Structure‐activity relationship in vasoconstrictor effects of sarafotoxins andendothelin‐1

Kitazumi, Kazuhiro; Shiba, Toshiharu; Nishiki, Katsuyuki; Furukawa, Yasuo; Takasaki, Chikahisa; Tasaka, Kenjí

doi:10.1016/0014-5793(90)80120-8

Cited by 21 publications

(7 citation statements)

References 13 publications

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“…37 for the vasoconstrictor activity of endothelin in porcine coronary artery strips (ETa). 44 ET [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] has been shown to be inactive,45 while the hydrophobic C-terminal hexapeptide ET [16][17][18][19][20][21] has been reported to be a partial agonist in guinea pig isolated bronchus, rat vas deferens, and rabbit pulmonary artery.46•47 Structure-activity studies of the C-terminal hexapeptide of ET-1 have indicated the importance of individual amino acids to receptor recognition in a variety of tissue beds.48•49 However, we have found that this fragment is devoid of functional activity in several tissue preparations including rat aorta and rabbit pulmonary artery. 49 Other studies attempting to demonstrate the agonist activity originally reported for the ET [16][17][18][19][20][21] fragment have likewise met with little suc- The peptides prepared by Boc chemistry were deprotected and cleaved from the resin using anhydrous liquid HF/ anisóle or HF/p-cresol (9:1 v/v) followed by N-terminal acetylation with 90% acetic acid and an excess of acetic anhydride.…”

Section: Introductionmentioning

confidence: 99%

Structure-activity relationships of C-terminal endothelin hexapeptide antagonists

Am¹,

Wl²,

Pl³

et al. 1993

J. Med. Chem.

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The discovery of selective endothelin (ET) receptor antagonists will facilitate identification of the physiological and pathological roles for ET and its isopeptides. Structure-activity studies of the C-terminal hexapeptide of ET have been carried out to elucidate those amino acids important for receptor binding and agonist or antagonist activity. Binding studies were performed in rat heart ventricle, rabbit renal artery vascular smooth muscle cells, and rat cerebellum. In addition, many of the compounds have been evaluated functionally for their effects on endothelin-1-induced arachidonic acid release and inositol phosphate accumulation in specific cell lines. Selected compounds have been evaluated in a functional bioassay in tissue preparations specifically expressing either ETA or ETB receptors. We have previously described the structure-activity relationships in the hydrophobic C-terminal hexapeptide of ET, a region known to be highly important for receptor recognition. A mono-D-amino acid scan of the ET[16-21] revealed that substitution at His gave rise to analogs with significantly enhanced binding affinity. We have further evaluated the C-terminal region and will describe the design, synthesis, and pharmacological evaluation of several novel and potent ET peptide receptor antagonists.

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Section: Introductionmentioning

confidence: 99%

Structure-activity relationships of C-terminal endothelin hexapeptide antagonists

Am¹,

Wl²,

Pl³

et al. 1993

J. Med. Chem.

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“…Furthermore, the amino acid sequences of sarafotoxins, found in the venom of the burrowing snake Atractaspis engaddensis, are very similar to those of endothelins (Kloog & Sokolovsky, 1989). All the endothelins and sarafotoxins are bioactive but differences exist in their pharmacological potencies and profiles (Kitazumi et al, 1990;Cardell et al, 1992). Two distinct receptor subtypes for endothelins, namely ETA (Arai et al, 1990) and ETB (Sakurai et al, 1990) have been cloned and biochemically characterized.…”

Section: Introductionmentioning

confidence: 99%

Endothelin receptors mediating contraction in goat cerebral arteries

Salom

Torregrosa

Barberá

et al. 1993

British J Pharmacology

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1 The aim of the present study was to identify the subtype of receptor mediating contraction to endothelin-1 and sarafotoxin S6b in goat isolated middle cerebral arteries. 2 Endothelin-1, endothelin-2 and endothelin-3 contracted cerebral arteries in a concentration-dependent manner. Although the three peptides were full agonists, the order of potency was endothelin-1 = endothelin-2 > endothelin-3, with a relative potency of endothelin-1 and endothelin-2 versus endothelin-3 of -280. Sarafotoxin S6b induced concentration-dependent contractions with lower potency than endothelin-1 /endothelin-2, higher potency than endothelin-3 and a higher maximum response than the three endothelins.3 The selective ETA-receptor antagonist, BQ-123, did not induce changes in either the resting tension or in the active tone developed by depolarization. In contrast, BQ-123 produced concentrationdependent relaxations of endothelin-1-precontracted cerebral arteries, and to a greater extent of sarafotoxin S6b-precontracted arteries. 4 Concentration-response curves to endothelin-1 and sarafotoxin S6b were competitively antagonized by BQ-123 (pA2 of 7.43 ± 0.12 and 8.41 ± 0.09, respectively). In contrast, BQ-123 had no effect on 5-hydroxytryptamine-elicited contractions even at 10-6 M. 5 It is concluded that both the order of potency of endothelin isopeptides and the antagonism of BQ-123 point to the existence of ETA receptors mediating vasoconstriction to endothelin-1 and sarafotoxin S6b in the goat middle cerebral artery. The different antagonistic potency of BQ-123 against endothelin-I and sarafotoxin S6b suggests the existence of subtypes of ETA receptors.

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“…Sarafotoxins (SRTs), having chemical structures similar to those of ETs, also consist of a novel cardiotoxic peptide family [2] and these peptides interact witla ET receptors [1]. A diverse set of pharmacological activities with different potencies exerted by ET/SRT family peptides [3][4][5][6] suggested the existence of ET/SRT receptor subtypes. We have reported that two distinct subclasses of ET receptors, namely, ET-l-specific and ET/SRT family-common receptors, are distributed in various proportions in human and porcine tissues [7].…”

Section: Introductionmentioning

confidence: 99%

Presence of non‐selective type of endothelin receptor on vascular endothelium and its linkage to vasodilation

et al. 1991

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Wc studied the role of non.selecttv© tyi~ (ET.) of ¢ndothelin (ET} receptor in the vaseulature, using a ligand specific to the fiT. receptor) [Olu~] • sarafotoxin S6b ([Olu'*lgR'rh}. Endothelium.containln8 rat thoracic aorta pos~s~d specific binding sites For ~)l.[OhP]SRTb. which were almost diminatcd by removal ctf the endothelium, while ET.3-sl~cific binding sites were not detected in tl' c endothdium.intaet rat aorl=. Only ET, receptor was deIected in the membranes From the endothdium of porcine thoracic aorta. [GIu'~ISR.Tb exerted only vasodilalion in rat aortic rinB. These findings indicate that El?. receptors are located on vascular endothellum and linked to vasodilation.

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Structure‐activity relationship in vasoconstrictor effects of sarafotoxins andendothelin‐1

Cited by 21 publications

References 13 publications

Structure-activity relationships of C-terminal endothelin hexapeptide antagonists

Structure-activity relationships of C-terminal endothelin hexapeptide antagonists

Endothelin receptors mediating contraction in goat cerebral arteries

Presence of non‐selective type of endothelin receptor on vascular endothelium and its linkage to vasodilation

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