Ro 25-1553: a novel, long-acting vasoactive intestinal peptide agonist. Part I: In vitro and in vivo bronchodilator studies.
Ro 25-1553, a cyclic peptide analog of vasoactive intestinal peptide (VIP), was designed to overcome many of the deficiencies inherent in this natural neuropeptide. On isolated guinea pig tracheal smooth muscle, Ro 25-1553 produces concentration-dependent relaxation of contractile responses to a number of different spasmogens. Depending on the contractile stimulus, Ro 25-1553 is 24 to 89 times more potent than VIP as a relaxant of guinea pig trachea. The high potency of Ro 25-1553 extends to studies on isolated, histamine-contracted, human bronchial smooth muscle, where Ro 25-1553 exhibits a 390-fold enhancement over native VIP and is more potent than other bronchodilating drugs, such as the beta 2-adrenoceptor agonists isoproterenol and salbutamol. Ro 25-1553 was shown to displace the radioligand 125I-VIP from rat forebrain membranes with an IC50 value of 4.98 nM, thereby demonstrating that it acts at a VIP receptor. In addition, when tested in a battery of 40 other binding assays (e.g., muscarinic, histamine, LTs, Ca++, TxA2, endothelin, alpha and beta adrenergic, platelet-activating factor, neurokinins, etc.) at concentrations as high as 10 microM, Ro 25-1553 was found to be inactive; thus it appears to be specific for VIP receptors. The potent smooth muscle relaxant activity exhibited in vitro by Ro 25-1553 is also evident after in vivo intratracheal administration or aerosolization of the compound. Pulmonary responses evoked by histamine, leukotriene D4, platelet-activating factor and acetylcholine are inhibited dose-dependently by intratracheally instilled Ro 25-1553 with nearly identical potency (ED50 values ranging from 0.07 micrograms to 0.26 micrograms).(ABSTRACT TRUNCATED AT 250 WORDS)
O'Donnell
M
M
Department of Bronchopulmonary Research, Hoffmann-La Roche, Inc., Nutley, New Jersey.
Garippa
R J
RJ
Rinaldi
N
N
Selig
W M
WM
Simko
B
B
Renzetti
L
L
Tannu
S A
SA
Wasserman
M A
MA
Welton
A
A
Bolin
D R
DR
D000280:Administration, Inhalation; D000595:Amino Acid Sequence; D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000502:physiology; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008969:Molecular Sequence Data; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects / Q000502:physiology; D014660:Vasoactive Intestinal Peptide / Q000819:agonists* / Q000031:analogs & derivatives* / Q000494:pharmacology
D001993:Bronchodilator Agents; D010456:Peptides, Cyclic; C089777:Ro 25-1553; D014660:Vasoactive Intestinal Peptide