Structure-Acitivity Relationships of Alpha-Human Atrial Natriuretic Peptide (α-hANP) Analogs : Role of Charged Groups in α-hANP

Abstract

To determine whether the addition of a methylene unit in the side chain of the Asp or Arg residue in α-human atrial natriuretic peptide (α-hANP) influences its biological activity, analogs of α-hANP, [Glu¹³]-α-hANP (7-28) (1), [Aad¹³]-α-hANP (7-28) (2), and [Harⁿ]-α-hANP(7-28) (where n is any possible combination of 11, 14 and 27) (3-9), where the original Asp or Arg residue was replaced by a homo-amino acid, were synthesized by the solid-phase synthesis method. All the analogs were evaluated for their receptor binding, cyclic guanosine monophosphate (cGMP) accumulation activity in rat vascular smooth muscle cells (VSMC), and for vasorelaxant activity employing rat aorta. 1 and 2 were 0.9 and 0.03 times as potent as α-hANP (7-28), respectively, in binding. Har-containing analogs (3-9) were as potent as α-hANP (7-28) in binding. Among the Har-containing analogs, [Har^{11, 14}]-α-hANP (7-28) (6) and [Har^{11, 27}]-α-hANP (7-28) (7) were remarkably vasorelaxant active, being 4.2 and 5.3 times potent than α-hANP (7-28), respectively, in spite of relatively lower cGMP accumulation activity in the case of 7. The roles of the chargeable amino acid residues in biological activity are discussed.