AbstractWe 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/V1aantagonists, in potent and selective cyclic and linear AVP V1aantagonists, 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. Tic3substitution in AVP led to drastic losses of V2, V1aand oxytocic agonistc activities in peptide 1.L‐ andD‐Tic2substitutions led to drastic losses of anti‐V2/anti‐V1aand anti‐oxytocic potencies in peptides 2, 4, 8 and 11 (peptide 2 retained substantial anti‐oxytocic potency; pA2= 7.25 ± 0.25). Whereas Tic3substitution in the selective V1aantagonist d(CH2)5[Tyr(Me)2, Ala‐NH29]APV(C) led to a drastic reduction in anti‐V1apotency (from anti‐V1apA2) 8.75 to 6.37 for peptide 5, remarkably, Tic3substitution in the V2/V1aantagonist d(CH2)5[D‐Tyr(Et)2]VAVP(B) led to full retention of anti‐V2potency and a 95% reduction in anti‐V1apotency. With an anti‐V2pA2= 7.69 ± 0.05 and anti‐V1apA2= 6.95 ± 0.03, d(CH2)5[D‐Tyr(Et)2,Tic3]VAVP exhibits a 13‐fold gain in anti‐V2/anti‐V1aselectivity compared to (B). Tic7substitutions 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 Tic3substitutions reported here may provide promising leads to the design of more selective and possibly orally active V2antagonists for use as pharmacological tools and a