and Tyr-MIF-1 showed affinity in the close range of the native peptide SP(1-7). The affinity of endomorphin-2 for the spinal cord site was 10 times lower than that of SP(1-7) but more than 100 times higher than the affinity recorded for endomorphin-1. Tyr-MIF-1 but not Tyr-w-MIF-1 showed similar affinity as endomorphin-2 for SP(1-7) site. All peptides exhibiting high affinity at the SP(1-7) site, have a phenylalanine or a leucine residue in their C-terminal structure.Further, synthetic analogues of SP(1-7) were tested for their affinity for the SP(1-7) receptor in the rat spinal cord. An important finding here was that the receptor-ligand-interaction was favoured by the C-terminal region of SP(1-7). Residues at positions 5-7 appeared crucial for binding to the specific SP(1-7) site. The presence of the amidated Phe7 residue was extremely critical for binding to the SP(1-7) site.The analogue Gln5-Gln6-Phe7-NH2 was almost equipotent with the parent peptide in the SP (1-7) receptor binding assay.Furthermore, the SP(1-7)-amide potently and dose dependently reduced several signs of the reaction to morphine withdrawal and was significantly attenuated by the addition of the sigma agonist SK-10047.In conclusion, the work presented in this thesis has contributed the characterization of the properties of highly selective binding sites for SP(1-7) in the rat spinal cord and VTA. These sites appear to be distinct from the µ-opioid receptor or any of the known neurokinin receptors. The study further indicates that the SP(1-7)-amide mimics the effect of the nativ heptapeptide and that the mechanisms for its action involve a sigma receptor site.
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| 3. |
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| 4. |
- Botros, Milad, et al.
(författare)
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Endomorphins interact with the substance P (SP) aminoterminal SP (1-7) binding in the ventral tegmental area of the rat brain
- 2008
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Ingår i: Peptides. - : Elsevier BV. - 0196-9781 .- 1873-5169. ; 29:10, s. 1820-1824
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Tidskriftsartikel (refereegranskat)abstract
- We have recently identified a specific binding site for the tachykinin peptide substance P (SP) fragment SP1-7 in the rat spinal cord. This site appeared very specific for SP1-7 as the binding affinity of this compound highly exceeded those of other SP fragments. We also observed that endomorphin-2 (EM-2) exhibited high potency in displacing SP1-7 from this site. In the present work using a [H-3]-labeled derivative of the heptapeptide we have identified and characterized [H-3]-SP1-7 binding in the rat ventral tegmental area (VTA). Similarly to the [H-3]-SP1-7 binding in the spinal cord the affinity of unlabeled SP1-7 to the specific site in VTA was significantly higher than those of other SP fragments. Further, the tachykinin receptor NK-1, NK-2 and NK-3 ligands showed no or negligible binding to the identified site. However, the mu-opioid peptide (MOP) receptor agonists DAMGO, EM-1 and EM-2 did, and significant difference was observed in the binding affinity between the two endomorphins. As recorded from displacement curves the affinity of EM-2 for the SP1-7 site was 4-5 times weaker than that for SP1-7 but about 5 times higher than that of EM-1. The opioid receptor antagonists naloxone and naloxonazine showed weak or negligible binding. it was concluded that the specific site identified for SP1-7 binding in the rat VTA is distinct from the MOP receptor although it exhibits high affinity for EM-2.
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| 5. |
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| 6. |
- Fransson, Rebecca, et al.
(författare)
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Discovery of Dipeptides with High Affinity to the Specific Binding Site for Substance P1-7
- 2010
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 53:6, s. 2383-2389
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Tidskriftsartikel (refereegranskat)abstract
- Substance P 1-7 (SP1-7, 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 p-opioid receptor agonist endomorphin-2 (EM-2, H-Tyr-Pro-Phe-Phe-NH2) has been found to also interact with the specific binding site of SP1-7 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 SP1-7 binding site. An alanine scan and truncation study led to the unexpected discovery of the dipeptide H-Phe-Phe-NH2 (K-i = 1.5 nM), having equal affinity as the endogenous heptapeptide SP1-7. Moreover, the studies show that the C-terminal phenylalanine amide is crucial for the affinity of the dipeptide.
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| 7. |
- Fransson, Rebecca, et al.
(författare)
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Small peptides mimicking substance P (1-7) and encompassing a C-terminal amide functionality
- 2008
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Ingår i: Neuropeptides. - : Elsevier BV. - 0143-4179 .- 1532-2785. ; 42:1, s. 31-37
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Tidskriftsartikel (refereegranskat)abstract
- Some of the biological effects demonstrated after administration of substance P (SP) in vivo can indirectly be attributed to the fragmentation of the undecapeptide to its N-terminal bioactive fragment SP1–7. This heptapeptide (H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH) is a major bioactive metabolite from SP that frequently exerts similar biological effects as the parent peptide but also, in several cases, completely opposite actions. Specific binding sites for the heptapeptide SP1–7 that are separate from the SP preferred NK receptors have been identified. In this study we demonstrate that (a) the C-terminal part of the SP metabolite SP1–7 is most important for binding as deduced from an Ala scan and that a replacement of Phe7 for Ala is deleterious, (b) truncation of the N-terminal amino acid residues of SP1–7 delivers peptides with retained binding activity, although with somewhat lower binding affinities than SP1–7 and (c) a C-terminal amide group as a replacement for the terminal carboxy group of SP1–7 and for all of the truncated ligands synthesized affords approximately 5–10-fold improvements of the binding affinities.
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| 8. |
- Georgsson, Jennie, et al.
(författare)
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Angiotensin II Pseudopeptides Containing 1,3,5-Trisubstituted Benzene Scaffolds with High AT2 Receptor Affinity
- 2005
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 48:21, s. 6620-6631
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Tidskriftsartikel (refereegranskat)abstract
- Two 1,3,5-trisubstituted aromatic scaffolds intended to serve as γ-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 Ki of 1.85 nM. Four pseudopeptides were AT2 selective, while one (5) also exhibited good affinity for the AT1 receptor (Ki = 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 γ-turn mimics.
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| 9. |
- Georgsson, Jennie, et al.
(författare)
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Short pseudopeptides containing turn scaffolds with high AT(2) receptor affinity
- 2006
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 14:17, s. 5963-5972
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Tidskriftsartikel (refereegranskat)abstract
- Two pentapeptides, Ac-Tyr-Ile-His-Pro-Phe/Ile, were synthesized and shown to have angiotensin II AT(2) receptor affinity and agonistic activity. Based on these peptides, a new series of 13 pseudopeptides was synthesized via introduction of five different turn scaffolds replacing the Tyr-Ile amino acid residues. Pharmacological evaluation disclosed subnanomolar affinities for some of these compounds at the AT(2) receptor. Substitution of Phe by Ile in this series of ligands enhanced the AT(2) receptor affinity of all compounds. These results suggest that the C-terminal amino acid residues can be elaborated on to enhance the AT(2) receptor affinity in truncated Ang II analogues.
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| 10. |
- Georgsson, Jennie, et al.
(författare)
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Synthesis of a new class of druglike angiotensin II C-terminal mimics with affinity for the AT2 receptor
- 2007
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 50:7, s. 1711-1715
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Tidskriftsartikel (refereegranskat)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.
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| 11. |
- Mahalingam, A. K., et al.
(författare)
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Selective angiotensin II AT(2) receptor agonists with reduced CYP 450 inhibition
- 2010
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 18:12, s. 4570-4590
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Tidskriftsartikel (refereegranskat)abstract
- Structural alterations to the benzylic position of the first drug-like selective angiotensin II AT(2) receptor agonist (1) have been performed, with the emphasis to reduce the CYP 450 inhibitory property of the initial structure. The imidazole moiety, responsible for the CYP 450 inhibitory effect in 1, was replaced with various heterocycles. In addition, the modes of attachment of the heterocycles, that is, carbon versus nitrogen attachment, and introduction of carbonyl functionalities to the benzylic position have been evaluated. In all the three series, AT(2) receptor ligands with affinity in the lower nanomolar range were identified. None of the analogues, regardless of the substituents, exhibited any affinity for the AT(1) receptor. Compounds with substantially reduced inhibition of the CYP 450 enzymes were obtained. Among them the compound 60 was found to induce neurite elongation in NG 108-15 cells and served as potent AT(2) selective agonist.
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| 12. |
- Murugaiah, A. M. S., et al.
(författare)
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Selective angiotensin II AT(2) receptor agonists devoid of the imidazole ring system
- 2007
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 15:22, s. 7166-7183
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Tidskriftsartikel (refereegranskat)abstract
- A versatile parallel synthetic method to obtain three series of non-cyclic analogues of the first drug-like selective angiotensin II AT2 receptor agonist (1) has been developed. In analogy with the transformation of losartan to valsartan it was demonstrated that a non-cyclic moiety could be employed as an imidazole replacement to obtain AT2 selective compounds. In all the three series, AT2 receptor ligands with affinities in the lower nanomolar range were found. None of the analogues exhibited any affinity for the AT1 receptor. Four compounds, 17, 22, 39 and 51, were examined in a neurite outgrowth cell assay. All four compounds were found to exert a high agonistic effect as deduced from their capacity to induce neurite elongation in neuronal cells, as does angiotensin II.
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| 13. |
- Rosenström, Ulrika, et al.
(författare)
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A Selective AT2 Receptor Ligand with a γ-Turn-Like Mimetic replacing the Amino Acid Residues 4-5 of Angiotensin II
- 2004
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 47:4, s. 859-870
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Tidskriftsartikel (refereegranskat)abstract
- Three angiotensin II (Ang II) analogues encompassing a benzodiazepine-based γ-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 AT1 receptor. However, one of the compounds displayed considerable affinity to the pig uterus AT2 receptor (Ki = 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 AT2 receptor was that the guanidino group of the Arg2 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−CH2−S)[Cys3,5]Ang II which is known to bind with high affinity to the AT2 receptor (Ki = 0.62 nM). This comparison showed that, in the compounds with high AT2 receptor affinity, the guanidino group of the Arg2 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 Arg2 for Ala2 in the analogue having the high affinity. This analogue lacked affinity to AT2 receptors, which supports the role of the guanidino group in receptor binding.
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| 14. |
- Rosenström, Ulrika, et al.
(författare)
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Design, synthesis, and incorporation of a beta-turn mimetic in angiotensin II forming novel pseudopeptides with affinity for AT(1) and AT(2) receptors
- 2006
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 49:20, s. 6133-6137
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Tidskriftsartikel (refereegranskat)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 AT(2) receptor, and one also displayed high affinity for the AT(1) receptor. Molecular modeling showed that the high-affinity compounds could be incorporated into a previously derived model of AT(2) receptor ligands.
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| 15. |
- Rosenström, Ulrika, et al.
(författare)
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New selective AT2 receptor ligands encompassing a γ-turn mimetic replacing the amino acid residues 4-5 of angiotensin II act as agonists
- 2005
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 48:12, s. 4009-4024
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Tidskriftsartikel (refereegranskat)abstract
- New benzodiazepine-based γ-turn mimetics with one or two amino acid side chains were synthesized. The γ-turn mimetics were incorporated into angiotensin II (Ang II) replacing the Val3-Tyr4-Ile5 or Tyr4-Ile5 peptide segments. All of the resulting pseudopeptides displayed high AT2/AT1 receptor selectivity and exhibited AT2 receptor affinity in the low nanomolar range. Molecular modeling was used to investigate whether the compounds binding to the AT2 receptor could position important structural elements in common areas. A previously described benzodiazepine-based γ-turn mimetic with high affinity for the AT2 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 AT2 receptor agonists being able to induce outgrowth of neurite cells, stimulate p42/p44mapk, and suppress proliferation of PC12 cells.
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| 16. |
- Rosenström, Ulrika, et al.
(författare)
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Synthesis and AT2 receptor-binding properties of angiotensin II analogues
- 2004
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Ingår i: Journal of Peptide Research. - : Wiley. - 1397-002X .- 1399-3011. ; 64:5, s. 194-201
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Tidskriftsartikel (refereegranskat)abstract
- The present study investigates the importance of the amino acid side chains in the octapeptide angiotensin II (Ang II) for binding to the AT2 receptor. A Gly scan was performed where each amino acid in Ang II was substituted one-by-one with glycine. The resulting set of peptides was tested for affinity to the AT2 receptor (porcine myometrial membranes). For a comparison, the peptides were also tested for affinity to the AT1 receptor (rat liver membranes). Only the substitution of Arg2 reduced affinity to the AT2 receptor considerably (92-fold when compared with Ang II). For the other Gly-substituted analogues the affinity to the AT2 receptor was only moderately affected. To further investigate the role of the Arg2 side chain for receptor binding, we synthesized some N-terminally modified Ang II analogues. According to these studies a positive charge in the N-terminal end of angiotensin III [Ang II (2–8)] is not required for high AT2 receptor affinity but seems to be more important in Ang II. With respect to the AT1 receptor, [Gly2]Ang II and [Gly8]Ang II lacked binding affinity (Ki > 10 μm). Replacement of the Val3 or Ile5 residues with Gly produced only a slight decrease in affinity. Interestingly, substitution of Tyr4 or His6, which are known to be very important for AT1 receptor binding, resulted in only 48 and 14 times reduction in affinity, respectively.
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| 17. |
- Wallinder, Charlotta, et al.
(författare)
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Interconversion of Functional Activity by Minor Structural Alterations in Nonpeptide AT2 Receptor Ligands
- 2015
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Ingår i: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 6:2, s. 178-182
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Tidskriftsartikel (refereegranskat)abstract
- Migration of the methylene imidazole side chain in the first reported selective drug-like AT, receptor agonist C21/M024 (1) delivered the AT, receptor antagonist C38/M132 (2). We now report that the AT, receptor antagonist compound 4, a biphenyl derivative that is structurally related to 2, is transformed to the agonist 6 by migration of the isobutyl group. The importance of the relative position of the methylene imidazole and the isobutyl substituent is highlighted herein.
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| 18. |
- Wallinder, Charlotta, et al.
(författare)
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Selective angiotensin II AT2 receptor agonists : Benzamide structure–activity relationships
- 2008
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 16:14, s. 6841-6849
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Tidskriftsartikel (refereegranskat)abstract
- In the investigation of the structure–activity relationship of nonpeptide AT2 receptor agonists, a series of substituted benzamide analogues of the selective nonpeptide AT2 receptor agonist M024 have been synthesised. In a second series, the biphenyl scaffold was compared to the thienylphenyl scaffold and the impact of the isobutyl substituent and its position on AT1/AT2 receptor selectivity was also investigated. Both series included several compounds with high affinity and selectivity for the AT2 receptor. Three of the compounds were also proven to function as agonists at the AT2 receptor, as deduced from a neurite outgrowth assay, conducted in NG108-15 cells.
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| 19. |
- Wu, Xiongyu, et al.
(författare)
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Selective angiotensin II AT(2) receptor agonists : Arylbenzylimidazole structure-activity relationships
- 2006
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 49:24, s. 7160-7168
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Tidskriftsartikel (refereegranskat)abstract
- Structural alterations in the 2- and 5-positions of the first drug-like selective angiotensin II AT(2) receptor agonist (1) have been performed. The imidazole ring system was proven to be a strong determinant for the AT(2) selectivity, and with few exceptions all variations gave good AT(2) receptor affinities and with retained high AT(2)/AT(1) selectivities. On the contrary to the findings with AT(1) receptor agonists, the impact of structural modifications in the 5-position of the AT(2) selective compounds were less pronounced regarding activation of the AT(2) 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.
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| 20. |
- Zhou, Qin, et al.
(författare)
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The C-terminal amidated analogue of the Substance P (SP) fragment SP (1-7) attenuates the expression of naloxone- precipitated withdrawal in morphine dependent rats
- 2009
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Ingår i: Peptides. - : Elsevier BV. - 0196-9781 .- 1873-5169. ; 30:12, s. 2418-2422
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Tidskriftsartikel (refereegranskat)abstract
- We previously demonstrated that intracerebroventricular (i.c.v.) administration of the substance P (SP) aminoterminal fragment SP(1-7) attenuates the expression of morphine withdrawal in the male rat. In this study we have used a synthetic analogue of this peptide, i.e. the SP(1-7) amide showing higher binding potency than the native heptapeptide, in a similar experimental set-up. Thus, Wistar male rats were made tolerant to morphine by daily injections of the opiate during 8 days. Following peptide administration (i.c.v.) and a subsequent naloxone challenge a variety of physical syndromes of withdrawal were recorded. We observed that the SP(1-7) amide potently and dose-dependently reduced several signs of reaction to morphine withdrawal. Interestingly, the effect of the peptide amide was significantly attenuated by the addition of the sigma agonist (+)-SKF-10047. We conclude that the SP(1-7) amide mimics the effect of the native SP fragment and that the mechanisms for its action involve a sigma receptor site.
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