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Publication Detail

Title: In vitro and in vivo pharmacological profile of PL-3994, a novel cyclic peptide (Hept-cyclo(Cys-His-Phe-d-Ala-Gly-Arg-d-Nle-Asp-Arg-Ile-Ser-Cys)-Tyr-[Arg mimetic]-NH(2)) natriuretic peptide receptor-A agonist that is resistant to neutral endopeptidase and acts as a bronchodilator.

Authors: Edelson, Jeffrey D; Makhlina, Marie; Silvester, Kevin R; Vengurlekar, Shailesh S; Chen, Xiaomei; Zhang, Jie; Koziol-White, Cynthia J; Cooper, Philip R; Hallam, Trevor J; Hay, Douglas W P; Panettieri Jr, Reynold A

Published In Pulm Pharmacol Ther, (2013 Apr)

Abstract: The pharmacological and airways relaxant profiles of PL-3994 (Hept-cyclo(Cys-His-Phe-d-Ala-Gly-Arg-d-Nle-Asp-Arg-Ile-Ser-Cys)-Tyr-[Arg mimetic]-NH(2)), a novel natriuretic peptide receptor-A (NPR-A) agonist, were evaluated. PL-3994, a full agonist, has high affinity for recombinant human (h), dog, or rat NPR-As (K(i)s of 1, 41, and 10 nm, respectively), and produced concentration-dependent cGMP generation in human, dog and rat NPR-As (respective EC(50)s of 2, 3 and 14 nm). PL-3994 has a K(i) of 7 nm for hNPR-C but was without effect on cGMP generation in hNPR-B. PL-3994 (1 μm) was without significant effect against 75 diverse molecular targets. PL-3994 or BNP, a natural NPR ligand, produced concentration-dependent relaxation of pre-contracted guinea-pig trachea (IC(50)s of 42.7 and 10.7 nm, respectively). PL-3994, and also BNP, (0.1 nm-100 μm) elicited a potent, concentration-dependent but small relaxation of pre-contracted human precision-cut lung slices (hPCLS). Intratracheal PL-3994 (1-1000 μg/kg) produced a dose-dependent inhibition of the bronchoconstrictor response evoked by aerosolized methacholine, but was without significant effect on cardiovascular parameters. PL-3994 was resistant to degradation by human neutral endopeptidase (hNEP) (92% remaining after 2 h), whereas the natural ligands, ANP and CNP, were rapidly metabolized (≤1% remaining after 2 h). PL-3994 is a potent, selective NPR agonist, resistant to NEP, with relaxant effects in guinea-pig and human airway smooth muscle systems. PL-3994 has the profile predictive of longer clinical bronchodilator activity than observed previously with ANP, and suggests its potential utility in the treatment of asthma, in addition to being a useful research tool to evaluate NPR biology.

PubMed ID: 23154072 Exiting the NIEHS site

MeSH Terms: Animals; Bronchodilator Agents/pharmacology*; Dogs; Dose-Response Relationship, Drug; Guinea Pigs; HEK293 Cells; Humans; Male; Natriuretic Peptide, Brain/pharmacology; Neprilysin/metabolism*; Peptides, Cyclic/metabolism; Peptides, Cyclic/pharmacology*; Piperazines/pharmacology*; Rats; Rats, Wistar; Receptors, Atrial Natriuretic Factor/agonists*; Trachea/drug effects; Trachea/physiology

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