Document Detail

Conjugates of catecholamines. IV. In vitro and in vivo pharmacological activity of monodisperse oligopeptide conjugates.
MedLine Citation:
PMID:  6138424     Owner:  NLM     Status:  MEDLINE    
Conjugates of low molecular weight amines with inert peptide carriers can be made to preserve some pharmacologic effects of the ligand. No previous studies of conjugates have systematically derivatized the ligand to optimize its activity or affinity to receptors; or have pharmacophores been selected for conjugation on the basis of their effects making them particularly interesting as ligands. Chemically pure and characterizable conjugates ranging from single blocked amino acid derivatives to isomeric pentapeptides were constructed and tested for beta adrenergic properties. Sixteen conjugates with varying water solubility, amino acid composition and sequence, charged groups and spacer length between ligand and carrier showed potencies and duration of action widely different from isoproterenol. In the in vitro S-49 mouse lymphoma assay a range of relative potencies (as compared to isoproterenol) from 10(-6) to 1 time as potent was obtained, whereas in the in vivo rat blood pressure assay these compounds were shown to be from one-fifth to 4 times as potent as isoproterenol. The most potent compound tested, Boc-Phe(NH)-Gly-NHCH3, was also tested in a guinea-pig atrial preparation as well as in an anesthetized cardiovascular dog preparation. The results indicated that the compound was approximately 3.5 times more potent in producing an inotropic response than isoproterenol. In some instances, ostensively trivial changes quite distant from the pharmacophores in amino acid sequence of the carrier made major changes in potency and efficacy of the compound.
R P Rosenkranz; K A Jacobson; M S Verlander; L Klevans; M O'Donnell; M Goodman; K L Melmon
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  227     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  1983 Nov 
Date Detail:
Created Date:  1983-12-17     Completed Date:  1983-12-17     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  267-73     Citation Subset:  IM    
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MeSH Terms
Adrenergic beta-Antagonists / pharmacology*
Amino Acid Sequence
Blood Pressure / drug effects
Cells, Cultured
Guinea Pigs
Heart Atria / drug effects
Isoproterenol / analogs & derivatives*
Myocardial Contraction / drug effects
Oligopeptides / pharmacology
Rats, Inbred Strains
Receptors, Adrenergic, beta / drug effects
Stimulation, Chemical
Structure-Activity Relationship
Grant Support
Reg. No./Substance:
0/Adrenergic beta-Antagonists; 0/Oligopeptides; 0/Receptors, Adrenergic, beta; 7683-59-2/Isoproterenol

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