CONJUGATES OF CATECHOLAMINES .4. INVITRO AND INVIVO PHARMACOLOGICAL ACTIVITY OF MONODISPERSE OLIGOPEPTIDE CONJUGATES

  • 1 January 1983
    • journal article
    • research article
    • Vol. 227  (2) , 267-273
Abstract
Conjugates of low MW 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. Conjugates (16) with varying water solublity, 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; in the in vivo rat blood pressure assay these compounds were from 1/5 to 4 times as potent as isoproterenol. The most potent compund 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 compound was .apprx. 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.

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