TY - JOUR
T1 - Study of the Structural Requirements for Dopa Potentiation and Oxotremorine Antagonism by L-Prolyl-L-leucylglycinamide
AU - Johnson, Rodney L.
AU - Smissman, Edward E.
AU - Plotnikoff, Nicholas P.
PY - 1978
Y1 - 1978
N2 - 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.
AB - 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.
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U2 - 10.1021/jm00200a004
DO - 10.1021/jm00200a004
M3 - Article
C2 - 23433
AN - SCOPUS:0017800462
SN - 0022-2623
VL - 21
SP - 165
EP - 169
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 2
ER -