Design and synthesis of highly selective in vitro and in vivo uterine receptor antagonists of oxytocin: comparisons with Atosiban

摘要: We report the solid phase synthesis and some pharmacological properties of seven position two analogues (peptides 1-7) one our lead oxytocin antagonists, des-9-glycinamide[1-(beta-mercapto-beta,beta-pentamethylenepropionic+ ++ acid),2-O-methyltyrosine,4-threonine]ornithinevasotocin(desGly+ ++-NH2, d(CH2)5-[Tyr(Me)2,Thr4]OVT) (A). Peptides 1-7 have following substituents at (1) D-Tyr(Me); (2) L-Tyr(Et); (3) D-Tyr(Et); (4) L-Tyr; (5) D-Tyr; (6) D-Phe (7) D-Trp. These were evaluated for agonistic antagonistic activities in vitro vivo OT assays, vasopressor (V1a-receptor) assays antidiuretic (V2-receptor) assays. None peptides exhibits oxytocic or agonism. 1, 2, 4, 6 7 are extremely weak V2 agonists (V2 range from 0.001 to 0.02 U/mg). 3 5 exhibit antagonism (pA2 < 6.0 5.5, respectively). potent (no Mg2+) (anti-OT pA2 values 7.66 8.03). 1 4-7 antagonism. Estimated anti-OT 7.06 7.79 2 not tested). With anti-V1a 5.17-6.25 all reduced potencies relative parent peptide (A) (anti-V1a = 6.46). Four these (4-7) striking gains anti-OT/anti-V1a selectivities compared which has an selectivity 30 18. The D-Tyr2 (5), D-Trp2 (7), D-Phe2 L-Tyr2 (in vitro)/anti-V1a 240, 390, 404 540, respectively. (4), exhibited vivo)/anti-V1a 72, 80, 88 95, appear be most selective antagonists reported date. In this regard it may noted that they as more much than closely related antagonist 1-deamino[D-Tyr(Et)2,Thr4]OVT (Atosiban) is currently undergoing clinical trial a potential therapeutic agent prevention premature labor. Atosiban (peptide 8) was resynthesized pharmacologically laboratories. potencies. Anti-OT vitro, no 7.71; 7.05; 6.14 anti-V2 approximately 5.9. Its 8. Some suitable candidates evaluation tocolytic agents use treatment pre-term They could also serve useful new tools studies on physiological roles oxytocin. Finally, findings presented here provide clues design antagonists.