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.
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.
authors.affiliation: Palatin Technologies, Inc., 4B Cedar Brook Drive, Cranbury, NJ 08512, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Edelson
authors.forename: Marie
authors.initials: M
authors.lastname: Makhlina
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Silvester
authors.forename: Shailesh S
authors.initials: SS
authors.lastname: Vengurlekar
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Chen
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Koziol-White
authors.forename: Philip R
authors.initials: PR
authors.lastname: Cooper
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Hallam
authors.forename: Douglas W P
authors.initials: DW
authors.lastname: Hay
authors.forename: Reynold A
authors.initials: RA
authors.lastname: Panettieri
mesh_terms: D000818:Animals; D001993:Bronchodilator Agents / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D020097:Natriuretic Peptide, Brain / Q000494:pharmacology; D015260:Neprilysin / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000378:metabolism / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017461:Receptors, Atrial Natriuretic Factor / Q000819:agonists*; D014132:Trachea / Q000187:drug effects / Q000502:physiology
chemical_list: D001993:Bronchodilator Agents; C583022:PL-3994; D010456:Peptides, Cyclic; D010879:Piperazines; D020097:Natriuretic Peptide, Brain; D015260:Neprilysin; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A