PL-3994, a natriuretic peptide receptor-A (NPR-A) agonist resistant to neutral endopeptidase, functions as a bronchodilator, eliciting a concentration-dependent relaxation of pre-contracted guinea-pig trachea, evidenced by an IC50 of 42.7 nM [1].

PL-3994 exhibits high binding affinity to recombinant NPR-As in human, canine, and rat models, with inhibition constants (K i) of 1 nM, 41 nM, and 10 nM, respectively.

Intratracheal administration of PL-3994 at doses ranging from 1 to 1000 mg/kg (i.t.; single dose) elicits a dose-dependent attenuation of bronchoconstriction triggered by aerosolized methacholine; this occurs without markedly impacting cardiovascular parameters [1]. Notably, PL-3994 exhibits substantial resistance to human neutral endopeptidase (hNEP) degradation, maintaining 92% integrity after 2 hours, in contrast to the swift metabolism of natural counterparts, ANP and CNP, which display less than or equal to 1% remaining after 2 hours [1].