Dual bronchodilatory and pulmonary anti-inflammatory activity of RO5024118, a novel agonist at vasoactive intestinal peptide VPAC2 receptors.
OBJECTIVE
Vasoactive intestinal peptide is expressed in the respiratory tract and induces its effects via its receptors, VPAC(1) and VPAC(2). RO5024118 is a selective VPAC(2) receptor agonist derived via chemical modification of an earlier VPAC(2) agonist, RO0251553. In the present studies, we characterized the pharmacological activity of RO5024118.


METHODS
Stability of RO5024118 to human neutrophil elastase was assessed. Bronchodilatory activity of RO5024118 was investigated in guinea pig and human isolated airway smooth muscle preparations and in a guinea pig bronchoconstriction model. Pulmonary anti-inflammatory activity of RO5024118 was investigated in a lipopolysaccharide mouse model and in a porcine pancreatic elastase (PPE) rat model.


RESULTS
RO5024118 demonstrated increased stability to neutrophil elastase compared with RO0251553. In human and guinea pig isolated airway preparations, RO5024118 induced bronchodilatory effects comparable with RO0251553 and the long-acting β-agonist salmeterol and was significantly more potent than native vasoactive intestinal peptide and the short-acting β-agonist salbutamol. In 5-HT-induced bronchoconstriction in guinea pigs, RO5024118 exhibited inhibitory activity with similar efficacy as, and longer duration than, RO0251553. In a lipopolysaccharide-mouse model, RO5024118 inhibited neutrophil and CD8(+) cells and myeloperoxidase levels. In rats, intratracheal instillation of PPE induced airway neutrophilia that was resistant to dexamethasone. Pretreatment with RO5024118 significantly inhibited PPE-induced neutrophil accumulation.


CONCLUSIONS
These results demonstrate that RO5024118 induces dual bronchodilatory and pulmonary anti-inflammatory activity and may be beneficial in treating airway obstructive and inflammatory diseases.


BACKGROUND
This article is part of a themed section on Analytical Receptor Pharmacology in Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2010.161.issue-6.
Tannu
S A
SA
RNA Therapeutics, Roche, Nutley, New Jersey 07110, USA.
Renzetti
L M
LM
Tare
N
N
Ventre
J D
JD
Lavelle
D
D
Lin
T A
TA
Morschauser
A
A
Paciorek
J
J
Bolin
D R
DR
Michel
H
H
Singer
L
L
Hargaden
M
M
Knowles
Id
I
Gardiner
P
P
Cazzola
M
M
Calzetta
L
L
Matera
M G
MG
Hicks
A
A
D000595:Amino Acid Sequence; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000494:pharmacology*; D016084:Bronchoconstriction / Q000187:drug effects* / Q000502:physiology; D001993:Bronchodilator Agents / Q000378:metabolism / Q000494:pharmacology*; D006168:Guinea Pigs; D019073:HT29 Cells; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D051381:Rats; D051239:Receptors, Vasoactive Intestinal Peptide, Type II / Q000819:agonists* / Q000378:metabolism; D013552:Swine; D014660:Vasoactive Intestinal Peptide / Q000819:agonists / Q000378:metabolism / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001993:Bronchodilator Agents; C561404:RO5024118; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D014660:Vasoactive Intestinal Peptide