Ala scan analogues of HOE 140. Synthesis and biological activities

Quartara, Laura; Ricci, Renzo; Meini, Stefania; Patacchini, Riccardo; Giolitti, Alessandro; Amadesi, Silvia; Rizzi, Caterina; Rizzi, Anna; Varani, Katia; Borea, Pier Andrea; Maggi, Carlo Alberto; Regoli, Doménico

doi:10.1016/s0223-5234(00)01182-x

Cited by 9 publications

(9 citation statements)

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“…The K d value for the interaction between B2702p1 and VCAM-1 was approximately 15 mmol/L, a value about 50-fold higher than that for B2702, consistent with the observation that a decrease in ligand affinity frequently occurs with the alanine scan methodology (17). Several peptidic VCAM-1 ligands were recently described.…”

Section: Discussionsupporting

confidence: 82%

“…Additional modifications were also performed by inverting 2 residues before reiterating the alanine scan methodology on the premodified peptide (Table 1). The alanine scan strategy has been previously used to investigate the structure-activity relationship of peptidic receptor antagonists (17). Alanine scan modifications have been described as either decreasing, having no effect on, or possibly increasing the potency and metabolic stability of the peptide being modified (17)(18)(19).…”

Section: Discussionmentioning

confidence: 99%

“…Despite specific binding to aortic atherosclerotic lesions overexpressing VCAM-1 after in vivo injection and ex vivo autoradiographic imaging, the significant circulating blood activity of 99m Tc-and 123 I-B2702p prevented in vivo image acquisition. Discrete modifications in the amino acid sequence of a peptide might allow improvements in the in vivo biodistribution properties of the molecule without affecting its binding specificity (17)(18)(19). We therefore generated 20 derivatives of the previously evaluated B2702p peptide to test the hypothesis that limited modifications to the B2702p sequence might improve the blood elimination kinetics of the tracer while retaining VCAM-1-specific binding properties suitable for the in vivo imaging of VCAM-1 expression in an apolipoprotein E double-knockout (ApoE 2/2 ) mouse model of atherosclerosis.…”

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confidence: 99%

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In Vivo Molecular Imaging of Atherosclerotic Lesions in ApoE^−/− Mice Using VCAM-1–Specific, ^99mTc-Labeled Peptidic Sequences

et al. 2013

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Vascular cell adhesion molecule 1 (VCAM-1) plays a major role in the chronic inflammatory processes involved in vulnerable atherosclerotic plaque development. We previously showed that the 99m Tc-labeled major histocompatibility complex 1-derived peptide B2702p bound specifically to VCAM-1 and allowed the ex vivo imaging of atherosclerotic lesions in Watanabe heritable hyperlipidemic rabbits. However, B2702p target-to-background ratio was suboptimal for the in vivo imaging of VCAM-1 expression in atherosclerotic lesions. To improve the target-to-background ratio, 20 derivatives of B2702p (B2702p1-B2702p20) were synthesized using the alanine scan methodology. We hypothesized that 99m Tc-radiolabeled B2702p derivatives might allow the molecular imaging of VCAM-1 expression in an experimental model of atherosclerosis. Methods: A mouse model of focal atherosclerotic plaque development induced by left carotid artery ligation in apolipoprotein E double-knockout (ApoE 2/2 ) mice was used (n 5 82). 99m Tc-B2702p and 99m Tc-B2702p1-99m Tc-B2702p20 were injected intravenously in anesthetized animals 3 wk after the ligation. Whole-body planar imaging was performed for 3 h. SPECT imaging of 6 additional ligated ApoE 2/2 mice was also performed with 99m Tc-B2702p1. The animals were then euthanized, and the biodistribution of 99m Tc-labeled peptides was evaluated by g-well counting of excised organs. Expression of VCAM-1 in the ligated and contralateral carotid arteries was evaluated by immunohistology. Results: Robust VCAM-1 immunostaining was observed in the left carotid atherosclerotic lesions as a consequence of artery ligation, whereas no VCAM-1 expression was detected in the contralateral carotid artery. Among all evaluated peptides, 99m Tc-B2702p1 exhibited the most favorable properties. By g-well counting, there was a significant 2.0-fold increase in the 99m Tc-B2702p1 left-to-right carotid artery activity ratio (2.6 6 0.6) and a 3.4-fold increase in the left carotid-to-blood activity ratio (1.4 6 0.4) in comparison to 99m Tc-B2702p (1.3 6 0.2 and 0.4 6 0.1, respectively, P , 0.05 for both comparisons). Similarly, planar image quantification indicated a higher left-to-right carotid activity ratio in 99m Tc-B2702p1-than in 99m Tc-B2702p-injected mice (1.2 6 0.1 vs. 1.0 6 0.0, respectively, P , 0.05). Finally, a significantly higher 99m Tc-B2702p1 activity in the left than in the right carotid artery was observed by SPECT imaging (2.2 6 0.4 vs. 1.4 6 0.3 cpm/mm 2 / injected dose, respectively, P , 0.05). Conclusion: 99m Tc-B2702p1 is a potentially useful radiotracer for the in vivo molecular imaging of VCAM-1 expression in atherosclerotic plaques.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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In Vivo Molecular Imaging of Atherosclerotic Lesions in ApoE^−/− Mice Using VCAM-1–Specific, ^99mTc-Labeled Peptidic Sequences

et al. 2013

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“…36-38 Alanine is traditionally selected for this positional scanning approach since it does not usually alter the backbone conformation and does not impose extreme electrostatic or steric effects. 36 Alanine positional scanning studies have been reported for many different natural and synthetic ligands, including the gastric inhibitory polypeptide, 39 HOE 140 (antagonist at the kinin B 2 receptors), 40 angiotensin II, 38 and bradykinin, 37 and γ-MSH. 41, 42 There have been two reported Ala positional scans of α-MSH, examining the binding affinities and biological potencies of α-MSH derivatives using B16 murine melanoma cells believed to express the mouse MC1R 43 and the binding affinities of Ala-substituted α-MSH ligands with HEK293 cells expressing the rat (r) MC3R.…”

Section: Introductionmentioning

confidence: 99%

Comparative Functional Alanine Positional Scanning of the α-Melanocyte Stimulating Hormone and NDP-Melanocyte Stimulating Hormone Demonstrates Differential Structure–Activity Relationships at the Mouse Melanocortin Receptors

Todorović

Ericson

Palusak

et al. 2016

ACS Chem. Neurosci.

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The melanocortin system has been implicated in the regulation of various physiological functions including melanogenesis, steroidogenesis, energy homeostasis, and feeding behavior. Five melanocortin receptors have been identified to date and belong to the family of G protein-coupled receptors (GPCR). Post-translational modification of the proopiomelanocortin (POMC) prohormone leads to the biosynthesis of the endogenous melanocortin agonists, including α-melanocyte stimulating hormone (α-MSH), β-MSH, γ-MSH, and adrenocorticotropic hormone (ACTH). All the melanocortin agonists derived from the POMC prohormone contain a His-Phe-Arg-Trp tetrapeptide sequence that has been implicated in eliciting the pharmacological responses at the melanocortin receptors. Herein, an alanine (Ala) positional scan is reported for the endogenous α-MSH ligand and the synthetic, more potent, NDP-MSH peptide (Ac-Ser1-Tyr2-Ser3-Nle4-Glu5-His6-DPhe7-Arg8-Trp9-Gly10-Lys11-Pro12-Val13-NH2) at the cloned mouse melanocortin receptors to test the assumption that the structure-activity relationships of one ligand would apply to the other. Several residues outside of the postulated pharmacophore altered potency at the melanocortin receptors, most notably the 1560-, 37-, and 15-fold potency loss when the Glu5 position of α-MSH was substituted with Ala at the mMC1R, mMC3R, and mMC4R, respectively. Importantly, the altered potencies due to Ala substitutions in α-MSH did not necessarily correlate with equivalent Ala substitutions in NDP-MSH, indicating that structural modifications and corresponding biological activities in one of these melanocortin ligands may not be predictive for the other agonist.

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“…The ligands 12 and 13 were designed based on the biological activities of Ala scan analogues of Hoe 140. 30 In ligands 12 and 13 we replaced the 4 th position hydroxyl proline and 7 th position serine with Dap (2,3-diaminopropionic acid) in Hoe 140, and the opioid pharmacophore was attached to the side chain amino group of Dap.…”

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confidence: 99%

Design, synthesis and biological evaluation of multifunctional ligands targeting opioid and bradykinin 2 receptors

Srinivas

Rankin

Davis

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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We report here the design and synthesis of novel multifunctional ligands that act as (μ/δ) opioid agonists and bradykinin 2 receptor antagonists. These multifunctional ligands were designed to interact with the multiple receptors to show an enhanced analgesic effect, with no opioid-induced tolerance. We designed our multifunctional ligands based on the well-known second generation bradykinin 2 receptor antagonist Hoe 140 (DArg-Arg-Pro-Hyp-Gly-Thi-Ser-DTic-Oic-Arg-OH) and the opioid enkephalin analogues Tyr-DAla-Phe, Tyr-DAla-Gly-Phe and Tyr-Pro-Phe. We explored the conjugation of opioid pharmacophore to the Hoe 140 (DArg-Arg-Pro-Hyp-Gly-Thi-Ser-DTic-Oic-Arg-OH) in various positions with and without a linker. These bifunctional ligands showed very good binding affinity towards the both μ and δ opioid receptors. Among these bifunctional ligands 8, 11 and 12 showed excellent and balanced binding affinity at both μ and δ opioid receptors (0.5 nM, 2.0 nM; 0.3 nM, 2 nM; 2 nM and 3 nM) respectively. On the other hand these bifunctional ligands showed very weak and no binding affinity for rat brain bradykinin 2 receptors. Similarly, the Hoe 140 showed very low affinity (> 10000 nM and 9000 nM) against [3H] BK binding in rat brain membranes and in HEK293 cells respectively. In contrast, the Hoe 140 showed very good binding affinity in guinea pig ileum (0.43 nM) similar to that of previously reported. The bradykinin 2 receptors are known to be present in rat brain membrane, guinea pig ileum (GPI) and rabbit jugular vein. Previsously the binding affinity of Hoe 140 for bradykinin 2 receptor was reported using guinea pig ileum. The above results suggest that the bradykinin 2 receptors present in rat brain membrane are a different sub type than the bradykinin 2 receptor present in guinea pig ileum (GPI).

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Ala scan analogues of HOE 140. Synthesis and biological activities

Cited by 9 publications

References 25 publications

In Vivo Molecular Imaging of Atherosclerotic Lesions in ApoE^−/− Mice Using VCAM-1–Specific, ^99mTc-Labeled Peptidic Sequences

In Vivo Molecular Imaging of Atherosclerotic Lesions in ApoE^−/− Mice Using VCAM-1–Specific, ^99mTc-Labeled Peptidic Sequences

Comparative Functional Alanine Positional Scanning of the α-Melanocyte Stimulating Hormone and NDP-Melanocyte Stimulating Hormone Demonstrates Differential Structure–Activity Relationships at the Mouse Melanocortin Receptors

Design, synthesis and biological evaluation of multifunctional ligands targeting opioid and bradykinin 2 receptors

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Ala scan analogues of HOE 140. Synthesis and biological activities

Cited by 9 publications

References 25 publications

In Vivo Molecular Imaging of Atherosclerotic Lesions in ApoE−/− Mice Using VCAM-1–Specific, 99mTc-Labeled Peptidic Sequences

In Vivo Molecular Imaging of Atherosclerotic Lesions in ApoE−/− Mice Using VCAM-1–Specific, 99mTc-Labeled Peptidic Sequences

Comparative Functional Alanine Positional Scanning of the α-Melanocyte Stimulating Hormone and NDP-Melanocyte Stimulating Hormone Demonstrates Differential Structure–Activity Relationships at the Mouse Melanocortin Receptors

Design, synthesis and biological evaluation of multifunctional ligands targeting opioid and bradykinin 2 receptors

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In Vivo Molecular Imaging of Atherosclerotic Lesions in ApoE^−/− Mice Using VCAM-1–Specific, ^99mTc-Labeled Peptidic Sequences

In Vivo Molecular Imaging of Atherosclerotic Lesions in ApoE^−/− Mice Using VCAM-1–Specific, ^99mTc-Labeled Peptidic Sequences