ISOSTERIC SUBSTITUTION OF ASN(5) IN ANTAGONISTS OF OXYTOCIN AND VASOPRESSIN LEADS TO HIGHLY SELECTIVE AND POTENT OXYTOCIN AND V-1A RECEPTORANTAGONISTS - NEW APPROACHES FOR THE DESIGN OF POTENTIAL TOCOLYTICS FOR PRETERM LABOR

Substitution of Asn(5) in oxytocin (OT) or vasopressin (VP) invariably leads to a dramatic loss of the biological activities of the peptides . Because of this observation, few structure-activity-relationship stu dies of OT and VP peptides have involved modifications in the 5 positi on. It is now recognized that peptide agonists and antagonists may use different structural and conformational features in their interaction s with the receptors. Our prior studies showed that OT and VP antagoni sts, unlike the agonists, tolerate amino acid substitutions in the 5 p osition. This opens new approaches for the design of antagonists. We d escribe the effects of isosteric replacement of Asn(5) by diaminopropi onic acid (Dap) or diaminobutyric acid (Dab) in three OT and VP antago nists: (1) the V-1a (vasopressor receptor) antagonist d(CH2)(5)[Tyr(Me )(2)]AVP; (2) the OT (uterine OT receptor) antagonist d(CH2)(5)[Tyr(Me )(2),Thr(4),Tyr-NH29]OVT and (3) three selective OT antagonists, desGl y-NH2,d(CH2)(5)[D-Tyr(2),Thr(4)]OVT, desGly-NH2,d(CH2)(5)[D-Phe(2),Thr (4)]OVT and desGly-NH2,d(CH2)(5)-[D-Trp(2),Thr(4)]OVT. The Dap(5) and Dab(5) substitutions were tolerated ated remarkably well, with the les s isosteric Dap(5) substitution leading to a greater retention of anti -OT potency than the Dab(5) substitution. Furthermore, the Dap(5) and Dab(5) OT and VP antagonist analogues were surprisingly shown to be mu ch more selective than their respective parent compounds. The Dab(5) a nalogue of (1) was devoid of anti-OT activity. The three Dap(5) analog ues of (3) were devoid of anti-V-1a activities. These appear to be the first single-receptor-type-selective OT and VP antagonists discovered to date. These findings could provide new leads for the development o f single-receptor-type-selective receptor probes for the localization and characterization of OT and VP receptors and potential selective to colytics for the treatment of premature labor.