Study of the structural requirements for dopa potentiation and oxotremorine antagonism by L-prolyl-L-leucylglycinamide.
A number of analogs of the tripeptide L-prolyly-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 beta-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-prolyl-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.
D000374:Aggression / Q000187:drug effects; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004295:Dihydroxyphenylalanine / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D009075:MSH Release-Inhibiting Hormone / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D010095:Oxotremorine / Q000037:antagonists & inhibitors*; D010293:Pargyline / Q000494:pharmacology; D013237:Stereoisomerism
D010095:Oxotremorine; D004295:Dihydroxyphenylalanine; D009075:MSH Release-Inhibiting Hormone; D010293:Pargyline