Study of the Structural Requirements for Dopa Potentiation and Oxotremorine Antagonism by L-Prolyl-L-leucylglycinamide

Rodney L. Johnson, Edward E. Smissman, Nicholas P. Plotnikoff

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Nicholas P. Plotnikoff Division of Medicinal Chemistry and Pharmacology, Abbott Laboratories, North Chicago, Illinois 66064. A number of analogues of the tripeptide L-prolyl-L-leucylglycinamide (1) were synthesized and evaluated in the Dopa potentiation and oxotremorine antagonism tests. The replacement of the glycinamide residue with either the glycine methylamide, glycine, aminoacetonitrile, amino-2-propanone, semicarbazide, or β-alaninamide residues resulted in a loss of activity in both tests. A 1:1 mixture of L-prolyl-L-leucyl-(-)-thiazolidine-2-carboxamide (8) and L-pro-lyl-L-leucyl-(+)-thiazolidine-2-carboxamide (9) showed marked activity in the Dopa potentiation test but was unable to antagonize the tremors induced by oxotremorine. L-Prolyl-L-leucyl-L-prolinamide (11), on the other hand, was active in the oxotremorine antagonism test but inactive in the Dopa potentiation test. The replacement of the pyrrolidine ring of 1 with either a thiazolidine or cyclopentane ring system caused a loss of activity. The cyclopentanecarboxylic acid analogue 13, however, was found to have moderate activity in the serotonin potentiation test.

Original languageEnglish (US)
Pages (from-to)165-169
Number of pages5
JournalJournal of medicinal chemistry
Volume21
Issue number2
DOIs
StatePublished - Jan 1 1978

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