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]-NH2) natriuretic peptide receptor-A agonist that is resistant to neutral endopeptidase and acts as a bronchodilator

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 n m , respectively), and produced concentration-dependent cGMP generation in human, dog and rat NPR-As (respective EC 50 s of 2, 3 and 14 n m ). PL-3994 has a K i of 7 n m for hNPR-C but was without effect on cGMP generation in hNPR-B. PL-3994 (1 μ m ) 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 n m , respectively). PL-3994, and also BNP, (0.1 n m –100 μ m ) 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.