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Journal of Pharmacology and Experimental Therapeutics

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Abstract

Ro 25-1553: a novel, long-acting vasoactive intestinal peptide agonist. Part I: In vitro and in vivo bronchodilator studies.

M O'Donnell, R J Garippa, N Rinaldi, W M Selig, B Simko, L Renzetti, S A Tannu, M A Wasserman, A Welton and D R Bolin
Journal of Pharmacology and Experimental Therapeutics September 1994, 270 (3) 1282-1288;
M O'Donnell
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R J Garippa
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N Rinaldi
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W M Selig
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B Simko
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L Renzetti
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S A Tannu
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M A Wasserman
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A Welton
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D R Bolin
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Abstract

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)

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Journal of Pharmacology and Experimental Therapeutics
Vol. 270, Issue 3
1 Sep 1994
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Abstract

Ro 25-1553: a novel, long-acting vasoactive intestinal peptide agonist. Part I: In vitro and in vivo bronchodilator studies.

M O'Donnell, R J Garippa, N Rinaldi, W M Selig, B Simko, L Renzetti, S A Tannu, M A Wasserman, A Welton and D R Bolin
Journal of Pharmacology and Experimental Therapeutics September 1, 1994, 270 (3) 1282-1288;

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Abstract

Ro 25-1553: a novel, long-acting vasoactive intestinal peptide agonist. Part I: In vitro and in vivo bronchodilator studies.

M O'Donnell, R J Garippa, N Rinaldi, W M Selig, B Simko, L Renzetti, S A Tannu, M A Wasserman, A Welton and D R Bolin
Journal of Pharmacology and Experimental Therapeutics September 1, 1994, 270 (3) 1282-1288;
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