NO-302, A NEWLY SYNTHESIZED [PGLU(4),CYT(6)]AVP(4-9) ANALOG, PREVENTSTHE DISRUPTION OF AVOIDANCE-BEHAVIOR

We investigated the effects of [pGlu(4),Cyt(6)]AVP(4-9) fragments and its analogues on cycloheximide (CHX)-induced learning impairment in ra ts using the step-through-type passive avoidance test in rats. CHX (2. 8 mg/kg, s.c.) significantly shortened the step-through latency in the retention trial. pGlu-Asn-Cys(Cys)-Pro-Arg-Gly-NH2 ([pGlu(4),Cyt(6)] AVP(4-9); 10 ng/kg s.c.), a major metabolite of arginine vasopressin, improved the CHX-induced learning impairment. Asn-Cys-Pro-Arg-OH ([Cys (6)]AVP(5-8); 1 ng/kg) corrected avoidance learning in the CHX-treated group, whereas neither Cys(Cys)-Pro-Arg-OH nor pGlu-Asn-Cys(Cys)-Pro- OH had any effect (1, 10 and 100 ng/kg, s.c.). pGlu-Asn-Ser-Pro-Arg-Gl y-NH2 (No. 302), a newly synthesized [pGlu(4),Cyt(6)] AVP(4-9) analogu e, significantly prolonged the latency shortened by CHX at doses of 0. 1, 1 and 10 ng/kg (s.c.). Asn-Ser-Pro-Arg-OH also improved the learnin g disruption induced by CHX, although the effective dose was 100 times higher than that of No. 302. The half-life of No. 302 in rat blood wa s about 5.5, 22 and 25 times longer than that of [pGlu(4),Cyt(6)] AVP( 4-9), [Cys(6)] AVP(5-8) and Asn-Ser-Pro-Arg-OH, respectively. These re sults suggest that [Cys(6)]AVP(5-8) is the minimal effective amino aci d sequence in [pGlu(4),Cyt(6)]AVP(4-9), and show that No. 302 is a pot ent, pharmacologically active peptide with high stability in the blood .