Dopamine receptor modulation by conformationally constrained analogues of Pro-Leu-Gly-NH2.
Two series of conformationally constrained analogues of Pro-Leu-Gly-NH2 (PLG) have been synthesized. In one series of analogues, the Leu-Gly-NH2 dipeptide segment of PLG was replaced with the gamma-lactam residues 3(S)- and 3(R)-amino-2-oxopyrrolidineacetamide and the delta-lactam residue 3(S)-amino-2-oxopiperidineacetamide. The corresponding gamma-lactam analogues of less than Glu-Leu-Gly-NH2 were also synthesized. In a second series of analogues, the glycinamide residue of PLG was replaced with the 2-ketopiperazine, 3(S)-amino-2-pyrrolidone, and 3(S)-amino-2-piperidone residues. The above analogues were tested for their ability to enhance the binding of the dopamine receptor agonist 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN) to striatal dopamine receptors. Of the conformationally constrained analogues of PLG synthesized in this study, only the gamma-lactam analogue 3(R)-(N-L-prolylamino)-2-oxo-1-pyrrolidineacetamide (3) was found to possess significant activity. This analogue was 10,000 times more active than PLG, under preincubation conditions. It significantly enhanced the binding of ADTN at concentrations of 10(-9) and 10(-10) M.
Yu
K L
KL
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis 55455.
Rajakumar
G
G
Srivastava
L K
LK
Mishra
R K
RK
Johnson
R L
RL
D000818:Animals; D002417:Cattle; D002421:Caudate Nucleus / Q000378:metabolism*; D055598:Chemical Phenomena; D002621:Chemistry; D003342:Corpus Striatum / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007769:Lactams; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D011487:Protein Conformation; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000378:metabolism
D007769:Lactams; D009842:Oligopeptides; D011954:Receptors, Dopamine; D013764:Tetrahydronaphthalenes; C011639:ADTN; C029463:prolyl-lysyl-glycinamide