A dicarba analog of β‐atrial natriuretic peptide (β‐ANP) inhibits guanosine 3′,5′‐cyclic monophosphate production induced by α‐ANP in cultured rat vascular smooth muscle cells

Abstract

The synthesis and biological properties are described of [As~'~~']-/l-ANP-(7-28) (Asu, L-a-aminosuberic acid), a dicarba analog of p-atria1 natriuretic peptide (8-ANP, an antiparallel dimer of human a-ANP with the chains linked by 7-23' and 7-23 disulfide bonds). This Asu-analog (referred to as analog III) displaced 12SI-a-ANP specifically bound to cultured rat vascular smooth muscle cells (VSMC) with an apparent Ki of 2.1 x 10-s M, but did not stimulate formation of intracellular cGMP at 10-8-10-5 M. Analog III inhibited the a-ANP-stimulated cGMP production in VSMC competitively with a pA, value of 7.45 and behaved as an antagonist of a-ANP in rat aorta smooth muscle relaxation. In addition, /I-ANP was also shown to inhibit the a-ANP-induced cGMP production in a dose-dependent manner. The mechanism of action of /I-ANP is also discussed.Atria1 natriuretic peptide analog; Atria1 natriuretic peptide receptor antagonist; Receptor binding; cyclic GMP production; Vasorelaxation; (Cultured vascular smoothmuscle cell)

Structure activity in the atrial natriuretic peptide (ANP) family

“…D). Combining these findings with former results of the Ala substitution study (84), the most potent analogue made using this logic, was cyclo[Phe106,D-Ala107,Glulll, Ala114,Arg120,Pro121]ANP- (105)(106)(107)(108)(109)(110)(111)(112)(113)(114)(115)(116)(117)(118)(119)(120)(121). This 17-mer analogue has 53% of the potency of ANP-(105-126) in relaxation of rabbit renal artery.…”

“…The relatively weak but significant activities (88,121) obtained with linear analogues in various in vitro assays has led to the hypothesis that the intramolecular disulfide bridge present in the native ANP stabilizes a conformation that interracts optimally with the receptor (86,88). The observation that DAla at position 107 increases vasorelaxant potency in such linear analogues has been interpreted as a conformational effect (P-bend) (86).…”

Natriuretic peptides in the pathophysiology of congestive heart failure

“…Thus, plasma beta-ANP becomes a major molecular form of ANP in severe heart failure and may have biologic significance for this sodium-retaining and vasoconstrictive state. Such a concept is supported by evidence that beta-ANP may not effectively bind to the NPR-A receptor, resulting in reduced ability to activate cGMP production [48].…”

Strategies for the Development of Conotoxins as New Therapeutic Leads

“…1.34 Å) [88]. Although these atomic distances do result in stereochemical variations proximal to the introduced bridge, this has not been shown to significantly affect the overall structure, as evidenced by several examples where biological function has been maintained [89,90]. A further advantage of disulfide isosteres is their increased stability, resulting in improved pharmacokinetic properties [91,92].…”