Angiotensin II analogs. 12. Role of the aromatic ring of position 8 phenylalanine in pressor activity

Hsieh, Kun-Hwa; Jorgensen, Eugéne C.; Lee, Thomas C.

doi:10.1021/jm00195a005

Cited by 19 publications

(6 citation statements)

References 13 publications

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“…The remaining hydrochloride salt was dissolved in water and extracted with tert-butyl methyl ether to remove unwanted organic residues. The ether layer was discarded, then the aqueous layer was brought to pH = 9-10 by addition of 28% NH 4 in CHCl 3 (20 mL) was added at room temperature triethylamine (505 µL, 5 mmole) and di-tert-butyl dicarbonate (1.09 g, 5 mmole). The reaction mixture was refluxed overnight and then concentrated under vacuum.…”

Section: Methodsmentioning

confidence: 99%

Efficient Method for the Synthesis of an Important Precursor of Constrained Peptides

Brunel¹

2005

PPL

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Section: Methodsmentioning

confidence: 99%

Efficient Method for the Synthesis of an Important Precursor of Constrained Peptides

Brunel¹

2005

PPL

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“…Introduction of the Boc‐group required treatment of the tetramethylammonium salts of DL‐Bip and DL‐Dip in 1 : 4 of dimethylsulphoxide‐ t ‐butanol with di‐ t ‐butyl dicarbonate (Boc 2 O) at 60°C overnight (40). Boc‐2Ind was prepared by standard Boc 2 O addition to 2Ind in aqueous NaOH‐ t ‐butanol at room temperature (40, 46). Other Boc‐amino acids were commercially available.…”

Section: Methodsmentioning

confidence: 99%

Cyclic and linear bradykinin analogues: implications for B₂ antagonist design

Hsieh

Stewart

1999

The Journal of Peptide Research

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Bradykinin (BK, Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) antagonists are potentially useful for treating inflammation, pain and severe trauma. To identify what chemical features might promote effective antagonism, we replaced Arg1 and Pro7 with structurally constrained and proteolytic-resistant residues, such as Bip (biphenylalanine), Dip (diphenylalanine) or 2Ind (indane amino acid). To determine which BK folding might lead to favourable interactions with receptors, the effects of cyclo(3,8) vs. cyclo(5,8) analogues were compared. The resulting BK analogues were examined for their agonistic and antagonistic activities in guinea pig ileum, rat uterus and depressor assays. The results suggest that co-planarity of the residue-7 side chain with its backbone NH is important for potent agonism as well as antagonism, and a D-directed side chain is crucial for antagonism. For residue-1 an L-orientation is important, and Dip1 may mimic a folded Arg1 side chain to elicit agonistic activities, with Bip1 mimicking an extended Arg1 side chain to elicit inhibitory activities. However, ileal and uterine receptors appear to prefer differently folded BK. For ileum, a BK conformation in which residues-3 and -8 are proximal to each other, but apart from residue-5, led to improved pA2.

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“…The [b-(benzylthio)-b,b-cyclopentamethylenepropionic acid [75], 2-aminoindan-2-carboxylic acid (Aic) [49,54], Boc-Aic [53], D,L-2-aminotetralin-2-caboxylic acid (Atc) [45,49] and Boc-D,L-Atc [48] were synthesized in this laboratory using routine procedures. For both Aic and D,L-Atc the spirohydantoin version of the Strecker synthesis [51,52] was applied.…”

Section: Experimental Partmentioning

confidence: 99%

Position Three in Vasopressin Antagonist Tolerates Conformationally Restricted and Aromatic Amino Acid Substitutions: A Striking Contrast with Vasopressin Agonists

et al. 1997

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We report the solid-phase synthesis and some pharmacological properties of 12 position three modified analogues (peptides 1-12) of the potent non-selective antagonist of the antidiuretic (V2-receptor), vasopressor (V1a-receptor) responses to arginine vasopressin (AVP) and of the uterine contracting (OT-receptor) responses to oxytocin (OT), [1(-beta mercapto-beta,beta-pentamethylenepropionic acid)-2-O-ethyl-D-tyrosine 4-valine] arginine vasopressin [d(CH2)5D-Tyr(Et)2VAVP] (A) and two analogues of (B) (peptides 13,14), the 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid3 (Tic3) analogue of (A). Peptides 1-12 have the following substituents at position three in (A): (1) Pro; (2) Oic; (3) Atc; (4) D-Atc; (6) D-Phe; (7) Ile; (8) Leu; (9) Tyr; (10) Trp; (11) Hphe; (12) [HO]Tic; Peptide (13) is the Tyr-NH2(9) analogue of (B): Peptide (14) is the D-Cys(6) analogue of (B). All 14 new peptides were evaluated for agonistic and antagonistic activities in in vivo V2 and V1a assays and in vitro (no Mg2+)n oxytocic assays. With the exception of the D-Phe3 peptide (No. 6), which exhibits very weak V2 agonism (approximately 0.0017 U/mg), none of the remaining 13 peptides exhibit any agonistic activities in these assays. In striking contrast to their deleterious effects on agonistic activities in AVP, the Pro3, Oic3, Tyr3 and Hphe3 substitutions in (A) are very well tolerated, leading to excellent retention of V2, V1a and OT antagonistic potencies. All are more potent as V2 antagonists than the Ile3 and Leu3 analogues of (A). The Tyr-NH2(9) and D-Cys(6) substitutions in (B) are also well tolerated. The anti-V2 pA2 values of peptides 1-5 and 7-14 are as follows (1) 7.77 +/- 0.03; (2) 7.41 +/- 0.05; (3) 6.86 +/- 0.02; (4) 5.66 +/- 0.09; (5) approximately 5.2; (7) 7.25 +/- 0.08; (8) 6.82 +/- 0.06; (9) 7.58 +/- 0.05; (10) 7.61 +/- 0.08; (11) 7.59 +/- 0.07; (12) 7.20 +/- 0.05; (13) 7.57 +/- 0.1; (14) 7.52 +/- 0.06. All analogues antagonize the vasopressor responses to AVP, with anti-V1a pA2 values ranging from 5.62 to 7.64, and the in vitro responses to OT, with anti-OT pA2 values ranging from 5.79 to 7.94. With an anti-V2 potency of 7.77 +/- 0.03, the Pro3 analogue of (A) is surprisingly equipotent with (A), (anti-V2 pA2 = 7.81 +/- 0.07). These findings clearly indicate that position three in AVP V2/V1a antagonists, in contrast to position three in AVP agonists, is much more amenable to structural modification than had heretofore been anticipated. Furthermore, the surprising retention of V2 antagonism exhibited by the Pro3, Oic3, Tyr3, Trp3 and Hphe3 analogues of (A), together with the excellent retention of V2 antagonism by the Tyr-NH2(9) and D-Cys6 analogues of (B) are promising new leads to the design of potent and possibly orally active V2 antagonists for use as pharmacological tools and/or as radioiodinatable ligands and for development as potential therapeutic agents for the treatment of the hyponatremia caused by the syndrome of the inappropriate secretion of the antidiuretic hormone (SIADH).

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Angiotensin II analogs. 12. Role of the aromatic ring of position 8 phenylalanine in pressor activity

Cited by 19 publications

References 13 publications

Efficient Method for the Synthesis of an Important Precursor of Constrained Peptides

Efficient Method for the Synthesis of an Important Precursor of Constrained Peptides

Cyclic and linear bradykinin analogues: implications for B₂ antagonist design

Position Three in Vasopressin Antagonist Tolerates Conformationally Restricted and Aromatic Amino Acid Substitutions: A Striking Contrast with Vasopressin Agonists

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Angiotensin II analogs. 12. Role of the aromatic ring of position 8 phenylalanine in pressor activity

Cited by 19 publications

References 13 publications

Efficient Method for the Synthesis of an Important Precursor of Constrained Peptides

Efficient Method for the Synthesis of an Important Precursor of Constrained Peptides

Cyclic and linear bradykinin analogues: implications for B2 antagonist design

Position Three in Vasopressin Antagonist Tolerates Conformationally Restricted and Aromatic Amino Acid Substitutions: A Striking Contrast with Vasopressin Agonists

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Cyclic and linear bradykinin analogues: implications for B₂ antagonist design