Synthesis and some pharmacological properties of [3-.beta.-(2-thienyl)-L-alanine]-8-lysine-vasopressin

Smith, Clark W.; Ferger, Martha F.; Çhan, W. Y.

doi:10.1021/jm00242a012

Cited by 21 publications

(6 citation statements)

References 12 publications

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“…Boc-Gly (1.0 g) was esterified to 10 g of resin following standard procedures,22 giving material substituted with 0.2 mmol of Gly/g of resin. Each amino acid was added to the growing chain according to the following sequence of washes and reactions with use of 8 mL of solvent/g of resin: (1 and 2) three washes with ethanol, followed by three washes with AcOH; (3) (a) 1.2 N HC1 in AcOH for 30 min or (b) TFA for 20 min for Gin, DiHPhe, and amino acids following DiHPhe; (4-6) three washes with AcOH, followed by three washes with EtOH, followed by three washes with CHC13; (7) 10% NEtg-CHClg for 10 min; (8) three washes with CHC13; (9) (a) three washes with CH2C12 (for DCCI coupling) or (b) three washes with DMF (for active esters); (10) (a) addition of 3 equiv of Boc-protected amino acid in a minimal volume of CH2C12 for 10 min, followed by 3 equiv of DCCI in CH2C12 (50%, w/v; reaction for 4 h), or (b) 3 equiv of Boc-protected amino acid NPE in a minimal volume of DMF (reaction for 18 h); (11) three washes with (a) CH2C12 or (b) DMF. After the last amino acid had been added, steps 1-8 were repeated.…”

Section: Methodsmentioning

confidence: 99%

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[3-(1,4-Cyclohexadienyl)-L-alanine,8-lysine]vasopressin synthesis and some pharmacological properties

Banerjee¹,

Diamond²,

Ressler³

et al. 1979

J. Med. Chem.

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[3-(1,4-Cyclohexadienyl)-L-alanine,8-lysine]vasopressin, otherwise known as [3-(2,5-dihydrophenylalanine),8-lysine]vasopressin or [DiHPhe3]lysine-vasopressin, has been synthesized in an attempt to utilize 2,5-dihydrophenylalanine (DiHPhe) to evaluate the contribution of aromaticity in position 3 to biological activity. The analogue has the same primary structure as lysine-vasopressin, except that two additional hydrogen atoms are present on the ring moiety of the phenylalanine residue in position 3. The key intermediate was the protected nonapeptide N-carbobenzoxy-S-benzyl-L-cysteinyl-L-tyrosyldihydrophenyl-L-alanyl-L-glutaminyl-L-asparaginyl-S-benzyl-L-cysteinyl-L-prolyl-N epsilon-tosyl-L-lysylglycinamide that was synthesized stepwise by the solid-phase technique. Deprotection with sodium in liquid ammonia was followed by sulfhydryl oxidation with I2 to give the hormone analogue. [DiHPhe3]lysine-vasopressin exhibited 125--130 units/mg of antidiuretic, 129--132 units/mg of rat pressor, and 6 units/mg of rat uterus contracting activity. To confirm the presence of DiHPhe in the analogue, an enzymatic procedure employing Aspergillus oryzae was developed that liberates in high yield the amino acid residue in position 3 of the posterior pituitary hormone structure. This study should be applicable to other biologically active peptides.

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Section: Methodsmentioning

confidence: 99%

“…In this respect, DiHPhe should have an advantage over ß-2-thienylalanine which has recently served a similar purpose, i.e., to assess the contribution of aromaticity to biological activity by substitution for Phe in LVP. 11 The thiophene ring has about 70% of the resonance energy of the benzene ring.…”

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confidence: 99%

[3-(1,4-Cyclohexadienyl)-L-alanine,8-lysine]vasopressin synthesis and some pharmacological properties

Banerjee¹,

Diamond²,

Ressler³

et al. 1979

J. Med. Chem.

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“…In an earlier investigation of the steric and electronic functions of the disulfide group on biological activity, an analogue of deamino-oxytocin, [cydo-(l-/3-alanine,6-aspartic acid)]oxytocin, in which the disulfide has been replaced by an amide group was synthesized.20 As an extension of this work we wish to report the synthesis and some pharmacological properties of "oxytocin lactam", [cyc(o-(l-aspartic acid,6-a,/3-diaminopropionic acid)]oxytocin, (Figure 1) in which the amide group is in reverse direction of acylation as that in the previously reported "deamino-oxytocin lactam". 20,21 The synthetic route followed is summarized in Scheme I. In brief, the COOH-terminal tripeptide amide was extended in a stepwise manner using Ñ"-benzoxycarbonyl (Z) protected amino acids coupled with dicyclohexylcarbodiimide (DCC) mediated by 1-hydroxybenzotriazole22 (HOBt) except for the NH2-terminal aspartic acid residue which was coupled as the AMiydroxysuccinimide active ester.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and some pharmacological properties of [4-.beta.-(2-thienyl)-L-alanine]oxytocin

Smith¹,

Skala²,

Walter³

1978

J. Med. Chem.

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The synthesis and some biological activities of [4-beta-(2-thienyl)-L-alanine]oxytocin are reported. This analogue has been studied in an ongoing exploration of the biological effects of introducing amino acid residues with bulky hydrophobic side chains into the second corner position of the beta turn present in the conformation of the 20-membered ring portion of oxytocin. The analogue was synthesized in stepwise manner by solution techniques utilizing ethylcarbamoyl protection for cysteine side chains. The presence of thienylalanine in position 4 evokes a drastic reduction in both affinity and intrinsic activity; the reduction in intrinsic activity was greater than that found for [Leu4]oxytocin or [Phe4]oxytocin. The analogue possesses 0.51 +/- 0.03 unit/mg of rat uterotonic potency and less than 0.05 unit/mg of rat pressor and rat antidiuretic potency and behaves as a competitive inhibitor of the response to oxytocin in the avian vasodepressor assay with a pA2 value of 7.44 +/- 0.19.

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“…Due to the incompatibility of the thienylalanine and naphthylalanine residues with the Na/ NH 3 procedure [25,43], it was necessary to use the Rink amide resin [35] and the Fmoc strategy [36,37] for the synthesis of peptides 1 and 13. The deprotections were carried out with 20% piperidine/DMF [36].…”

Section: Peptide Synthesismentioning

confidence: 99%

“…The Ser 3 , Tyr 3 and Trp 3 analogs of LVP exhibit drastic reductions in antidiuretic and vasopressor potencies relative to LVP [3,[21][22][23][24] (Table 2). Thus, based on these position-3 analogs of LVP and, notwithstanding the pharmacological profile of AVT [3,19,20] and a later report that the thienylalanine 3 analog of LVP, [Thi 3 ]LVP [25], exhibits surprisingly high antidiuretic and vasopressor potencies, position 3 in AVP has long been considered intolerant of changes [3 -5,21-24,26]. Consequently, this position has been virtually ignored in structure/activity studies of AVP.…”

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confidence: 99%

An investigation of position 3 in arginine vasopressin with aliphatic, aromatic, conformationally-restricted, polar and charged amino acids

Stoev¹,

Cheng²,

Olma³

et al. 1999

J. Peptide Sci.

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We report the solid-phase synthesis and some pharmacological properties of 23 new analogs of arginine vasopressin (AVP) which have the Phe3 residue replaced by a broad variety of amino acids. Peptides 1-9 have at position 3: (1) the mixed aromatic/aliphatic amino acid thienylalanine (Thi) and the aliphatic amino acids; (2) cyclohexylalanine (Cha); (3) norleucine (Nle); (4) Leu; (5) norvaline (Nva); (6) Val; (7) alpha-aminobutyric acid (Abu); (8) Ala; (9) Gly. Peptides 10-23 have at position 3: the aromatic amino acids, (10) homophenylalanine (Hphe): (11) Tyr; (12) Trp; (13) 2-naphthylalanine (2-Nal); the conformationally-restricted amino acids (14) Pro; (15) 2-aminotetraline-2-carboxylic acid (Atc); the polar amino acids (16) Ser; (17) Thr; (18) Gln; and the charged amino acids (19) Asp; (20) Glu; (21) Arg; (22) Lys; (23) Orn. All 23 new peptides were evaluated for agonistic and, where appropriate, antagonistic activities in in vivo antidiuretic (V2-receptor) and vasopressor (V1a-receptor) assays and in in vitro (no Mg2+) oxytocic assays. The corresponding potencies (units/mg) in these assays for AVP are: 323+/-16; 369+/-6 and 13.9+/-0.5. Peptides 1-9 exhibit the following potencies (units/mg) in these three assays: (1) 379+/-14; 360+/-9; 36.2+/-1.9; (2) 294+/-21: 73.4+/-2.7; 0.33+/-0.02; (3) 249+/-28; 84.6+/-4.3; 4.72+/-0.16; (4) 229+19; 21.4+/-0.6; 2.1+/-0.2; (5) 134+/-5; 31.2+/-0.9; 28.4+/-0.2; (6) 114+/-9; 45.3+2.3; 11.3+/-1.6; (7) 86.7+/-2.5; 4.29+/-0.13; 0.45+/-0.03; (8) 15.5+/-1.5; 0.16+/-0.01; approximately 0.02: (9) 3.76+/-0.03; < 0.02; in vitro oxytocic agonism was not detected. These data show that the aliphatic amino acids Cha, Nle, Leu, Nva and Val are well-tolerated at position 3 in AVP with retention of surprisingly high levels of antidiuretic activity. Peptides 2-9 exhibit significant gains in both antidiuretic/vasopressor (A/P) and antidiuretic/oxytocic (A/O) selectivities relative to AVP. [Thi3]AVP appears to be a more potent antidiuretic and oxytocic agonist than AVP and is equipotent with AVP as a vasopressor agonist. The antidiuretic potencies of peptides 10-23 exhibit drastic losses relative to AVP. They range from a low of 0.018+/-0.001 units/mg for the Lys3 analog (peptide 22) to a high of 24.6+/-4.6 units,mg for the Hphe3 analog (peptide 10). Their vasopressor potencies are also drastically reduced. These range from a low of < 0.002 units/mg for peptide 22 to a high of 8.99+0.44 units/mg for the Atc3 analog (peptide 15). Peptides 10-23 exhibit negligible or undetectable in vitro oxytocic agonism. The findings on peptides 10-23 show that position 3 in AVP is highly intolerant of changes with aromatic, conformationally-restricted, polar and charged amino acids. Furthermore, these findings are in striking contrast to our recent discovery that position 3 in the potent V2/V1a/OT antagonist d(CH2)5D-Tyr(Et)2VAVP tolerates a broad latitude of structural change at position 3 with many of the same amino acids, to give excellent retention of antagonistic potencies. The data on peptides 1-4 offer pr...

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Synthesis and some pharmacological properties of [3-.beta.-(2-thienyl)-L-alanine]-8-lysine-vasopressin

Cited by 21 publications

References 12 publications

[3-(1,4-Cyclohexadienyl)-L-alanine,8-lysine]vasopressin synthesis and some pharmacological properties

[3-(1,4-Cyclohexadienyl)-L-alanine,8-lysine]vasopressin synthesis and some pharmacological properties

Synthesis and some pharmacological properties of [4-.beta.-(2-thienyl)-L-alanine]oxytocin

An investigation of position 3 in arginine vasopressin with aliphatic, aromatic, conformationally-restricted, polar and charged amino acids

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