Syntheses and biological activities of atrial natriuretic polypeptide analogs

Abstract

Recently several peptides with natriuretic and diuretic potencies were isolated from human and rat atrial extract, and the precursors of the peptides were sequenced. Of the peptides, α-human and rat atrial natriuretic polypeptides (α-hANP, α-rANP), consisting of 28 amino acids, are thought to be essential to the potency and to play an important role in the blood pressure regulation system. The amino acid sequence of α-hANP ${\text{(SLRRS}}{\text{NSFRY)}}$ is different from that of α-rANP only at the position 12 (isoleucine in α-rANP). In the present study, we synthesized ANPs and their analogs using a new deprotection procedure based on the concept of push-pull mechanism. Using the synthetic ANP analog, we also developed a radioimmunoassay for α-ANP and examined the structure-activity relationship. Synthetic α-hANP caused potent, rapid, and short-acting increases in Na⁺ and Cl⁻ excretion, and also an increase in urine flow and K⁺ excretion of lesser magnitude, when injected into rat. Also, we synthesized a cyclic part of α-hANP, α-ANP(7–23)-NH₂. Since this peptide had a little diuretic and natriuretic potency, we attempted to synthesize a chemically stable α-hANP analog. We considered that the disulfide bond would be equivalent to propylene with regard to interatomic distance and employed 8-aminocaprylic acid instead of cystine. This cyclic peptide, named cyclonatrin-54, had a somewhat higher potency than α-hANP(7–23)-NH₂ for diuresis and natriuresis, as expected. Furthermore, using a synthetic intermediate of cyclonatrin-54, we prepared a linear ANP analog, α-hANP(8–22), Phe-Gly-Gly-Arg-Met-Asp-Arg-Ile-Gly-Ala-Gln-Ser-Gly-Leu-Gly. This linear 15-amino acid peptide had a dose-dependent natriuretic and diuretic activity, but no hypotensive effect. It was surprising that a linear peptide exhibited a potent natriuretic activity. For the first time, a linear peptide has been prepared that has substantial natriuretic and diuretic potency. We synthesized some analogs of this 15-amino acid peptide and investigated the structure-activity relationship.