No. 302, a newly synthesized [pGlu4,Cyt6]AVP(4-9) analogue, prevents the disruption of avoidance behavior

We investigated the effects of [pGlu4,Cyt6]AVP(4-9) fragments and its analogues on cycloheximide (CHX)-induced learning impairment in rats 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 ([pGlu4, Cyt6]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 ([Cys6]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-Gly-NH2 (No. 302), a newly synthesized [pGlu4,Cyt6]AVP(4-9) analogue, 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 learning 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 was about 5.5, 22 and 25 times longer than that of [pGlu4,Cyt6]AVP(4-9), [Cys6]AVP(5-8) and Asn-Ser-Pro-Arg-OH, respectively. These results suggest that [Cys6]AVP(5-8) is the minimal effective amino acid sequence in [pGlu4,Cyt6]AVP(4-9), and show that No. 302 is a potent, pharmacologically active peptide with high stability in the blood.