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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Abstract
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 V2/V1a antagonists, in potent and selective cyclic and linear AVP V1a antagonists, in a potent and selective oxytocin antagonist and in a new potent linear oxytocin antagonist Phaa‐D‐Tyr(Me)‐Ile‐Val‐Asn‐Orn‐Pro‐Orn‐NH2 (10). We report here the solid‐phase synthesis of peptide 10 together with the following Tic‐substituted peptides: 1, [Tic3]AVP; 2, d(CH2)5[D‐Tic2]VAVP; 3, d(CH2)5[D‐Tyr(Et)2Tic3]VAVP; 4, d(CH2)5[Tic2Ala‐NH29]AVP; 5, d(CH2)5[Tyr(Me)2, Tic3, Ala‐NH29]AVP; 6, d(CH2)5 [Tyr(Me)2, Tic7]AVP; 7, Phaa‐D‐Tyr(Me)‐Phe‐Gln‐Asn‐Lys‐Tic‐Arg‐NH2; 8, desGly‐NH2,d(CH2)5[Tic2,Thr4]OVT; 9, desGly‐NH2d(CH2)5[Tyr(Me)2Thr4, Tic7]OVT; 11, Phaa‐D‐Tic‐Ile‐Val‐Asn‐Orn‐Pro‐Orn‐NH2, 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 (in vitro, without Mg2+) and AVP antidiuretic (V2‐receptor) and vasopressor (V1a‐receptor) assays. Tic3 substitution in AVP led to drastic losses of V2, V1a and oxytocic agonistc activities in peptide 1.L‐ and D‐Tic2 substitutions led to drastic losses of anti‐V2/anti‐V1a and anti‐oxytocic potencies in peptides 2, 4, 8 and 11 (peptide 2 retained substantial anti‐oxytocic potency; pA2 = 7.25 ± 0.25). Whereas Tic3 substitution in the selective V1a antagonist d(CH2)5[Tyr(Me)2, Ala‐NH29]APV(C) led to a drastic reduction in anti‐V1a potency (from anti‐V1a pA2) 8.75 to 6.37 for peptide 5, remarkably, Tic3 substitution in the V2/V1a antagonist d(CH2)5[D‐Tyr(Et)2]VAVP(B) led to full retention of anti‐V2 potency and a 95% reduction in anti‐V1a potency. With an anti‐V2 pA2 = 7.69 ± 0.05 and anti‐V1a pA2 = 6.95 ± 0.03, d(CH2)5[D‐Tyr(Et)2,Tic3]VAVP exhibits a 13‐fold gain in anti‐V2/anti‐V1a selectivity compared to (B). Tic7 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 Tic3 substitutions reported here may provide promising leads to the design of more selective and possibly orally active V2 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).

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