Development of more potent atrial natriuretic factor (ANF) analogs.
Four modified atrial natriuretic factor (ANF) analogs were designed and synthesized by the solid-phase method. Using human ANF-(99-126) as the reference compound the receptor binding affinity and biological activity of these analogs were examined by radioreceptor assay and in vivo experiments. PLO68, a 21 amino peptide with structural modifications des-Ser103,104-[Mpr105,D-Ala107,114]APII-amide exhibited 2.5 and 2.2 fold more activity than human ANF-(99-126) in lowering blood pressure and causing natriuresis in urethane anesthetized rats. Receptor binding assays using rat lung membranes showed that PLO68 had a Kd of 200 +/- 12 pM compared to a Kd of 620 +/- 12 pM for human ANF-(99-126). Similar chemical modifications, except for substitution of glycine and alanine at the positions 115 and 118, and 120 by D-alanine resulted in three analogs PLO63 and PLO64, PLO67 respectively. PLO63, PLO64 and PLO69 had similar affinities and in vivo potency as human ANF-(99-126). These data suggest that the structural modifications made in PLO68 can cause an increase in the receptor binding ability and an enhancement of biological activities.
Song
D L
DL
Department of Medicine, Stanford University School of Medicine, CA.
Madsen
B
B
Chang
J K
JK
Perlman
A J
AJ
D000595:Amino Acid Sequence; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000138:chemical synthesis / Q000494:pharmacology*; D005260:Female; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011955:Receptors, Drug / Q000187:drug effects
D007457:Iodine Radioisotopes; D011955:Receptors, Drug; D009320:Atrial Natriuretic Factor