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Manning, Maurice; Cheng, Ling Ling; Stoev, Stoytcho; Bankowski, Krzysztof; Przybyiski, Jozef; Klis, Wieslaw A.; Sawyer, Wilbur H.; Wo, Nga Ching; Chan, W. Y.

An exploration of the effects of L‐ and D‐tetrahydroisoquinoline‐3‐carboxylic acid substitutions at positions 2,3 and 7 in cyclic and linear antagonists of vasopressin and oxytocin and at position 3 in arginine vasopressin

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  • Media type: E-Article
  • Title: An exploration of the effects of L‐ and D‐tetrahydroisoquinoline‐3‐carboxylic acid substitutions at positions 2,3 and 7 in cyclic and linear antagonists of vasopressin and oxytocin and at position 3 in arginine vasopressin
  • Contributor: Manning, Maurice; Cheng, Ling Ling; Stoev, Stoytcho; Bankowski, Krzysztof; Przybyiski, Jozef; Klis, Wieslaw A.; Sawyer, Wilbur H.; Wo, Nga Ching; Chan, W. Y.
  • imprint: Wiley, 1995
  • Published in: Journal of Peptide Science
  • Language: English
  • DOI: 10.1002/psc.310010109
  • ISSN: 1075-2617; 1099-1387
  • Keywords: Organic Chemistry ; Drug Discovery ; Pharmacology ; Molecular Biology ; Molecular Medicine ; General Medicine ; Biochemistry ; Structural Biology
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>We have investigated the effects of mono‐substitutions with the conformationally restricted amino acid, 1,2,3,4 tetrahydroisoquinoline‐3‐carboxylic acid (Tic) at position 3 in arginine vasopressin (AVP), at positions 2, 3 and 7 in potent non‐selective cyclic AVP V<jats:sub>2</jats:sub>/V<jats:sub>1a</jats:sub> antagonists, in potent and selective cyclic and linear AVP V<jats:sub>1a</jats:sub> antagonists, in a potent and selective oxytocin antagonist and in a new potent linear oxytocin antagonist Phaa‐<jats:sc>D</jats:sc>‐Tyr(Me)‐Ile‐Val‐Asn‐Orn‐Pro‐Orn‐NH<jats:sub>2</jats:sub> (10). We report here the solid‐phase synthesis of peptide 10 together with the following Tic‐substituted peptides: 1, [Tic<jats:sup>3</jats:sup>]AVP; 2, d(CH<jats:sub>2</jats:sub>)<jats:sub>5</jats:sub>[<jats:sc>D</jats:sc>‐Tic<jats:sup>2</jats:sup>]VAVP; 3, d(CH<jats:sub>2</jats:sub>)<jats:sub>5</jats:sub>[<jats:sc>D</jats:sc>‐Tyr(Et)<jats:sup>2</jats:sup>Tic<jats:sup>3</jats:sup>]VAVP; 4, d(CH<jats:sub>2</jats:sub>)<jats:sub>5</jats:sub>[Tic<jats:sup>2</jats:sup>Ala‐NH<jats:sub>2</jats:sub><jats:sup>9</jats:sup>]AVP; 5, d(CH<jats:sub>2</jats:sub>)<jats:sub>5</jats:sub>[Tyr(Me)<jats:sup>2</jats:sup>, Tic<jats:sup>3</jats:sup>, Ala‐NH<jats:sub>2</jats:sub><jats:sup>9</jats:sup>]AVP; 6, d(CH<jats:sub>2</jats:sub>)<jats:sub>5</jats:sub> [Tyr(Me)<jats:sup>2</jats:sup>, Tic<jats:sup>7</jats:sup>]AVP; 7, Phaa‐<jats:sc>D</jats:sc>‐Tyr(Me)‐Phe‐Gln‐Asn‐Lys‐Tic‐Arg‐NH<jats:sub>2</jats:sub>; 8, desGly‐NH<jats:sub>2</jats:sub>,d(CH<jats:sub>2</jats:sub>)<jats:sub>5</jats:sub>[Tic<jats:sup>2</jats:sup>,Thr<jats:sup>4</jats:sup>]OVT; 9, desGly‐NH<jats:sub>2</jats:sub>d(CH<jats:sub>2</jats:sub>)<jats:sub>5</jats:sub>[Tyr(Me)<jats:sup>2</jats:sup>Thr<jats:sup>4</jats:sup>, Tic<jats:sup>7</jats:sup>]OVT; 11, Phaa‐D‐Tic‐Ile‐Val‐Asn‐Orn‐Pro‐Orn‐NH<jats:sub>2</jats:sub>, using previously described methods. The protected precursors were synthesized by the solid‐phase method, cleaved, purified and deblocked with sodium in liquid ammonia to give the free peptides 1–11 which were purified by methods previously described. Peptides 1–11 were examined for agonistic and antagonistic potency in oxytocic (<jats:italic>in vitro</jats:italic>, without Mg<jats:sup>2+</jats:sup>) and AVP antidiuretic (V<jats:sub>2</jats:sub>‐receptor) and vasopressor (V<jats:sub>1a</jats:sub>‐receptor) assays. Tic<jats:sup>3</jats:sup> substitution in AVP led to drastic losses of V<jats:sub>2</jats:sub>, V<jats:sub>1a</jats:sub> and oxytocic agonistc activities in peptide 1.<jats:sc>L</jats:sc>‐ and <jats:sc>D</jats:sc>‐Tic<jats:sup>2</jats:sup> substitutions led to drastic losses of anti‐V<jats:sub>2</jats:sub>/anti‐V<jats:sub>1a</jats:sub> and anti‐oxytocic potencies in peptides 2, 4, 8 and 11 (peptide 2 retained substantial anti‐oxytocic potency; pA<jats:sub>2</jats:sub> = 7.25 ± 0.25). Whereas Tic<jats:sup>3</jats:sup> substitution in the selective V<jats:sub>1a</jats:sub> antagonist d(CH<jats:sub>2</jats:sub>)<jats:sub>5</jats:sub>[Tyr(Me)<jats:sup>2</jats:sup>, Ala‐NH<jats:sub>2</jats:sub><jats:sup>9</jats:sup>]APV(C) led to a drastic reduction in anti‐V<jats:sub>1a</jats:sub> potency (from anti‐V<jats:sub>1a</jats:sub> pA<jats:sub>2</jats:sub>) 8.75 to 6.37 for peptide 5, remarkably, Tic<jats:sup>3</jats:sup> substitution in the V<jats:sub>2</jats:sub>/V<jats:sub>1a</jats:sub> antagonist d(CH<jats:sub>2</jats:sub>)<jats:sub>5</jats:sub>[<jats:sc>D</jats:sc>‐Tyr(Et)<jats:sup>2</jats:sup>]VAVP(B) led to full retention of anti‐V<jats:sub>2</jats:sub> potency and a 95% reduction in anti‐V<jats:sub>1a</jats:sub> potency. With an anti‐V<jats:sub>2</jats:sub> pA<jats:sub>2</jats:sub> = 7.69 ± 0.05 and anti‐V<jats:sub>1a</jats:sub> pA<jats:sub>2</jats:sub> = 6.95 ± 0.03, d(CH<jats:sub>2</jats:sub>)<jats:sub>5</jats:sub>[<jats:sc>D</jats:sc>‐Tyr(Et)<jats:sup>2</jats:sup>,Tic<jats:sup>3</jats:sup>]VAVP exhibits a 13‐fold gain in anti‐V<jats:sub>2</jats:sub>/anti‐V<jats:sub>1a</jats:sub> selectivity compared to (B). Tic<jats:sup>7</jats:sup> substitutions are very well tolerated in peptides 6, 7 and 9 with excellent retention of the characteristic potencies of the parent peptides. The findings on the effects of Tic<jats:sup>3</jats:sup> substitutions reported here may provide promising leads to the design of more selective and possibly orally active V<jats:sub>2</jats:sub> antagonists for use as pharmacological tools and as therapeutic clinical agents for the treatment of the syndrome of the inappropriate secretion of antidiuretic hormone (SIADH).</jats:p>